Overdose- and Abuse-Resistant Polysubunit Opioid Prodrugs

Abstract

To provide constructs such that hydrolysis of the construct by a specified gastrointestinal enzyme directly or indirectly releases an opioid when taken orally as prescribed.SOLUTION: The invention provides constructs such that hydrolysis of the construct by a specified gastrointestinal enzyme directly or indirectly releases an opioid when taken orally as prescribed. The gastrointestinal enzyme mediated release of the opioid from the constructs of the invention is designed to be attenuated in vivo via a saturation or inhibition mechanism when overdoses are ingested. The invention further provides constructs that are highly resistant to oral overdose, chemical tampering, and abuse via non-oral routes of administration.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with United States Government support by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH) of the Department of Health and Human Services, under SBIR Award No. 1R44DA037900.

[0002] Technical Field The present invention relates to compounds, methods and formulations for preventing and / or treating pain. More particularly, the present invention relates to pharmaceutical agents that interact with analgesic receptors, methods for preparing such pharmaceutical agents, and their use for analgesia, pain and other conditions while protecting against overdose and abuse. [Background technology]

[0003] background Pharmacologically, opioid agonists represent an important class of medications for the management of pain. Their use in patient treatment is often limited due to the high liability for abuse of opioid agonists, resulting in undertreatment of pain and severe social and financial costs. The U.S. Food and Drug Administration has recently described prescription opioid analgesics as central to a major public health crisis of addiction, misuse, abuse, overdose and death (FDA / Center for Drug Evaluation and Research, Joint Meeting of the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, Meeting Transcript, July 23-4, 2010.

[0004] A class of drugs that exhibit opium or morphine-like properties are termed opioid agonists or opioids, and they interact with opioid receptors in the brain, peripheral nervous system, and other tissues. The three major subtypes of opioid receptors are mu, delta, and kappa. Each of these receptors has a unique anatomical distribution in the central nervous system, peripheral nervous system, and gastrointestinal tract. The majority of clinically used opioids exert their desired therapeutic action (i.e., analgesia) at the mu receptor subtype. Opioids include morphine, codeine, oxycodone, hydrocodone, hydromorphone, and the like. Examples of opioid products marketed in the United States include OxyContin®, Vicodin®, and Percocet®. Opioids have a variety of effects, including analgesia, euphoria, drowsiness, mood changes, and alterations of the endocrine glands and autonomic nervous system. Opioid analgesics comprise the major class of drugs used to manage moderate to severe pain. As a class, opioids are one of the most prescribed drugs in the United States. Data provided by IMS Health, Inc. indicates that approximately 9 billion hydrocodone-containing pills are prescribed each year. However, there are some concerns regarding the non-medical use and abuse of opioids. There is a need for pharmaceutical products that provide the therapeutic benefits of opioids to subjects, but are less prone to abuse. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] FDA / Center for Drug Evaluation and Research, Joint Meeting of the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, Meeting Transcript, July 23-4, 2010 Summary of the Invention [Means for solving the problem]

[0006] Summary of the Invention Provided herein is a single-molecule polysubunit composition, comprising at least one GI enzyme-sensitive opioid-releasing subunit that can release opioid agonist when GI enzyme acts, wherein at least one GI enzyme-sensitive opioid-releasing subunit is covalently linked to at least one non-opioid-releasing GI enzyme subunit that can be cleaved by said GI enzyme.In some embodiments, at least one GI enzyme-sensitive opioid-releasing subunit and at least one non-opioid-releasing GI enzyme subunit are covalently linked via scaffold moiety.For example, scaffold moiety comprises peptide, polypeptide or polysaccharide.

[0007] Similarly, the present invention provides a single molecule composition comprising at least one GI enzyme-sensitive opioid-releasing subunit that can release opioid agonist when GI enzyme acts, and wherein at least one GI enzyme-sensitive opioid-releasing subunit is covalently linked to at least one GI enzyme inhibitor moiety.In some embodiments, at least one GI enzyme-sensitive opioid-releasing subunit and at least one GI enzyme inhibitor moiety are covalently linked via scaffold moiety.For example, scaffold moiety can comprise peptide, polypeptide or polysaccharide.

[0008] Similarly, provided herein is a pharmaceutical composition comprising opioid prodrug; gastrointestinal enzyme inhibitor; and opioid prodrug and inhibitor are covalently bonded scaffold.In some embodiments, at least one non-opioid releasing GI enzyme subunit is an inverse substrate.In some embodiments, at least one non-opioid releasing GI enzyme subunit is a GI enzyme inhibitor.

[0009] In some embodiments, the GI enzyme is trypsin or chymotrypsin.

[0010] In some embodiments, the GI enzyme-sensitive opioid-releasing subunit releases an opioid agonist, including, for example, full, partial, mixed, inverse or biased agonists, including, but not limited to, morphine, heroin, hydromorphone, oxymorphone, buprenorphine, levorphanol, butorphanol, codeine, dihydrocodeine, hydrocodone, oxycodone, meperidine, methadone, nalbulphine, opium, pentazocine, propoxyphene, and the like. Compounds that are less widely used (alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, clonitazene, cyclazocine, desomorphine, dextromorphamide, dezocine, diampromide, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, hydroxypethidine, isomethadone) phenamidine, ketobemidone, levallorphan, levophenacylmorphan, lofentanil, meptazinol, metazocin, metopon, myrofin, narceine, nicomorphine, norpipanone, papvretum, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, propiram, sufentanil, tapentadol, tramadol, tilidine, PZM021 and its analogs, TRY130 and its analogs, BU08028 and its analogs, and salts thereof, prodromal The compounds may include amines and mixtures.

[0011] In some embodiments, the non-opioid releasing GI enzyme subunit is more susceptible to cleavage by digestive enzymes than the GI enzyme sensitive opioid releasing subunit, and can saturate or inhibit the GI enzyme. In some embodiments, the GI enzyme inhibitor subunit can inhibit the GI enzyme. In some embodiments, the non-opioid releasing GI enzyme subunit is more susceptible to cleavage by GI enzymes, and can saturate the GI enzyme. In some embodiments, the non-opioid releasing GI enzyme subunit can reduce the expected systemic exposure of the delivered opioid agonist when co-ingested orally in a dose that exceeds the prescribed dose. In some embodiments, the bound GI enzyme inhibitor can inhibit the digestive enzyme. In some embodiments, the GI enzyme inhibitor can reduce the expected systemic exposure of the delivered opioid agonist when co-ingested orally in a dose that exceeds the prescribed dose.

[0012] In some embodiments, the compounds of the invention have the following formula: [ka] (In the formula, each S1 is independently a non-opioid releasing GI enzyme subunit or a GI enzyme inhibitor; each S2 is independently an opioid agonist releasing GI enzyme subunit and each S3 is an opioid antagonist releasing moiety; M is a covalent scaffold; Each Z is independently a linking moiety; r, m, and n each independently represent an integer ranging from 1 to 10, 1 to 100, 1 to 1,000, 1 to 100,000, 1 to 1,000,000, or 1 to 1,000,000,000; p is an integer in the range of 0-10, 0-100, 0-1,000, 0-100,000, 0-1,000,000, or 0-1,000,000,000. has.

[0013] In some embodiments, the compounds of the invention have the following formula: [ka] (In the formula, each S1 is independently a non-opioid releasing GI enzyme subunit or a GI enzyme inhibitor; each S2 is independently an opioid agonist releasing GI enzyme subunit and each S3 is an opioid antagonist releasing moiety; Each Z is independently a linking moiety; Each n is independently an integer ranging from 1 to 10; m is an integer ranging from 1 to 10; p and r are independently integers ranging from 0 to 10. has.

[0014] In some embodiments, the S1-Z-subunit is: [ka] [ka] (In the formula, Y is amidine, guanidine, benzylamine, alkyl-substituted amidine, alkyl-substituted guanidine, alkyl-substituted benzylamine, benzyl amidine, benzyl guanidine, alkyl-substituted benzyl amidine or alkyl-substituted benzyl guanidine; Z is a linking moiety, K o each is independently hydrogen or methyl; A is an amino acid side chain, r is an integer from 0 to 10; m is an integer from 1 to 10; o is an integer from 0 to 6; p is an integer from 1 to 10; n is an integer from 0 to 10, R is independently an alkyl, alkylene, alkynyl, or aryl group, or a substituted alkyl, alkylene, alkynyl, or aryl group; each R' is independently alkyl, aryl, substituted alkyl, substituted aryl, acyl, substituted acyl group, or polyethylene glycol-containing acyl group, aryl group, or alkyl group; Each R'' is independently a hydrogen, a methyl group, an alkyl group, or an aryl group. is selected from the group consisting of:

[0015] In some embodiments, at least one of Z and Ko comprises an electron donating or withdrawing group. For example, the electron donating group is alkyl, substituted alkyl, -OH, -OR, -NH2, -NR2, -SH, -SR, or -NHC(O)R. Alternatively, the electron withdrawing group is -C(O)OH, -C(O)OR, -C(O)NH2, -C(O)NR2, -NO2, -NR3 +, -C(O)CF3, halogen, -CF3, cyano, -SO3H, -SO3R, -CHO, -COR, -C(NH)NH2 or -NHC(=NH)NH2.

[0016] In some embodiments, m is 1 to 10, and r and p are 0. In some embodiments, the S2 subunit can be a reversible or non-reversible (i.e., covalently bond forming) trypsin inhibitor.

[0017] In some embodiments, the S2 subunit has the following structure: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, amino acid mimetic, or linking moiety (Z); A2 is an amino acid side chain or an amino acid side chain mimic that can be recognized by a GI enzyme. has.

[0018] In some embodiments, the S2 subunit has the following structure: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, amino acid mimetic, or linking moiety (Z);

[0019] A2 is an amino acid side chain or an amino acid side chain mimic that can be recognized by a GI enzyme. has.

[0020] In some embodiments, the S2 subunit has the following structure: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; R 1 , R 2 and R 3 can be R', or R 2 and R 3 can be linked to form an optionally substituted spirocyclic ring, or R 2 Or R 3 is R 1 may be linked to form an optionally substituted heterocyclic ring, or R 2 Or R 3 can be joined with R' to form an optionally substituted ring, or R' can be linked with a geminal R' to thereby form an optionally substituted spirocyclic ring; Each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyethylene glycol, or a polyethylene glycol-containing moiety, or a linking moiety -Z, or -Z-(S2). n Or -Z-(S x ) n and Z is as defined herein; Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme. has.

[0021] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl, or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimetic that can be recognized by digestive enzymes leading to site-specific hydrolysis of the S2 subunit prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof, and R″ is as defined above. It is.

[0022] In some embodiments, the S2 subunit has the following structure: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, polyethylene glycol, or a polyethylene glycol-containing moiety, or a linking moiety, Z, as previously defined; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid side chain, an amino acid side chain mimetic, or a linking moiety, Z, as defined herein; Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme. has.

[0023] In some embodiments, A2 is: [ka] wherein R is each or independently hydrogen or methyl, R″ is as defined above, r is each or independently an integer from 1 to 6, n is an integer from 0 to 10, R′″ is hydrogen, methyl, —C(═NR)—NR2, and R is each or independently hydrogen or methyl; [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimetic that can be recognized by digestive enzymes leading to site-specific hydrolysis of the S2 subunit prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof; R″ is as defined above; m is an integer from 0 to 10; n is an integer from 0 to 10, p is an integer from 0 to 4. It is.

[0024] In some embodiments, the S3-Z-subunit is: [ka] [ka] (In the formula, R is cyclopropylmethyl or allyl, R' is hydrogen, methyl, alkyl, aryl, substituted alkyl or substituted aryl, acyl or substituted acyl, and Z is a linker as defined herein. is selected from the group consisting of:

[0025] In some embodiments, the opioid antagonist is naltrexone or naloxone.

[0026] In some embodiments, the S2 subunit has a structure selected from the group consisting of: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; R 1 and R 2 are each independently R or R′, or R 1 and R 2 can be linked to form an optionally substituted spirocyclic ring; R 3 is R″ or R 3 is R 1 Or R 2 and linked to form an optionally substituted heterocyclic ring, Each R is independently hydrogen, methyl, or alkyl, e.g., lower alkyl, and each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, or -Z-(S2). n , or -Z-(S x ) n and Z is a linking moiety, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linking moiety, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; R 4 is hydrogen, methyl, -C(=NR)-NR2 (wherein each R is independently hydrogen or methyl), or a group of the formula: [ka] and each A2 is independently an amino acid side chain or an amino acid side chain mimetic capable of being recognized by a digestive enzyme; n is an integer ranging from 1 to 10;

[0027] r is an integer ranging from 1 to 6. has.

[0028] In some embodiments, the S2 subunit has a structure selected from the group consisting of: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; R 1 and R 2 are each independently R or R′, or R 1 and R 2can be linked to form an optionally substituted spirocyclic ring; R 3 is R″ or R 3 is R 1 Or R 2 and linked to form an optionally substituted heterocyclic ring, Each R is independently hydrogen, methyl, or alkyl, e.g., lower alkyl, and each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, or -Z-(S2). n , or -Z-(S x ) n and Z is a linking moiety, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linking moiety, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; R 4 is hydrogen, methyl, -C(=NR)-NR2 (wherein each R is independently hydrogen or methyl), or a group of the formula: [ka] and each A2 is independently an amino acid side chain or an amino acid side chain mimetic capable of being recognized by a digestive enzyme; n is an integer ranging from 1 to 10; r is an integer ranging from 1 to 6. has.

[0029] In some embodiments, Z is represented by one of the following formulas: [ka] (In the formula, Each F is independently [ka] and each R is independently hydrogen, methyl, lower alkyl, aryl, or arylalkyl; X can be carbon, oxygen or nitrogen; L can be a covalent bond or can be a linear, branched or polyvalent scaffold comprised of an alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyalkylene glycol, peptide, polypeptide, amide, polyamide, carbamate, polycarbamate, urea, polyurea, carbonate, polycarbonate, or combinations thereof).

[0030] For example, the linking moiety F forms a substituted ester, amide, amine, carbamate, ether, alkylane, arene, or urea, and L is a covalent bond or a linear, branched, or multivalent scaffold consisting of an alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, polyalkylene glycol, polypeptide, or polyamide.

[0031] In some embodiments, D is a morphone, a codon, or a morphine.

[0032] In some embodiments, the scaffold is an oligomeric or polymeric scaffold.

[0033] For example, the scaffold is a polyalkylene oxide, a polypeptide, a polysaccharide, or a biopolymer. Alternatively, the scaffold is a linear, branched, brush (or comb) polymer. In some embodiments, the scaffold is polycationic.

[0034] Similarly, provided herein is a method of treating pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a unimolecular polysubstrate of the invention. Additionally, provided is a pharmaceutical composition comprising the polysubstrate.

[0035] In one aspect, the present disclosure provides a compound represented by the structure of formula (I): [ka] or a salt thereof, wherein Q is independently selected from optionally substituted heteroalkyl and optionally substituted alkyl; L 1 is independently at each occurrence absent, a cleavable linker or a non-cleavable linker; L 2 is independently at each occurrence absent, a cleavable linker or a non-cleavable linker; R 1 are independently selected for each occurrence from a GI enzyme substrate, a GI enzyme inhibitor, and an opioid antagonist; R 2 is an opioid agonist covalently bound to a GI enzyme substrate, m and n are independently selected at each occurrence from 1 to 1,000,000.

[0036] In some embodiments, with respect to compounds or salts of Formula (I), Q is an optionally substituted heteroalkyl group.

[0037] In some embodiments, with respect to compounds or salts of Formula (I), Q is an optionally substituted peptide.

[0038] In some embodiments, for compounds or salts of formula (I), Q is an optionally substituted peptide having 1-500 amino acids. In some embodiments, for compounds or salts of formula (I), Q is an optionally substituted peptide having 1-50 amino acids. In some embodiments, for compounds or salts of formula (I), Q is an optionally substituted peptide having 1-10 amino acids. In some embodiments, for compounds or salts of formula (I), Q is an optionally substituted peptide having 1-3 amino acids.

[0039] In some embodiments, the compound or salt of formula (I) has the structure of formula (IA), (IB) or (IC): [ka] [ka] wherein W is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, and optionally substituted alkoxycarbonyl. It is represented by:

[0040] In some embodiments, the compound or salt of formula (I) has the structure of formula (ID), (IE) or (IF): [ka] It is represented by:

[0041] In some embodiments, R 1 is independently selected at each occurrence from a GI enzyme inhibitor. 1Q, at each occurrence, with respect to a compound or salt of Formula (I), is a serine protease inhibitor.

[0042] In some embodiments, with respect to the compound or salt of formula (I), R 1 -L 1 is the following: [ka] (In the formula, Y is independently selected from amidine, guanidine, benzylamine, alkyl-substituted amidine, alkyl-substituted guanidine, alkyl-substituted benzylamine, benzylguanidine, alkyl-substituted benzylamidine, or alkyl-substituted benzyl; Z is independently selected from hydrogen, cyano, nitro, halogen, alkyl and alkoxy. are independently selected for each occurrence from

[0043] In some embodiments, with respect to compounds or salts of Formula (I), Y is an amidine.

[0044] In some embodiments, with respect to the compound or salt of formula (I), R 1 -L 1 is the expression: [ka] It is represented by:

[0045] In some embodiments, with respect to the compound or salt of formula (I), L 1 Each occurrence is selected from a cleavable or non-cleavable linker containing 2 to 15 atoms.

[0046] In some embodiments, with respect to the compound or salt of formula (I), L 1 is -O-CH2-CH2-NH- or -O-CH2-CH2-O-.

[0047] In some embodiments, with respect to a compound or salt of formula (I), n is selected from 1 to 20. In some embodiments, with respect to a compound or salt of formula (I), n is selected from 1 to 10. In some embodiments, with respect to a compound or salt of formula (I), n is selected from 1 to 3.

[0048] In some embodiments, with respect to the compound or salt of formula (I), R 2 -L 2 is the following: [ka] (In the formula, D is an opioid agonist, R 101 and R 102 are independently selected from optionally substituted alkyl, amino acid side chains, and amino acid side chain mimetics. are independently selected for each occurrence from

[0049] In some embodiments, with respect to the compound or salt of formula (I), R 101 is selected from amino acid side chains, R 102 is optionally substituted alkyl. In some embodiments, with respect to the compound or salt of formula (I), R 101 is selected from an arginine side chain or a lysine side chain, R 102 is optionally substituted methyl. In some embodiments, with respect to the compound or salt of formula (I), R 102 is methyl substituted by -NH-acetyl.

[0050] In some embodiments, with respect to the compound or salt of formula (I), D is selected from morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, tapentadol, and buprenorphine. In some embodiments, with respect to the compound or salt of formula (I), D is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, tapentadol, and buprenorphine. [ka] It is represented by:

[0051] In some embodiments, with respect to a compound or salt of formula (I), m is selected from 1 to 20. In some embodiments, with respect to a compound or salt of formula (I), m is selected from 1 to 10. In some embodiments, with respect to a compound or salt of formula (I), m is 1 to 3.

[0052] In some embodiments, with respect to a compound or salt of formula (I), the compound has the formula: [ka] or a salt thereof.

[0053] In some embodiments, with respect to a compound or salt of formula (I), the compound has the formula: [ka] or a salt thereof.

[0054] In one aspect, the disclosure provides a method of treating pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or salt of formula (I).

[0055] In one aspect, the disclosure provides a compound of formula (I) or a salt, and a pharma- ceutically acceptable excipient.

[0056] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: Opioid prodrugs, Gastrointestinal enzyme inhibitors, and Scaffolds to which opioid prodrugs and inhibitors are covalently attached The present invention provides a pharmaceutical formulation comprising:

[0057] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: opioid prodrugs comprising an opioid covalently bonded to a promoiety, the promoiety comprising a moiety cleavable by an enzyme of the gastrointestinal tract; A reverse substrate for a gastrointestinal enzyme, wherein an opioid prodrug and a reverse substrate are covalently attached to a scaffold. The present invention provides a pharmaceutical composition comprising: Incorporation by Reference

[0058] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0059] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [Brief description of the drawings]

[0060] [Figure 1] FIG. 1 illustrates the effect of competitive enzyme inhibition.

[0061] [Diagram 2] FIG. 2 illustrates the kinetics of enzyme saturation.

[0062] [Diagram 3] FIG. 3 illustrates the predicted enzymatic pathways when the intended doses of the polysubstrates of the present disclosure are ingested (black font).

[0063] [Figure 4] FIG. 4 illustrates the predicted enzymatic pathway saturation when excess doses of the polysubstrates of the present disclosure are ingested (black font).

[0064] [Diagram 5] FIG. 5 is a graph illustrating examples of expected pharmacodynamic and pharmacokinetic parameters of (A) an opioid agonist and (B) an opioid agonist delivered by a polymatrix of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0065] Detailed Description Typically, opioids cross the blood-brain barrier (BBB) ​​quickly and reach peak concentrations that produce the euphoric or "high" experienced by opioid abusers. Strategies to reduce opioid abuse have focused on formulations or alternative delivery strategies (such as orally administered delayed release tablets and transdermal patches). Abusers easily inactivate these formulations by crushing, chewing, or dissolving them in commonly available household solvents, which allows them to reach the desired pharmacokinetic profile and / or parenteral routes of administration useful for reaching the "high." None of these technologies address the primary route of prescription opioid abuse, i.e., oral overdose. Thus, there is a need for opioid drug products used in analgesia that have less abuse potential than currently available opioid products. In particular, there is a need for novel opioid medications that (i) provide patients with safe and effective pain relief when taken as prescribed, (ii) prevent high plasma concentrations resulting from the co-ingestion of multiple pills, and at the same time (iii) effectively deter parenteral abuse.

[0066] The present disclosure seeks to address these and other needs by providing a new class of polysubstrate or polysubunit opioid analogs.The present disclosure provides a monomolecular polysubstrate or polysubunit composition comprising one or more GI enzyme-sensitive opioid-releasing substrates covalently bonded directly or indirectly via molecular, oligomeric or polymeric structures to one or more non-opioid-releasing GI enzyme substrates, and one or more optional opioid antagonist-releasing moieties.The present disclosure also provides a monomolecular polysubunit composition comprising one or more GI enzyme-sensitive opioid-releasing substrates covalently bonded directly or indirectly via molecular, oligomeric or polymeric structures to one or more non-opioid-releasing GI enzyme inhibitors, and one or more optional opioid antagonist-releasing moieties. These novel unimolecular polysubunit molecules are designed (i) to release the covalently attached opioid agonist at levels effective to treat pain when ingested at the intended dose by a compliant patient, (ii) to prevent oral overdose or abuse of the compositions through a novel enzyme saturation or inhibition process when multiple pills containing the compositions are co-ingested by a potential abuser (or accidentally by a child), and (iii) to produce a safe, non-abusable mixture of opioid agonist and opioid antagonist when a potential abuser tampers with a pill containing the compositions.

[0067] These polysubunit opioid analogs can be further designed to have a high molecular weight and / or a high charge state in the physiological pH range to prevent or minimize absorption from the GI tract, thereby (i) reducing their systemic exposure to the subject (and the resulting safety risks) and (ii) maximizing the efficiency of both opioid delivery and protection mechanisms against overdose.

[0068] In one aspect, the present invention provides a pharmaceutical composition comprising one or more GI enzyme-sensitive opioid-releasing substrates and one or more non-opioid-releasing GI enzyme substrates, wherein the GI enzyme-sensitive opioid-releasing substrates and the non-opioid-releasing GI enzyme substrates are covalently bound to each other directly or to a molecular scaffold.In another aspect, the present invention provides a pharmaceutical composition comprising one or more GI enzyme-sensitive opioid-releasing substrates and one or more non-opioid-releasing GI enzyme inhibitors, wherein the GI enzyme-sensitive opioid-releasing substrates and the non-opioid-releasing GI enzyme inhibitors are covalently bound to each other directly or to a molecular scaffold.When a patient ingests the pharmaceutical composition defined herein, endogenous GI enzymes release the targeted therapeutic level of opioid agonist. When an overdose of the pharmaceutical composition defined herein is taken, the GI enzyme that releases the opioid agonist becomes saturated or inhibited, so that the amount of opioid agonist released does not increase proportionally with the increase in the dose taken.The opioid agonist can be selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, tapentadol, and their pharmaceutically acceptable salts, prodrugs and mixtures.The opioid antagonist is selected from naltrexone and naloxone.In some embodiments, the molecular scaffold is an oligomeric scaffold.In other embodiments, the molecular scaffold is a polymeric scaffold. definition

[0069] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. Definitions of standard chemistry terms are provided in Carey and Sundberg (2004), "Advanced Organic Chemistry, 4th Edition" A and B. and B, Springer, New York. The procedures will employ, unless otherwise indicated, conventional methods of mass spectroscopy, protein chemistry, biochemistry, synthetic organic chemistry and pharmacology, within the skill of the art.

[0070] The terms "alkyl" or "lower alkyl," unless otherwise indicated, mean a monovalent branched or unbranched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from 1 to 12 carbon atoms, inclusive. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

[0071] The term "alkylene," as used herein, unless otherwise indicated, means a divalent linear or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms and having from 1 to 8, inclusive, carbon atoms. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, ethylethylene, and the like.

[0072] The term "alkenylene" means a divalent linear or branched unsaturated hydrocarbon radical containing at least one double bond and having from 2 to 8 carbon atoms (inclusive), unless otherwise indicated. Alkenylene radicals include cis or trans ((E) or (Z)) isomeric groups, or mixtures thereof, resulting from asymmetric carbons. Examples of alkenylene radicals include, but are not limited to, ethenylene, 2-propenylene, 1-propenylene, 2-butenyl, 2-pentenylene, and the like.

[0073] The term "aryl" means a monovalent monocyclic aromatic hydrocarbon radical, consisting of one ring or multiple fused rings, in which at least one ring is aromatic in nature, and which, unless otherwise indicated, may be optionally substituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, and / or trifluoromethyl. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthraquinolyl, and the like.

[0074] The term "agonist" refers to a molecule, such as a compound, drug, enzyme activator, or hormone, that enhances the activity of another molecule or the activity of a target receptor.

[0075] The term "amino acid" refers to any natural and / or unnatural or synthetic amino acid, both D- or L-optical isomers, their N-acyl and N-methyl derivatives, and amino acid analogs, isosteres, and peptidomimetics. Natural amino acids include alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, selenocysteine, and pyrrolysine.

[0076] Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, carboxyglutamic acid, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids, i.e., compounds with an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group (e.g., homoserine, norleucine, methionine sulfoxide, methionine, and methylsulfonium). Such analogs have modified side groups or modified peptide backbones, such as norleucine, homoarginine, homolysine, ε-N-methyllysine, ε,ε-N,N-dimethyllysine, ε,ε,ε-N,N,N-trimethyllysine, ornithine, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics (or mimetics) refer to compounds that have a structure that is different from the general chemical structure of an amino acid, but function in a manner similar to a naturally occurring amino acid. For example, the unnatural amino acid, L-(7-hydroxycoumarin-4-yl)ethylglycine (or 7-hydroxycoumarin-ethylglycine), finds use in accordance with the present invention.

[0077] The terms "enzymatically degradable" or "enzyme-sensitive" refer to a molecular entity that is subject to degradation by one or more enzymes under normal physiological conditions.

[0078] The term GI refers to "gastrointestinal." The term "gastrointestinal enzymes" or "GI enzymes" refers to enzymes located in, derived from, or on the gastrointestinal tract (GI tract), such as trypsin, chymotrypsin, elastase, tryptase, etc.

[0079] The term "polysubstrate" or "polysubunit" refers to a compound of the present invention that is designed to release an opioid agonist when administered to a subject. The release profile of the opioid agonist from the polysubstrate or polysubunit may be weakened by an enzymatic saturation mechanism in vivo when an overdose is taken. Furthermore, the polysubstrate or polysubunit of the present invention can also release an opioid antagonist when chemically tampered with by a potential abuser or when administered to a potential abuser via a parenteral route.

[0080] "Gastrointestinal enzyme substrate" or "GI enzyme substrate" refers to a group that contains a site that is susceptible to cleavage by a GI enzyme. For example, a "trypsin substrate" refers to a group that contains a site that is susceptible to cleavage by trypsin. Specifically, hydrolysis of a non-opioid-releasing GI enzyme substrate by a GI enzyme does not release an opioid, whereas enzyme-mediated hydrolysis of an opioid-releasing GI enzyme substrate results in the direct or indirect release of the opioid.

[0081] The term "opioid-releasing gastrointestinal enzyme substrate subunit" or "opioid-releasing GI enzyme substrate subunit" refers to a group that contains an opioid and a site that is susceptible to cleavage by a GI enzyme. For example, an "opioid-releasing trypsin substrate" refers to a group that contains a site that is susceptible to cleavage by trypsin that releases an opioid directly or indirectly after undergoing hydrolysis by trypsin.

[0082] The term "non-opioid releasing gastrointestinal enzyme substrate" or "non-opioid releasing GI enzyme substrate" refers to a group that contains a site that is easily cleaved by GI enzymes. For example, "non-opioid releasing trypsin substrate" refers to a group that contains a site that is easily cleaved by trypsin, which does not directly or indirectly release an opioid after hydrolysis by trypsin. Similarly, reverse substrates are also included. Reverse substrates refer to any agent that can act as a reverse substrate for digestive enzymes. Reverse substrates are designed to be bound to enzymes and hydrolyzed by enzymes in a manner that is "reverse" to the "normal" substrate. With the "normal" substrate, the amino acid (or amino acid mimic) recognized by the enzyme is connected to the C-terminus of a carbonyl-containing group (e.g., amide, ester, etc.) that is subject to hydrolysis, and the amino acid is further connected to a leaving group (e.g., amine or alcohol, etc.). In contrast, a reverse substrate has an amino acid or amino acid mimetic recognized by the enzyme directly attached to the leaving group of the carbonyl group that is hydrolyzed by the enzyme. The term also includes salts of gastrointestinal enzyme reverse substrates. For example, "trypsin reverse substrate" refers to any agent that can act as a reverse substrate for trypsin.

[0083] The term "halogen" as used herein refers to fluorine, bromine, chlorine and / or iodine.

[0084] The term "inhibitor" refers to any agent capable of inhibiting the action of an enzyme on a substrate. For example, a trypsin inhibitor refers to any agent capable of inhibiting the action of trypsin on a substrate.

[0085] The term "modulator" refers to a molecule that interacts with a target, including, but not limited to, agonist, antagonist, etc., as defined herein.

[0086] "PEG" or "polyethylene glycol," as used herein, is intended to encompass any water-soluble poly(alkylene oxide). Typically, the PEG oligomers used in the present invention have the structure -(CH2CH2O) n -or- (CH2CH2O) n Contains -CH2CH2-, but can also include polyalkylene glycols, including but not limited to polypropylene glycol or polybutylene glycol, and the number of monomer units can be from about 2 to about 1000, or from about 2 to about 200.

[0087] As used herein, the terms "treat" and "treatment" are used interchangeably and are intended to refer to delaying the onset of disease and / or reducing the severity of symptoms that are expected or currently expected to develop in the future. The term further includes amelioration of existing symptoms, prevention of further symptoms, and amelioration or prevention of underlying symptoms.

[0088] As used herein, the term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: non-human primates such as humans, chimpanzees and other ape and monkey species; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. The term does not imply a particular age or sex.

[0089] In one embodiment of the present invention, a composition comprising one or more GI enzyme-sensitive opioid agonist-releasing substrates (one or more S2 subunits), one or more non-opioid-releasing GI enzyme substrates (one or more S1 subunits), and one or more optional opioid antagonist-releasing moieties (one or more S3 subunits) is administered to a patient to prevent and / or treat pain. The GI enzyme-sensitive opioid agonist-releasing substrates (S2 subunits) and non-opioid-releasing gastrointestinal (GI) enzyme substrates (S1 subunits) and optional opioid antagonist-releasing moieties (S3 subunits) can be covalently bonded to each other via a suitable linker (Z), or can be constructed on a suitably functionalized oligomer, macromolecule or polymer, or can be independently bonded via a covalent linkage. In some embodiments, release of the opioid agonist is mediated by a specific GI enzyme, whereby the opioid agonist is released simultaneously with or following the action of a specific GI enzyme on a specific portion of the polysubstrate molecule.

[0090] In another embodiment of the present invention, a composition comprising one or more GI enzyme-sensitive opioid agonist-releasing substrates (one or more S2 subunits), one or more non-opioid-releasing GI enzyme inhibitors (one or more S1 subunits), and one or more optional opioid antagonist-releasing moieties (one or more S3 subunits) is administered to a patient to prevent and / or treat pain. The GI enzyme-sensitive opioid agonist-releasing substrates (S2 subunits) and non-opioid-releasing gastrointestinal (GI) enzyme inhibitors (S1 subunits) and optional opioid antagonist-releasing moieties (S3 subunits) may be covalently bonded to each other via a suitable linker (Z), or may be constructed on a suitably functionalized oligomer, macromolecule or polymer, or may be independently bonded via a covalent linkage. In some embodiments, release of the opioid agonist is mediated by a specific GI enzyme, whereby the opioid agonist is released simultaneously with or following the action of a specific GI enzyme on a specific portion of the polysubstrate molecule.

[0091] Opioid agonist releasing GI enzyme substrates (S2) include: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levomorphine ... The compound may release ruphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, mylophine, narceine, nicomorphine, norlevorphanol, normetadone, nalorphine, nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propeptadine, promedol, properidine, propoxyphene, sufentanil, tapentadol, tilidine, tramadol, mixtures of any of the above, salts thereof, prodrugs thereof, and derivatives, analogs, homologs and polymorphs thereof. Opioid agonist-releasing and non-opioid-releasing GI enzyme substrates or inhibitors can be targeted by trypsin and can be alkylguanidine-, alkylamidine-, alkylamine-, arylguanidine-, arylamidine-, or arylamine-based substrates and their salts.The GI enzyme-sensitive opioid-releasing S2 substrate and the non-opioid-releasing S1 GI enzyme inverting substrate or inhibitor are preferably directly covalently linked to each other, or indirectly linked to each other by attachment to the same molecular scaffold in a suitable ratio, or co-constructed via covalent attachment to the same oligomer or polymer, such as poly-amino acids, poly-D-amino acids, poly N-methyl (D- or L-) amino acids, "biopolymers" or polyalkylene glycols (e.g., PEG).

[0092] The linking moiety or linker "Z" is utilized for the purposes of the present invention to covalently link one or more of the components defined herein (e.g., S1, S2, S3 and I subunits; and molecular, oligomeric or polymeric scaffolds). Based on this defined functionality, it is intended that the range of linkers useful in the present invention is broad. In order to define the broad range of useful linkers and to provide non-limiting examples of linkers for use in the present invention, a number of terminal functional groups that may be present on representative linkers and their chemical compositions are shown below. The specific selection of one or more linker units incorporated in a particular embodiment of the present invention will vary based on the molecular structure of the entity they colink, taking into account the available atoms or functional groups present on the particular elements they covalently link. Thus, it is intended that the specific composition of the linking moiety useful in the present invention can vary widely in terms of composition, size (i.e., length), shape, valence, and functional groups present at its termini. Linking moieties can be divalent (covalently linking two polymatrix components) or trivalent (linking several polymatrix components), or multivalent (linking multiple polymatrix components).

[0093] In some embodiments, the linking moiety "Z" used in the present invention has the general formula: [ka] Described by, [ka] Exemplary terminal linker functional groups "F", each or independently, can be as shown below: [ka] (In the formula, each R is independently hydrogen, methyl, lower alkyl, aryl, or arylalkyl; X is carbon, oxygen or nitrogen; L is a linear, branched or polyvalent scaffold that is an alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyalkylene glycol, polypeptide, polyamide, polycarbamate, polyurea or polycarbonate).

[0094] In some embodiments, L is formed from 0-100 atoms. In some embodiments, L is formed from 1-50 non-hydrogen atoms and additional hydrogen atoms. Such atoms can be, for example, C, N, O, P, or S. In other embodiments, L can connect two or more groups, including 1-50 consecutive bonds between the groups. L can have 1-40, 1-30, 1-20, 1-10, 1-5, 5-25, or 5-20 such consecutive bonds.

[0095] In some embodiments, the compounds or compositions of the invention can have the advantage that they and their post-enzymatic hydrolysis products are minimally or not absorbed at all by the subject, and the anticipated enzymatic hydrolysis of the compounds of the invention can be designed to result in systemic exposure only to opioid analgesics and metabolites that are generally regarded as safe (GRAS) after oral ingestion.

[0096] Additionally, the compositions of the present invention prevent overdosing by the oral route. When multiple pharmaceutical oral dosage forms are taken together, such as by co-ingestion of tablets or capsules containing the compositions of the present invention, The resulting concentrations reach levels in the small intestine that are high enough to effectively saturate or inhibit the digestive enzymes that mediate the release of opioids. Such saturation or inhibition of the digestive enzymes that mediate the release of opioids results from careful regulation of the rates involved in the enzymatic hydrolysis of the covalently constructed (i) non-opioid-releasing (S1) and (ii) opioid-releasing (S2) substrate subunits. In some preferred embodiments of the present invention, digestive enzymes (e.g., trypsin) recognize and interact with the non-opioid-releasing substrate moieties much more rapidly than they recognize and interact with the opioid-releasing substrate moieties. Importantly, due to the very low absorption of opioid-releasing polysubstrate analogs and the fact that the covalently constructed non-opioid-releasing (S1) and (S2) opioid-releasing substrate subunits cannot separate and move away from each other, the resulting saturation of the digestive enzymes that mediate the release of opioid agonists under overdose conditions can be extensive and sustained.Therefore, deliberate ingestion of multiple pills of the present invention will not allow abusers to reach the desired pharmacokinetic profile to reach a "high" or euphoric state.Furthermore, accidental co-ingestion of multiple pills by young children, elderly people or subjects will be unlikely to cause toxic or fatal effects.

[0097] Without being limited by theory, the present invention provides opioid-releasing compositions that can protect individuals from opioid overdose through an enzyme saturation mechanism. Enzyme inhibition and enzyme saturation are highly distinct processes detailed, for example, in Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis, Robert A. Copeland, 2000, Wiley-VCH, Inc., which is incorporated herein by reference in its entirety.

[0098] The mechanistic differences between enzyme inhibition and enzyme saturation are illustrated graphically in Figures 1 and 2. The solid "control" line in Figure 1 shows the relationship between substrate concentration and enzyme activity (i.e., the rate or "velocity") for a given enzyme and substrate system. max is the maximum velocity that an enzyme can attain, which is achieved at the substrate concentration at which the enzyme is saturated. m is the rate of the enzyme V max Km is the concentration of substrate at which V is equal to 1 / 2, or when 50% of the enzyme's active sites are occupied by the substrate. The dashed line in Figure 1 shows how enzyme activity is perturbed as a function of substrate concentration by the addition of another enzyme inhibitor molecule (e.g., a competitive inhibitor). Under competitive inhibitor conditions, the Km value increases while the V max It is important to note that the value of remains unchanged.

[0099] The process of enzyme saturation, depicted graphically in Figure 2, is distinct from enzyme inhibition. When an enzyme becomes "saturated," as represented by the curve in Figure 2, V max Until the substrate concentration reaches a level where the maximum rate of V is achieved, half of the enzyme active sites are occupied by substrate molecules. max K mThe rate at which a particular enzyme reacts with a particular substrate (i.e., the rate) increases as the substrate concentration increases through a concentration defined as saturation. At saturation, further increases in substrate concentration do not result in any further improvement in the rate at which the enzyme can process the substrate, and excess substrate molecules begin to accumulate.

[0100] The opioid-releasing polysubstrates of the present invention provide protection against overdose through the mechanism of enzyme saturation: when a prescribed dose of the polysubstrate is ingested, the rate at which the targeted digestive enzymes mediate opioid agonist release from the S2 subunit will be sufficient to provide the desired opioid agonist exposure in a compliant patient.

[0101] The enzyme kinetics associated with digestive enzyme-mediated delivery of opioid agonist after ingestion of a prescribed single dose and an overdose of polysubstrate are shown in Figures 3 and 4. By design, recognition of the S1 subunit by the targeted digestive enzyme proceeds at a much greater rate than recognition of the S2 substrate subunit (k1>>k2). This makes the pathway involving steps g, h, and k (shaded gray in Figures 3 and 4) a less likely or much less likely pathway for releasing opioid agonist from the S2 subunit of the polysubstrate after ingestion. By design, release of opioid agonist from the S2 subunit of the polysubstrate likely proceeds via a multi-step pathway described by a, b, d, and e in Figure 3. By design, the primary pathway for enzymatic hydrolysis of the polysubstrate of the present invention involves hydrolysis of the S1 subunit via pathways defined as a, b, and c. An important aspect of the design of the polysubstrate, and more particularly the design of the S1 substrate subunit, is that step c is a slow process (k3 is very small). At the intended dose of polysubstrate, the concentration of polysubstrate in the lumen of the gastrointestinal tract is such that there is a sufficient excess of active enzyme available after steps b and c have completed mediating steps d and e, resulting in efficient delivery of the opioid agonist from the S2 subunit of the polysubstrate molecule. In contrast, when an overdose of polysubstrate is ingested (Figure 4), the concentration of polysubstrate in the lumen of the gastrointestinal tract is such that there is not a sufficient excess of active enzyme available after steps b and c have completed effective mediation of steps d and e (here shaded grey in Figure 4). Under overdose conditions, the pathway defined by a, b and c effectively saturates the enzyme. As a result, delivery of the opioid agonist from the S2 subunit of the polysubstrate molecule is attenuated. Importantly, the critical relationship between k1, k2 and k3 can be modulated by chemical modifications to the S1 and S2 subunits (presented herein) to confer meaningful protection against oral overdose.Note that the optional opioid antagonist releasing S3 subunits that may be present in the polysubstrates of the invention are not digestive enzyme substrates and are therefore omitted from the polysubstrates illustrated in Figures 3 and 4 for mechanistic clarity.

[0102] By design, the rate of opioid agonist release will not be proportional to the number of doses (i.e., pills) co-ingested. Figure 5 graphically compares the plasma exposure (Cmax) and pharmacodynamic effect profile of a representative opioid agonist common to all current generic and new abuse-resistant opioid drug products (line A) with a representative polymatrix of the present invention that provides oral overdose protection (curve B).

[0103] Advantages of the targeted polysubunit approach include: (i) Chemical modifications to the nature and / or number of S1 and / or S2 subunits contained in the polysubstrate molecule can be used to obtain a “saturation profile” (i.e., V max and saturating concentrations), and thereby the profile of protection against overdosing, can be easily tuned. Furthermore, chemical modifications to the nature and / or number of S1 and / or S2 subunits contained in the polysubunit molecule can be used to easily tune the "inhibitory profile" (i.e., V max ), and that the protective profile against overdose can be easily adjusted thereby. (ii) the compounds of the invention are monomolecular, thereby preventing the covalently linked S1 and S2 substrate subunits from dissociating in vivo, and therefore the protection against overdose afforded by the compounds of the invention can last for the time required for transport through the gastrointestinal tract where digestive enzymes capable of effecting opioid agonist release are present. (iii) By design, the enzymatic pathways for hydrolysis of polysubstrates and polysubunits are chemoselective and are primarily mediated by the action of the digestive enzymes they are designed to target / saturate in the gastrointestinal tract. (iv) The compounds of the present invention can be high molecular weight and / or multi-charged molecules. In such an embodiment, the absorption of polysubstrate or polysubunit, or the resulting post-hydrolysis products, from the gastrointestinal tract into the systemic circulation is minimized. This serves to maximize the effectiveness of drug delivery, since effective opioid agonist delivery requires that polysubstrate or polysubunit be exposed to the digestive enzymes that are accessible primarily in the lumen of the gastrointestinal tract. Furthermore, by minimizing the systemic exposure of polysubstrate and polysubunit, important benefits can be realized from both safety and clinical development perspectives. (v) The compounds of the invention can be designed to release opioid antagonist molecules upon chemical tampering by a potential abuser or upon exposure to enzymes found in plasma, blood, liver or other systemically available tissues. Enzyme-sensitive opioid agonist-releasing polysubunit analogues

[0104] The present disclosure provides compounds and compositions that comprise gastrointestinal (GI) enzymes or subunits that interact with digestive enzymes.Such compositions can be specifically hydrolyzed by at least one of any of the GI enzymes disclosed herein.GI enzymes can be, for example, pepsin, trypsin, chymotrypsin, colipase, elastase, aminopeptidase, dipeptidyl aminopeptidase IV, tripeptidase, entropeptidase, carboxypeptidase, dipeptidyl aminopeptidase, pteroylpolyglutamate hydrolyase, gamma-glutamyltransferase, aminoaspartate aminopeptidase, amino-oligopeptidase, membrane Gly-Leu peptidase and zinc-stable Asp-Lys peptidase).

[0105] An example of a GI enzyme subunit is a protease substrate, such as a trypsin substrate or a chymotrypsin substrate.

[0106] As used herein, the term "trypsin substrate" refers to any agent that can be hydrolyzed by the action of trypsin, including salts of trypsin substrate.The ability of an agent to be a substrate for trypsin can be measured using assays well known in the art.For example, in a typical assay, the expected hydrolysis product formed in the incubation containing a specified concentration of digestive enzyme and substrate can be directly measured using common HPLC or spectrophotometric detection methods.

[0107] There are numerous trypsin substrates or inhibitors known in the art, including those specific for trypsin and those specific for other proteases, such as chymotrypsin. Trypsin substrates or inhibitors include natural, synthetic and semi-synthetic compounds. The present disclosure provides trypsin substrates or inhibitors that are proteins, peptides and small molecules. The present disclosure also provides trypsin substrates that are hydrolyzed via "normal" or "reverse" substrate mechanisms. The trypsin substrate or inhibitor can be an arginine mimetic or a lysine mimetic. In certain embodiments, the trypsin substrate or inhibitor is an arginine mimetic or a lysine mimetic, where the arginine mimetic or the lysine mimetic is a synthetic compound. As used herein, an arginine mimetic or a lysine mimetic can include a moiety that can bind to the specificity pocket of trypsin and / or interact with a functional group of the active site of trypsin. The arginine mimetic or the lysine mimetic can include a cleavable moiety. In some embodiments, cleavage of the cleavable moiety will directly or indirectly release the opioid agonist from the substrate moiety. In some embodiments, cleavage of the cleavable moiety will not release the opioid agonist from the substrate moiety. In some cases, when an over-therapeutic dose is taken, cleavage of the S1 subunit saturates the enzyme's ability to cleave the cleavable moiety, which directly or indirectly releases the opioid agonist, providing protection against overdose. In some cases, when an over-therapeutic dose is taken, gradual inhibition of the enzyme by the S1 subunit provides protection against overdose.

[0108] Examples of trypsin substrates that are arginine mimetics and / or lysine mimetics include cationic specificity pocket binding moieties that are designed to bind to the negatively charged specificity pocket of the enzyme, and hydrolyzable functional groups that are cleaved by the active site of the enzyme. Cationic specificity pocket binding moieties include, but are not limited to, alkyl-amines, alkylguanidines, alkylamidines, arylguanidines, benzamidines, benzylamines, naphthylamidines, naphthylguanidines, naphthylamines, etc. Hydrolyzable functional groups include, but are not limited to, amides, esters, carbamates, thioesters, carbonates, etc.

[0109] In one aspect of the present invention, the opioid agonist releasing GI enzyme substrate S2 subunit(s) and the non-opioid releasing GI enzyme substrate or enzyme inhibitor S1 subunit(s) are covalently linked to a scaffold, such as a polymeric, oligomeric or molecular scaffold. The S1 or S2 components can be linked directly or indirectly via a wide range of linkers described herein. The specific linkage and linking chemistry used will depend on the specific functional groups available on the S1, S2 and scaffold components. The presence of suitable functional groups in the S1, S2 and scaffold components, as well as the chemistry useful for linking strategies involving these suitable functional groups, can be easily determined by those skilled in the art based on the guidance provided herein. Specific examples of single molecule compositions consisting of linker (Z), S1 subunit, S2 subunit and / or S3 subunit, and / or molecular, oligomeric or polymeric scaffold are disclosed herein.

[0110] In another aspect of the invention, the compositions of the invention need not be orally bioavailable, and preferably are not orally bioavailable. Thus, in one aspect of the invention, the compositions according to the invention will demonstrate low (about 0% to about 30%) oral bioavailability. Oral bioavailability can be determined using suitable in vivo or in vitro assays. Thus, the polysubstrates of the invention will have oral bioavailability of about 0%, 0.25%, 0.5%, 0.75%, 1%, 2%, 5%, 10%, 15%, 25% or 30%, or less, as measured in a suitable model.

[0111] In one embodiment, the composition of the present invention comprises a compound of the formula: [ka] (In the formula, each S1 is independently a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; each S2 is independently an opioid agonist-releasing GI enzyme substrate; each S3 is independently an opioid antagonist releasing moiety; Each Z is independently a linking moiety; Each n is independently an integer ranging from 1 to 10; m is an integer ranging from 1 to 10; p and r are independently integers ranging from 0 to 10. It is represented by:

[0112] In another embodiment, the composition of the present invention comprises a compound of the formula: [ka] (In the formula, S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; S2 is an opioid agonist-releasing GI enzyme substrate subunit; S3 is an on-demand opioid antagonist releasing moiety; M is a covalent scaffold; Z is a linking moiety, r, m, and n are each independently an integer ranging from 1 to 10, 1 to 100, 1 to 1,000, 1 to 100,000, 1 to 1,000,000, or 1 to 1,000,000,000; p is an integer in the range of 0-10, 0-100, 0-1,000, 0-100,000, 0-1,000,000, or 0-1,000,000,000. It is represented by:

[0113] In some embodiments, the linking moiety Z between the covalent scaffold M and the S1, S2 and S3 subunits is sufficiently stable before and after administration to a subject.

[0114] The compositions of the present invention are not required to have, and preferably do not have, opioid agonist activity prior to processing with the enzyme of the opioid agonist-releasing GI enzyme substrate subunit. Thus, in one aspect of the present invention, the compositions according to the present invention will retain about 0% to about 30% of the specific activity of the delivered opioid agonist compound. Such activity can be determined using a suitable in vivo or in vitro assay, depending on the known activity of the particular opioid parent compound. For example, functional opioid receptor-based assays, or in vivo hot plate or tail flick analgesia assays can be used to assess the level of agonist activity of the polymer conjugates of the present invention. Thus, the compositions of the invention will have a specific activity of about 0%, or less than about 0.25%, 0.5%, 0.75%, 1%, 2%, 5%, 10%, 15%, 25%, 30% or 50% compared to the specific activity of the delivered opioid agonist when measured in a suitable model, such as those well known in the art.

[0115] In another embodiment of the invention, the compositions of the invention need not be orally bioavailable, and preferably are not orally bioavailable and / or do not cross the blood-brain barrier. For example, the compositions of the invention do not penetrate the central nervous system (CNS). Thus, in one embodiment of the invention, the compositions according to the invention will retain about 0% to about 30% of the oral bioavailability or CNS permeability of the delivered opioid agonist. Oral bioavailability and CNS permeability can be determined using a suitable in vivo assay. Thus, the compositions of the invention will have an oral bioavailability or CNS permeability of about 0%, or less than about 0.25%, 0.5%, 0.75%, 1%, 2%, 5%, 10%, 15%, 25% or 30% of that of the unmodified parent opioid, as measured in a suitable model, such as those well known in the art. Opioid agonists

[0116] Any opioid agonist known in the art may be used. The terms "opioid agonist" and "opioid" are used interchangeably herein and refer to any drug, both natural and synthetic, that has a morphine-like mechanism of action. Opioid agonists useful in the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketamine ... These include tobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, mylophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propeptadine, promedol, properidine, propoxyphene, sufentanil, tapentadol, tilidine, tramadol, mixtures of any of the above, salts thereof, prodrugs thereof, and derivatives, analogs, homologs, and polymorphs thereof. In certain embodiments, the amount of opioid agonist released can be from about 0.25 nmol to about 2.5 mmol. The specified amount of opioid released by the polymatrix compositions of the present invention will likely vary depending on the potency and bioavailability of the particular opioid agonist being released.

[0117] In some embodiments, the pharmaceutical compositions of the present invention include as the therapeutically active ingredient one or more opioids, such as hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and / or salts or prodrugs thereof.

[0118] In some embodiments, the unit dosage form contains an amount of opioid agonist that is about 0.003 mmol, about 0.015 mmol, about 0.03 mmol, about 0.045 mmol, about 0.075 mmol, about 1.50 mmol, about 0.225 mmol, about 0.3 mmol, about 0.375 mmol, about 0.45 mmol, about 0.525 mmol, or about 0.6 mmol. More typically, the drug can be present in an amount of about 0.003 mmol to about 1.66 mmol, preferably about 0.015 mmol to 0.6 mmol. As will be appreciated by those skilled in the art, the dosage form preferably contains an appropriate amount of drug to achieve a therapeutic effect. The dosage unit of the present invention can also include co-formulation with additional therapeutically active drugs, such as acetaminophen, ibuprofen, naltrexone, etc. Opioid antagonists

[0119] The term "opioid antagonist" as used herein refers to any molecule that blocks the action of an opioid agonist at one or more opioid receptor types. Opioid antagonists include so-called "agonist-antagonist" molecules (such as naloxone, naltrexone, nalorphine, or pentazocine) that act as antagonists at one opioid receptor type and agonists at another receptor type.

[0120] When co-administered with an opioid agonist, an opioid antagonist can block the effects of the opioid agonist. Antagonists such as norphine are often used to combat the effects of opioid agonist abuse and overdose. For example, naltrexone is commonly prescribed to help combat addiction to either alcohol or opioid drugs.

[0121] Suitable opioid antagonists include, but are not limited to, buprenorphine, cyclazocine, cyclorphan, naloxone, N-methylnaloxone, naltrexone, N-methylnaltrexone, nalmefene, 6-amino-6-desoxo-naloxone, levallorphan, nalbuphine, naltrendole, naltrindole, nalorphine, nor-binaltorphimine, oxylorphan, pentazocine, piperidine-N-alkylcarboxylate opioid antagonists such as those described in U.S. Pat. Nos. 5,159,081, 5,250,542, 5,270,328, and 5,434,171, and derivatives, mixtures, salts, polymorphs, or prodrugs thereof.

[0122] In one embodiment of the invention, the opioid antagonist includes naltrexone, naloxone, nalmefene, cyclazacine, levallorphan and mixtures thereof. In another embodiment of the invention, the opioid antagonist is naltrexone or naloxone.

[0123] In one embodiment of the invention, the antagonist is naloxone. Naloxone has little agonist effect. Subcutaneous doses of up to 12 mg of naloxone produce no discernible subjective effects, and 24 mg of naloxone causes only slight drowsiness. Small doses (0.4-0.8 mg) of naloxone administered intramuscularly or intravenously in humans block or reverse the effects of morphine-like opioid agonists. It has been reported that 1 mg of naloxone administered intravenously completely blocks the effects of 25 mg of heroin. The effects of naloxone are almost immediate after intravenous administration. The drug is absorbed after oral administration, but is reported to be rapidly and extensively metabolized to an inactive form by first-pass metabolism. Thus, it has been demonstrated that oral delivery is much less potent than parenteral administration.

[0124] Other exemplary opioid antagonists include cyclazocine and naltrexone, both of which have a cyclopropylmethyl substituent on the nitrogen and retain most of their potency by the oral route, and their duration of action is quite long, approaching 24 hours after oral dosing.

[0125] In another embodiment of the present invention, the antagonist is naltrexone.Naltrexone works by blocking opioid receptors in the brain and blocking the euphoric sensation felt when alcohol or opioid agonists are taken.According to the National Institutes of Health, this in turn reduces the desire for this substance.Naltrexone can be delivered both orally and intravenously. Naltrexone is known as a synthetic analog of oxymorphone that does not have opioid agonist properties and differs structurally from oxymorphone by replacing the methyl group located on the nitrogen atom of the oxyhormone with a cyclopropylmethyl group. As a result, the physicochemical properties of naltrexone (and chemically related antagonists) are almost identical to those inherent to structurally related opioid agonists. This makes physical separation of naltrexone-opioid agonist mixtures virtually impossible without the use of highly sophisticated chemical separation techniques (e.g., high performance liquid chromatography-HPLC). The hydrochloride salt of naltrexone is soluble in water up to about 100 mg / mL. After oral administration, naltrexone is rapidly absorbed (within 1 hour) and has an oral bioavailability ranging from 5 to 40%.

[0126] It is known that naltrexone, when co-administered with morphine, heroin, or other opioid agonists, can block the development of physical dependence on opioid agonists, reduce the "drug hook" in recreational abusers, induce withdrawal symptoms in opioid-dependent subjects, and completely block the effects of the co-delivered opioid agonist. Naltrexone has been used in the treatment of previously opioid-addicted patients to block the euphoric effects of opioid agonists. Naltrexone is commercially available in oral tablet form (Revia®) for the treatment of alcoholism and for blocking exogenously administered opioids. Revia, which comes in a 50 mg oral dose, blocks the pharmacological effects of 25 mg of IV-administered heroin for up to 24 hours.

[0127] When present, the molar ratio of opioid antagonist to opioid agonist in the compositions of the invention can be from about 0.001:1 to about 10:1, preferably from about 0.01:1 to about 3: 1. As will be appreciated by those of skill in the art, the compositions of the invention preferably contain an amount of opioid antagonist appropriate to achieve the desired abuse-deterrent effect upon release. Non-opioid releasing GI enzyme S1 subunit

[0128] The composition of the present invention comprises a non-opioid-releasing digestive enzyme substrate or inhibitor S1 subunit or a plurality of non-opioid-releasing digestive enzyme substrates or inhibitors S1 subunits that are covalently linked. In some embodiments, the non-opioid-releasing digestive enzyme substrate S1 subunit is a GI enzyme inverting substrate ester. For example, the non-opioid-releasing substrate is linked to the linking moiety Z via the carboxylate-containing component of the ester, and can be represented by one of the following moieties shown below: [ka] (In the formula, Y is amidine, guanidine, benzylamine, alkyl-substituted amidine, alkyl-substituted guanidine, alkyl-substituted benzylamine, benzyl amidine, benzyl guanidine, alkyl-substituted benzyl amidine or alkyl-substituted benzyl guanidine; Z is a linking moiety, K o each is independently hydrogen or methyl; A is an amino acid side chain, r is an integer from 0 to 10; m is an integer from 1 to 10; p is an integer from 1 to 10; n is an integer from 0 to 10, each R' is independently alkyl, aryl, substituted alkyl, substituted aryl, acyl, substituted acyl group, or polyethylene glycol-containing acyl group, aryl group, or alkyl group; Each R'' is independently a hydrogen, a methyl group, an alkyl group, or an aryl group.

[0129] In some embodiments, Z and K oAt least one of the S1 subunits contains an electron donating or electron withdrawing atom or functional group that affects the formation or hydrolysis of an acyl enzyme intermediate resulting from the interaction of the S1 subunit with the target digestive enzyme. For example, electron donating groups include alkyl, substituted alkyl, -OH, -OR, -NH2, -NR2, -SH, -SR and -NHC(O)R. For example, electron withdrawing groups include -C(O)OH, -C(O)OR, -C(O)NH2, -C(O)NR2, -NO2, -NR3 + , -C(O)CF3, halogen, -CCl3, cyano, -SO3H, -SO3R, -CHO, -COR, -C(NH)NH2 and -NHC(NH)NH2.

[0130] In other embodiments, the S1 subunit is connected to the scaffold or linking moiety via a phenolic moiety of an ester. Examples include, but are not limited to, those described below: [ka] (In the formula, Y is amidine, guanidine, benzylamine, alkyl-substituted amidine, alkyl-substituted guanidine, alkyl-substituted benzylamine, benzyl amidine, benzyl guanidine, alkyl-substituted benzyl amidine or alkyl-substituted benzyl guanidine; Z is a linking moiety, K o each is independently hydrogen or methyl; A is an amino acid side chain, r is an integer from 0 to 10; m is an integer from 1 to 10; p is an integer from 1 to 10; n is an integer from 0 to 10, R is independently an alkyl, alkylene, alkynyl, or aryl group, or a substituted alkyl, alkylene, alkynyl, or aryl group; each R' is independently alkyl, aryl, substituted alkyl, substituted aryl, acyl, substituted acyl group, or polyethylene glycol-containing acyl group, aryl group, or alkyl group; Each R'' is independently a hydrogen, a methyl group, an alkyl group, or an aryl group.

[0131] In some embodiments, Z and K o At least one of the S1 subunits may contain an electron donating or electron withdrawing atom or functional group that affects the formation or hydrolysis of an acyl enzyme intermediate resulting from interaction of the S1 subunit with the target digestive enzyme. For example, electron donating groups include alkyl, substituted alkyl, -OH, -OR, -NH2, -NR2, -SH, -SR and -NHC(O)R. For example, electron withdrawing groups include -C(O)OH, -C(O)OR, -C(O)NH2, -C(O)NR2, -NO2, -NR3 + , -C(O)CF3, halogen, -CCl3, cyano, -SO3H, -SO3R, -CHO, -COR, -C(NH)NH2 and -NHC(NH)NH2.

[0132] Hydrolysis of the ester S1 substrate subunits listed above by GI enzymes (e.g., by trypsin) results in the formation of carboxylic acid, amino acid, or benzoic acid metabolites. In some embodiments, hydrolysis of the ester S1 substrate subunits by GI enzymes (e.g., by trypsin) can be designed to produce generally regarded as safe (GRAS) acid metabolites. Hydrolysis of a representative S1 substrate subunit by a GI enzyme resulting in the release of a GRAS acid metabolite is illustrated by the following general mechanism: [ka]

[0133] "GRAS" stands for "Generally Regarded as Safe" and refers to compounds as defined by sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act. Exemplary GRAS acid metabolites include, but are not limited to, benzoic acid, salicylic acid, aspirin, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, gallic acid, 2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 6-methylsalicylic acid, o-cresotinic acid, (alkyl)-anacardic acid, o-thymotic acid, 3-O-methylgallic acid, and the like. , 4-O-methylgallic acid, syringic acid, 3,4,5-trimethoxybenzoic acid, diflusinal, p-anisic acid, 2,3-dihydroxybenzoic acid, alpha-resorcylic acid, anthranilic acid, 3-aminobenzoic acid, 4,5-dimethylanthranilic acid, N-methylanthranilic acid, protocatechuic acid, gentisic acid, piperonylic acid, 3-methoxysalicylic acid, fenamic acid, tolfenamic acid (toifenamic acid), mefenamic acid, flufenamic acid, vanillic acid, isovanillic acid, veratric acid, 3,5-dimethoxybenzoic acid, 2,4-diaminobenzoic acid, N-acetylanthranilic acid, 2-acetylamino-4-aminobenzoic acid, 2,4-diacetylaminobenzoic acid, 4-aminosalicylic acid, 3-hydroxyanthranilic acid, 3-methoxyanthranilic acid, nicotinic acid, isonicotinic acid, and cinnamic acid.

[0134] In one aspect of the present invention, the compositions, pharmaceutical preparations and methods disclosed herein comprise an S1 reverse substrate ester subunit for GI enzymes such as trypsin, chymotrypsin or tryptase. Thus, when trypsin is an exemplary GI enzyme, trypsin cleaves the C-terminal peptide bond of arginine and lysine, both of which are positively charged amino acids. The specificity pocket of trypsin has an aspartic acid residue (Asp-189), which is negatively charged and provides a negative electrostatic field in the substrate binding pocket, thereby attracting the positively charged side chains of arginine and lysine substrates. The negative electrostatic field in the substrate binding pocket also helps stabilize the positive charge in the enzyme-substrate complex.

[0135] Mechanistically, the hydrolysis of the ester-based reverse substrate S1 subunit catalyzed by the GI enzyme follows the following scheme: [ka] It can be explained using

[0136] In the scheme, E is the GI enzyme. s is the association constant of the enzyme-substrate complex, k2 is the rate constant for the acylation step, and k3 is the rate constant for the deacylation step. In the first step, the ester substrate and enzyme bind to form the enzyme-substrate complex. The reverse substrate ester S1 subunit is then irreversibly hydrolyzed to produce an alcohol (or phenol) fragment and an active site acyl-enzyme intermediate. The acyl-enzyme intermediate subsequently dissociates into free enzyme (E) and an acid fragment with a rate constant of k3. The rate at which the deacylation step occurs, k3, determines the lifetime of the acyl-enzyme intermediate and the trypsin-saturating properties of the specific S1 subunit.

[0137] Thus, in one aspect of the invention, the compositions, pharmaceutical formulations and methods disclosed herein include a non-opioid releasing ester substrate(s), where the ester substrate has an enzyme recognition moiety covalently linked to a carbonyl group that is capable of acylation of the active site of an enzyme.

[0138] Thus, in one aspect of the present invention, the products generated by hydrolysis of the S1 ester-based non-opioid releasing reverse substrate are acids and alcohols, such as substituted phenols, where the phenols may remain covalently bound to the polysubstrates of the present invention and, as a result, will generally not be systemically absorbed but rather will be excreted through the gastrointestinal system. Such ester-containing polysubstrates of the present invention can be designed to release GRAS acids, which have the advantage that GRAS have a well-characterized safety profile. Furthermore, these ester substrates are chemically stable in vivo and do not readily undergo hydrolysis by the acid in the patient's stomach or non-specific hydrolysis by the patient's digestive enzymes.

[0139] Representative, non-limiting examples of S1 subunits include: [ka] [ka] wherein Z is a linking moiety as described herein; X can be hydrogen, an amino acid, alkyl, heteroalkyl, aryl, substituted aryl, acyl, substituted acyl, a terminally functionalized polyethylene glycol chain, or X is a substituent (or multiple substituents) on a GRAS carboxylic acid as described above. In some embodiments, the non-opioid releasing digestive enzyme S1 subunit is a GI enzyme inhibitor. The non-opioid releasing S1 GI enzyme inhibitor subunit is linked to a linking moiety Z as represented by any one of the following non-limiting examples described below.

[0140] The S1 subunit may include, but is not limited to, the following: [ka] can be derived from amidinophenylpyruvate (APPA), including wherein Y can be O, NH, NR or S, and Z is a linker as defined above.

[0141] In another embodiment of the invention, the S1 subunit may be selected from the group consisting of, but not limited to, the following: [ka] can be derived from activated ketone derivatives, including In the formula, Y is N, O, NR or carbon; R is methyl, ethyl, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substitutes aryl, natural or is an unnatural amino acid, or a polypeptide chain comprising a natural or unnatural amino acid. The arginine side chain in the above structure can be replaced with a lysine side chain, or a natural or unnatural lysine or arginine side chain mimic.

[0142] In another embodiment of the invention, the S1 subunit is a chloroketone analog or an aldehyde analog as shown below: [ka] The chloroketone and aldehyde analogs exemplified above can also include side chain variations of natural or unnatural lysine or arginine mimetics. In another non-limiting embodiment of the invention, the S1 subunit inhibitors are selected from the group consisting of cycloheteroalkyl groups, naphthylamidines, arylguanidines, arylamidines, benzylamines, 4-guanidinopiperazines, and peptide-based structures, exemplified below: [ka] The S1 subunits exemplified above can also include natural or unnatural lysine or arginine mimetic side chain variants. Preparation of non-opioid releasing GI enzyme S1 subunit

[0143] Several synthetic procedures useful for the preparation of the S1 subunit have been reported in the literature (e.g., Tanizawa, K. et al., Chem. Pharm. Bull. 1999, 47(1), 104-110). Aoyama, T. et al., Chem. Pharm. Bull. 1985, 33(4), 1458-1 471; Bordusa, F. et al., Biochemistry, 1999, vol. 38, pp. 6056-6062; Tanizawa, K. et al., Chem. Pharm. Bull. 1996, vol. 44, pp. 1577-1579 , pp. 1585-1587, Lal, B. et al., Tetrahedron Lett. 1996, Vol. 37, pp. 2483-2486, Sekizaki, H. et al., Bioorganic & Medicinal Chemistry Letters, 2003, 13, 3809-3812; Tanizawa, K. et al., Acc. Chem. Res. 1987, 20, 337-343), generally involves coupling between an alcohol (or phenol) synthon and a carboxylic acid (e.g., benzoic acid) moiety that has either been preactivated for coupling by first converting it to an acid chloride or the like, or activated for coupling in situ with a suitable coupling reagent (e.g., DCC) to form the desired ester functionality. Amidine-substituted phenol synthons are commonly used in unprotected salt form, while guanidine-containing esters are often prepared by analogous coupling reactions using protected forms of arylguanidine synthons (e.g., bis-Cbz protected forms). Purification of the resulting esters can be accomplished using standard purification procedures, including normal or reverse phase HPLC, crystallization, trituration, and the like. The chemical identity of the S1 ester can be readily established by LC / MS and / or NMR analysis.

[0144] Some representative synthetic routes useful for the preparation of the S1 subunit are illustrated below. [ka] [ka] (In the formula, each R' is independently alkyl, aryl, substituted alkyl, substituted aryl, acyl, substituted acyl group, or polyethylene glycol-containing acyl group, aryl group, or alkyl group; Each R is independently a hydrogen atom, a methyl group, an alkyl group, or an aryl group; W is hydrogen or an atom or substituent that renders the benzoic acid metabolite of the S1 subunit a GRAS compound, or W is an electron donating or electron withdrawing atom or functional group that affects the formation or hydrolysis of an acyl enzyme intermediate resulting from the interaction of the S1 subunit with the target digestive enzyme; Z is a linking moiety, X is a covalent bond or an atom such as oxygen or nitrogen, or a functional group suitable for attachment to or incorporated by a linker group Z; (P) is an optional protecting group present at the end of the linker Z distal to the S1 subunit that may be used to improve the chemical efficiency of the coupling reaction to form the desired ester). Opioid agonist-releasing GI enzyme S2 subunit

[0145] The composition of the present invention comprises a covalently linked opioid agonist releasing digestive enzyme substrate S2 subunit(s). The released opioid agonist can be morphine, morphone, or other phenol-containing opioid agonist, or codon, or other ketone-containing opioid agonist, such as those illustrated by the following formula: The opioid agonist releasing substrate can be linked via a phenol, alcohol, or ketone (e.g., enol) functional group, as shown below: [ka]

[0146] In some embodiments, D is an opioid agonist linked to phenol. For example, D is selected from buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, oxymorphone, tapentadol, and the like.

[0147] In some embodiments, D is an opioid agonist linked to an enol, e.g., D is selected from acetylmorphone, hydrocodone, hydromorphone, oxycodone, oxymorphone, pentamorphone, ketobemidone, methadone, and the like.

[0148] According to one aspect, the present invention provides a pharmaceutical composition comprising an opioid agonist-releasing digestive enzyme S2 substrate. The present disclosure provides a novel digestive enzyme substrate moiety that is attached to an opioid agonist by a functional group present on the opioid agonist, where the functional group present on the opioid agonist comprises a reactive group. Any type of reactive group on the opioid agonist can provide a hook for a point of attachment to the S2 substrate moiety. Examples of reactive groups on opioid agonists include, but are not limited to, alcohols, phenols, ketones, aminos, and amides. The alcohol or phenol of the opioid agonist provides a point of attachment that reacts to form a linkage such as a carbamate. The ketone of the opioid agonist can provide a point of attachment that can be reacted to form a linkage such as an enol carbamate. The amino group of the opioid agonist can provide a point of attachment that can be reacted to form an amino linkage, including a quaternary salt, or an amide. The amide of the opioid agonist can provide a point of attachment that can be reacted to form an amide enol, or an N-alkylated or N-acylated amide, or other linkage.

[0149] The S2 substrate moiety can be linked to an amino-containing opioid agonist through an amino moiety, to an amide-containing opioid agonist through the enolic oxygen of an amide moiety or its imine tautomer, to an alcoholic or phenolic opioid agonist through modification of the alcohol or phenol moiety with the enolic oxygen atom of the ketone moiety. In each case, the opioid agonist-releasing digestive enzyme substrate contains an enzyme-cleavable moiety that is susceptible to cleavage by GI enzymes. The release of the opioid agonist is mediated by enzymatic cleavage by the digestive enzyme. Such cleavage can initiate drug release, can contribute to drug release, or can immediately effect drug release.

[0150] An example of an opioid agonist-releasing digestive enzyme S2 substrate moiety containing a releasable opioid agonist designated as D is shown below.

[0151] In some embodiments, the S2 subunit has one of the following formulas: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R is independently hydrogen, methyl, or alkyl, or a linking moiety Z; each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, or a linking moiety, Z; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, amino acid mimetic, or linking moiety Z; each A2 is independently an amino acid side chain or an amino acid side chain mimetic capable of being recognized by a digestive enzyme; p is an integer from 0 to 10. has.

[0152] In some embodiments, the amino acid side chain or amino acid side chain mimic A2 directs the site-specific digestive enzyme-mediated hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, the amino acid side chain can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof.

[0153] In some embodiments, the S2 subunit has one of the following formulas: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, or a linking moiety, Z; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid side chain, an amino acid side chain mimetic, or a linking moiety (Z); each A2 is independently an amino acid side chain or an amino acid side chain mimetic capable of being recognized by a digestive enzyme; r is an integer from 0 to 10; n is an integer that can range from 0 to 28. has.

[0154] In some embodiments, the amino acid side chain or amino acid side chain mimic A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, the amino acid side chain can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof.

[0155] In some embodiments, the S2 subunit has one of the following formulas: [ka] wherein D is an opioid agonist, e.g., where D is morphone, codon, or morphine; Each R is independently hydrogen, methyl, or alkyl; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, amino acid mimetic, or linking moiety Z; each A2 is independently an amino acid side chain or an amino acid side chain mimetic capable of being recognized by a digestive enzyme; R''' is hydrogen or methyl or -C(=NR)-NR2, where R is each and independently hydrogen or methyl; r is an integer from 1 to 6; n is an integer from 0 to 10. has.

[0156] In some embodiments, the amino acid side chain or amino acid side chain mimic A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, the amino acid side chain can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof.

[0157] In some embodiments, the S2 subunit has the following formula: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, amino acid mimetic, or linking moiety (Z); A2 is an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme. has.

[0158] In some embodiments, the amino acid side chain or amino acid side chain mimic A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, the amino acid side chain can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof.

[0159] In some embodiments, the S2 subunit has the following formula: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, amino acid mimetic, or linking moiety (Z); A2 is an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme. has.

[0160] In some embodiments, the amino acid side chain or amino acid side chain mimic A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, the amino acid side chain can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof.

[0161] As will be apparent to one of skill in the art, opioid agonist-releasing digestive enzyme substrates may be covalently attached to form polysubstrates of the invention via one or more linking moieties Z at any substitution point of the S2 subunit, so long as the linkage(s) does not interfere with either the necessary hydrolytic action of the digestive enzyme on the S2 substrate subunit or the subsequent release of the opioid agonist from the S2 substrate subunit.

[0162] In one aspect of the present invention, the opioid agonist is an alcohol, phenol or ketone-containing opioid agonist.Therefore, the alcohol, phenol or ketone-containing opioid agonist is linked to a linker through hydroxyl oxygen, phenol oxygen or enolic oxygen, and this linker is further linked to an enzymatically cleavable moiety.A single enzymatic hydrolysis of a cleavable moiety, or a cascade of enzymatic hydrolysis of multiple cleavable moieties, can release the opioid agonist by (i) directly cleaving the bond between the enzymatically cleavable moiety and the opioid agonist, or (ii) exposing a latent nucleophile such as an amine or carboxylate that subsequently undergoes intramolecular cyclization release reaction, or (iii) exposing one or more additional enzyme substrates that are further cleaved by digestive enzymes, ultimately releasing the opioid agonist that is linked to it.

[0163] The mechanism of enzyme-mediated release of an opioid agonist from a representative S2 substrate subunit is depicted in the following scheme.

[0164] General mechanism of enzyme-mediated release of opioid agonists from representative S2 subunits forming 2,5-diketopiperazines: [ka]

[0165] General mechanism for enzyme-mediated release of opioid agonists from representative lactam-forming S2 subunits: [ka]

[0166] General mechanism of enzyme-mediated release of opioid agonists from representative "multiply activated" S2 subunits: [ka] [ka]

[0167] General mechanism of enzyme-mediated release of opioid agonists from representative S2 subunits forming 2,4-oxazolidinedione: [ka]

[0168] General mechanism of enzyme-mediated release of opioid agonists from representative amino acid ester S2 subunits: [ka]

[0169] Representative non-limiting examples of S2 subunits include, but are not limited to, the following: [ka] [ka] where R′ and R″ are as defined above and X is hydrogen or —OH.

[0170] Representative synthetic routes useful for the preparation of S2 substrate subunits are illustrated below. The synthesis utilizes readily available peptide-derived synthons, well-established peptide-based couplings, and known protecting group strategies. Opioid attachment strategies forming enol-esters and enol-carbamates are also used. (P) is an optional protecting group present on the terminus of linker Z distal to the S2 subunit that may be used to improve chemical efficiency. Purification of the resulting S2 subunit can be accomplished using standard purification procedures including normal or reverse phase chromatography, crystallization, trituration, and the like. The chemical identity of the S2 subunit can be established by LC / MS and / or NMR analysis. [ka] [ka]

[0171] In some embodiments, the S2 subunit has one of the following formulas: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, polyethylene glycol or a polyethylene glycol containing moiety, or a linking moiety, Z; In some embodiments, R' can also form a spirocyclic ring or a fused aliphatic ring with a geminal or vicinal R' group; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, amino acid functional or structural mimetic, or a linking moiety, Z; Each A2 is independently an amino acid side chain, or an amino acid side chain functional or structural mimetic, capable of being recognized by a digestive enzyme. has.

[0172] In some embodiments, the amino acid side chain, or amino acid side chain functional or structural mimic A2, directs the site-specific digestive enzyme-mediated hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, the amino acid side chain can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof.

[0173] In some embodiments, the S2 subunit has one of the following formulas: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, polyethylene glycol or a polyethylene glycol containing moiety, or a linking moiety (Z); each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, an amino acid functional or structural mimetic, or a linking moiety (Z); Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme. has.

[0174] In some embodiments, A2 is: [ka] (In the formula, Each R is independently hydrogen or methyl; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, an amino acid functional or structural mimetic, or a linking moiety (Z); Each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl, -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by digestive enzymes leading to site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit, including but not limited to the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or structural / functional mimics thereof; R″ is as defined above, m is an integer from 0 to 10; r is an integer from 0 to 10; q is an integer from 0 to 27. It is.

[0175] In some embodiments, the amino acid side chain or amino acid side chain mimic A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, the amino acid side chain can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof.

[0176] In some embodiments, the S2 subunit has the following formula: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, polyethylene glycol or a polyethylene glycol containing moiety, or a linking moiety (Z); each R'' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid; an amino acid mimetic, or linking moiety (Z); Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme. has.

[0177] In some embodiments, A2 is: [ka] (In the formula, Each R is independently hydrogen or methyl; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, an amino acid functional or structural mimetic, or a linking moiety (Z); Each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl, -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimetic that can be recognized by digestive enzymes leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof; R″ is as defined above; n is an integer from 0 to 10. It is.

[0178] In some embodiments, the amino acid side chain or amino acid side chain mimic A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, the amino acid side chain can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof.

[0179] In some embodiments, the S2 subunit has the following formula: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, polyethylene glycol, or a polyethylene glycol-containing moiety, or a linking moiety, Z, as previously defined; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid side chain, an amino acid side chain mimetic, or a linking moiety, Z, as previously defined; Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme. has.

[0180] In some embodiments, A2 is: [ka] (In the formula, Each R is independently hydrogen or methyl; each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid, an amino acid functional or structural mimetic, or a linking moiety (Z); Each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl, -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by digestive enzymes leading to site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit, and can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof; R″ is as defined above, m is an integer from 0 to 10; n is an integer from 0 to 10, p is an integer from 0 to 4. It is.

[0181] In some embodiments, the amino acid side chain or amino acid side chain mimic A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, the amino acid side chain can be, but is not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof.

[0182] As will be apparent to one of skill in the art, opioid agonist-releasing digestive enzyme substrates may be covalently attached to form polysubstrates of the invention via one or more linking moieties Z at any substitution point of the S2 subunit, so long as the linkage(s) does not interfere with either the necessary hydrolytic action of the digestive enzyme on the S2 substrate subunit or the subsequent release of the opioid agonist from the S2 substrate subunit.

[0183] In one aspect of the present invention, the opioid agonist is an alcohol, phenol or ketone-containing opioid agonist.Therefore, the alcohol, phenol or ketone-containing opioid agonist is linked to a linker through hydroxyl oxygen, phenol oxygen or enolic oxygen, and this linker is further linked to an enzymatically cleavable moiety.A single enzymatic hydrolysis of a cleavable moiety, or a cascade of enzymatic hydrolysis of multiple cleavable moieties, can release the opioid agonist by (i) directly cleaving the bond between the enzymatically cleavable moiety and the opioid agonist, or (ii) exposing a latent nucleophile such as an amine or carboxylate that subsequently undergoes intramolecular cyclization release reaction, or (iii) exposing one or more additional enzyme substrates that are further cleaved by digestive enzymes, ultimately releasing the opioid agonist that is linked to it.

[0184] The mechanism of enzyme-mediated release of opioid agonists from a representative S2 substrate subunit is depicted below: General mechanism of enzyme-mediated release of opioid agonists from representative examples of cyclic urea-forming S2 subunits: [ka]

[0185] General mechanism of enzyme-mediated release of opioid agonists from representative examples of S2 subunits forming aliphatic fused cyclic ureas: [ka]

[0186] General mechanism of enzyme-mediated release of opioid agonists from representative examples of S2 subunits forming heterocyclic fused cyclic ureas: [ka]

[0187] General mechanism of enzyme-mediated release of opioid agonists from representative examples of S2 subunits forming aromatic fused cyclic ureas: [ka]

[0188] Representative non-limiting examples of S2 subunits include, but are not limited to, the following: [ka] (In the formula, X is hydrogen or hydroxyl; each R' is independently hydrogen, methyl, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, polyethylene glycol or a polyethylene glycol containing moiety, or a linking moiety, Z; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing moiety, or a natural or unnatural amino acid side chain, amino acid side chain mimetic, or linking moiety Z).

[0189] A representative synthetic route useful for the preparation of the S2 substrate subunit is illustrated below, utilizing readily available peptide-derived synthons, well-established peptide-based couplings, and known protecting group strategies.

[0190] Opioid binding strategies to form phenol and enol-carbamates that have been published in the art are also used (see, for example, U.S. Pat. Nos. 8,802,681, 8,685,916, 8,217,005 and 8,163,701, U.S. Pat. Nos. 8,685,916, 8,569,228, 8,497,237, and U.S. Patent Application No. 2014016935). (P) is an optional protecting group present at the end of the linker Z distal to the S2 subunit that may be used to improve chemical efficiency. Purification of the resulting S2 subunit can be performed using standard purification procedures including normal or reverse phase chromatography, crystallization, trituration, and the like. The chemical identity of the S2 subunit can be established by LC / MS and / or NMR analysis. [ka] [ka] Combination of S1 and S2 subunits

[0191] In some embodiments, the disclosure provides a compound comprising: One S1 subunit co-linked to one S2 subunit: [ka] (In the formula, R is [ka] where R' can be methyl, lower alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, a natural or unnatural amino acid, a polypeptide chain comprising natural and / or unnatural amino acids up to 10 amino acids in length, a linear or branched polyethylene glycol chain up to 5 kDa, benzyloxy, etc.; R'' can be acetyl, substituted acyl, a natural or unnatural amino acid, or a polypeptide chain comprising natural and / or unnatural amino acids up to 10 amino acids in length, AA is a natural or unnatural amino acid side chain that can be recognized by trypsin, and X is hydrogen or OH).

[0192] In some embodiments, the disclosure provides a compound comprising: One S1 subunit co-linked to two S2 subunits: [ka] (In the formula, R is [ka] where R' can be methyl, lower alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, a natural or unnatural amino acid, a polypeptide chain comprising natural and / or unnatural amino acids up to 10 amino acids in length, a linear polyethylene glycol chain up to 5 kDa, benzyloxy, etc.; R'' can be acetyl, substituted acyl, a natural or unnatural amino acid, or a polypeptide chain comprising natural and / or unnatural amino acids up to 10 amino acids in length, AA is a natural or unnatural amino acid side chain that can be recognized by trypsin, and X is hydrogen or OH).

[0193] In some embodiments, the disclosure provides a compound comprising: One S1 subunit co-linked to three S2 subunits: [ka] (In the formula, R is [ka] where R' can be methyl, lower alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, a natural or unnatural amino acid, a polypeptide chain comprising natural and / or unnatural amino acids up to 10 amino acids in length, a linear polyethylene glycol chain up to 5 kDa, benzyloxy, etc.; R'' can be acetyl, substituted acyl, a natural or unnatural amino acid, or a polypeptide chain comprising natural and / or unnatural amino acids up to 10 amino acids in length, AA is a natural or unnatural amino acid side chain that can be recognized by trypsin, and X is hydrogen or OH).

[0194] In some embodiments, the present disclosure provides a compound wherein R is [ka] wherein R' can be methyl or benzyloxy; R'' can be acetyl or substituted acyl, a natural or unnatural amino acid, or a dipeptide or tripeptide comprising a natural or unnatural amino acid; AA is a natural or unnatural amino acid side chain that can be recognized by trypsin; and X is hydrogen or OH.

[0195] In still other embodiments, the present disclosure provides a compound wherein R is: [ka] wherein R' can be methyl or benzyloxy; R'' can be acetyl, a natural or unnatural amino acid, or a dipeptide comprising a natural or unnatural amino acid; AA is the side chain of lysine or arginine; and X is hydrogen or OH.

[0196] In yet another embodiment, the present disclosure provides a compound wherein R is [ka] wherein R' can be methyl or benzyloxy; R'' can be acetyl, -Ala-NAc or -Gly-NAc; AA is the side chain of lysine or arginine; and X is hydrogen or OH.

[0197] Table 3 illustrates various compounds contemplated by the present disclosure. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] Opioid antagonist releasing S3 subunit

[0198] The polysubstrate of the present invention can optionally contain zero, one or more covalently linked opioid antagonist releasing S3 subunits. The opioid antagonist releasing S3 subunits preferably do not substantially release the bound opioid antagonist when orally ingested by a subject. By design, the S3 subunits may preferably be substrates for enzymes found in blood, plasma, liver or other systemically available tissues, rather than being digestive enzyme substrates. The opioid antagonist releasing GI enzyme substrates are designed to efficiently release the bound opioid antagonist in the systemic circulation (i.e., upon exposure to enzymes found in plasma, liver, red blood cells or other tissues located outside the gastrointestinal tract) and / or when a subject attempts to abuse the polysubstrate of the present invention by unintended parenteral routes (e.g., intravenous injection and / or nasal aspiration).

[0199] Specifically, the opioid antagonist releasing substrate is designed to release the bound opioid antagonist upon chemical tampering by a potential abuser. Chemical tampering methods capable of hydrolyzing the ester functional group contained within the S1 subunit in the polymatrix of the present invention, which attempt to destroy the S1 subunit saturating the digestive enzymes that mediate the release of the opioid agonist, will also effectively liberate the opioid antagonist from the S3 subunit upon oral overdose. As a result, both parenteral abuse and tampering methods that attempt to liberate the opioid agonist or negate oral overdose protection can be effectively thwarted by the presence of the S3 subunit in the polymatrix of the present invention. Suitable opioid antagonists include, but are not limited to, buprenorphine, cyclazocine, cyclorphan, naloxone, naltrexone, nalmefene, 6-amino-6-desoxo-naloxone, levallorphan, nalbuphine, naltrendole, naltrindole, nalorphine, nor-binaltorphimine, oxylorphan, pentazocine, piperidine-N-alkylcarboxylate opioid antagonists such as those described in U.S. Pat. Nos. 5,159,081, 5,250,542, 5,270,328, and 5,434,171, and derivatives, mixtures, salts, polymorphs, or prodrugs thereof.

[0200] The opioid antagonist releasing substrate may be linked to the phenol, alcohol or ketone (e.g., enol) functionalities found in naltrexone or naloxone via an ester or alternative chemically sensitive functional group, as illustrated below. [ka]

[0201] A non-limiting general example of an opioid antagonist-releasing S3 subunit comprising a chemically releasable opioid antagonist represented as NX and a linking moiety Z is shown below: [ka] (In the formula, NX is an opioid antagonist as defined above, which may preferably be naltrexone or naloxone; R is hydrogen or alkyl; Z is a linking moiety.

[0202] The general mechanism of chemically mediated release of opioid antagonists from the common S3 subunit is shown below: [ka]

[0203] In some embodiments, the S3-Z-subunit is: [ka] (In the formula, R is cyclopropylmethyl or allyl, R' is hydrogen, methyl, alkyl, aryl, substituted alkyl or substituted aryl, acyl or substituted acyl, and Z is a linker as defined herein. is selected from the group consisting of:

[0204] In some embodiments, the opioid antagonist is naltrexone or naloxone.

[0205] Representative synthetic routes useful for the preparation of S3 subunits are illustrated below. The synthesis utilizes readily available synthons, well-established chemistry, and known protecting group strategies. The reported enol-carbamate-forming opioid attachment strategy is also used (see U.S. Pat. Nos. 8,802,681, 8,685,916, 8,217,005, and 8,163,701, U.S. Pat. Nos. 8,685,916, 8,569,228, 8,497,237, and U.S. Patent Application No. 2014016935). The phenol protecting group P' used to improve chemical efficiency can be easily removed during the course of subsequent polysubstrate synthesis. (P) is an optional protecting group present at the end of the linker Z distal to the S3 subunit that may be used to improve chemical efficiency. Purification of the resulting S3 subunit can be accomplished using standard purification procedures, including normal or reverse phase chromatography, crystallization, trituration, etc. The chemical identity of the S3 subunit can be established by LC / MS and / or NMR analysis. [ka] scaffold

[0206] In some embodiments, the scaffolds (referred to herein as "shared" in the present specification) used in the preparation of the compounds of the present invention The binding scaffolds, interchangeably referred to as "binding scaffolds," are oligomeric or polymeric, such as, for example, PEG (or other polyalkylene oxides), polypeptides, polysaccharides, and biopolymers. Oligomers or polymers suitable for constructing the polymer analogs of the invention include, but are not limited to, linear, dendritic, branched, brush (or comb) polymers. In one aspect of the invention, the polymers can be polycationic materials, including natural and unnatural polyamino acids, which have a net positive charge at neutral pH, positively charged polysaccharides, and positively charged synthetic polymers. These polymers include N-vinylpyrrolidone, acrylamide, N,N-dimethylacrylamide, vinyl acetate, dextran, L-glutamic acid, L-aspartic acid, L-lysine, L-threonine, L-tyrosine, D-glutamic acid, D-aspartic acid, D-lysine, D-threonine, D-tyrosine, styrene, maleic anhydride, N-(2-hydroxypropyl)methacrylamide, N-(2-hydroxyethyl)methacrylamide, ethylene glycol, ethylene oxide, propylene glycol, propylene oxide, tetrahydrofuran, butylene glycol, tetrahydropyran, ethyl vinyl ether, non-peptide polyamines (poly(aminostyrene), poly(aminoacrylate), poly(N-methylamino)acrylate), poly(N-methylamino)acrylate, ... Poly(N,N-dimethylaminoacrylate), poly(N,N-diethylaminoacrylate), poly(aminomethacrylate), poly(N-methylamino-methacrylate), poly(N-ethylaminomethacrylate), poly(N,N-dimethylaminomethacrylate), poly(N,N-diethylaminomethacrylate), poly(ethyleneimine), etc.), polymers of quaternary amines (poly(N,N,N-trimethylaminoacrylate chloride), poly(methylacrylamidopropyltrimethylammonium chloride), etc.), and natural or synthetic polysaccharides (such as chitosan), as well as copolymers of the foregoing, including random, alternating, block, multiblock linear copolymers and star polymers.Polymers may be isotactic, syndiotactic or atactic as appropriate.Methods for synthesizing biopolymers and conjugating them to biological materials are well known in the art (see, for example, U.S. Patent Application Publication No. 20040043030; U.S. Patent No. 5,177,059; U.S. Patent No. 6,716,821; U.S. Patent No. 5,824,701; U.S. Patent No. 6,664,331; U.S. Patent No. 5,880,131; Kameda, Y. et al., Biomaterials 25:3259-3266, 2004; Thanou, M. et al., Current Opinion in Investigational Drugs 4(6):701-709, 2003; Veronese, FM et al., Il Farmaco 54:497-516, 1999).

[0207] Additionally, dendritic polymers may be used in the preparation of the compounds of the present invention. Suitable dendrimers include, but are not limited to, polyamidoamines (PAMAM) (Gunatillake et al., Macromolecules, 1988, vol. 21, p. 1556; U.S. Pat. No. 4,507,466). , polyethyleneimines (U.S. Pat. No. 4,631,337), polypropyleneimines (U.S. Pat. No. 5,530,092), and Frechet-type dendrimers terminated with amine, alcohol, or carboxylic acid surface groups (U.S. Pat. No. 5,041,516; Hawker et al., J. Am. Chem. Soc., 1991, vol. 113, p. 4583). A recent review of dendrimer synthesis is Tomalia et al., J. Polym. Sci., Part A: Polym. Chem., 2002, vol. 40, p. 2719. Polymers can be prepared by methods known in the art. They can be prepared according to the methods described above or they can be obtained from commercial sources.

[0208] In one embodiment of the invention, the molecular weight of the scaffold polymer portion of the polymer conjugate of the invention is greater than about 500 Daltons (Da), more preferably greater than about 2,000 Da. In another embodiment of the invention, the polymer has a molecular weight of about 10,000 Da to about 250,000 Da. Thus, the molecular weight range of the polymer portion of the conjugate is about 2,000 Da to about 200,000 Da, preferably about 5,000 Da to about 50,000 Da, More preferably, it can be about 7,000 Da to about 50,000 Da, or about 10,000 Da to about 50,000 Da. Polymer backbones having average molecular weights of about 5,000 Da, about 7,000 Da, about 10,000, about 15,000 Da, about 17,500 Da, about 20,000 Da, about 30,000 Da, about 35,000 Da, about 40,000 Da, about 45,000 Da, and about 50,000 Da are particularly preferred.

[0209] Commercially available polymers suitable for use in the present invention include, but are not limited to, mPEG-NH2 (MPEG-NH2 w Approximately 10 kDa, approximately 20 KDa), mPEG-OH (M w are approximately 1 kDa, 2 KDa, approximately 3 KDa, approximately 5 KDa, approximately 10 KDa, approximately 12 KDa, approximately 20 KDa), 3-arm PEG-triol (M w glycerol core of approximately 10 kDa, glycerol core of 15 kDa, and glycerol core of approximately 20 kDa), 4-arm PEG-tetrol (M w pentaerythritol core of about 2 kDa, pentaerythritol core of about 10 kDa, pentaerythritol core of about 15 kDa, pentaerythritol core of about 20 kDa), 8-arm PEG-octol (M w about 2 kDa hexaglycerin, about 10 kDa hexaglycerin, about 15 kDa hexaglycerin, about 20 kDa hexaglycerin, about 40 kDa hexaglycerin); e.g., poly(acrylic acid), M wApproximately 50 kDa, poly(1-glycerol methacrylate), poly(acrylamide-co-acrylic acid), poly(ethylene oxide-block-propylene oxide), poly(L-lysine) hydrobromide, poly(styrenesulfonic acid), poly(vinyl alcohol), poly(vinylamine) hydrochloride, poly(caprolactone)diol; O,O'-bis(2-carboxyethyl)dodecaethylene glycol, poly(allylamine), poly(antholsulfonic acid, sodium salt), poly(caprolactone)triol 1,1,1-tris(hydroxymethyl)propane core, poly(di(ethylene glycol)phthalate)diol, poly(di(ethylene glycol) / trimethylolpropane-alt-adipic acid), polyol, PEG-bis(3-aminopropyl)terminated, PEG-bis(carboxymethyl)ether, M w is approximately 250 Da, PEG-bis(carboxymethyl)ether, M w is approximately 600 Da, and PEG-block-PPG-block-PEG diol (M w are approximately 1,100 Da, approximately 1,900 Da, approximately 2,000 Da, approximately 2,800 Da, approximately 2,900 Da, approximately 4,400 Da, approximately 5,800 Da, approximately 8,400 Da, approximately 14,600 Da), PEG-ran-PPG diol (M w is about 2,500 Da, about 12,000 Da, about 970 Da, about 1,700 Da, about 3,900 Da), PEG-tetrahydrofurfuryl ether, poly(2-hydroxyethyl methacrylate), polyoxyethylene bis(amine), M w is about 2,000 Da, polyoxyethylene bis(amine), M w is about 20,000 Da, PPG diol (M w approximately 425 Da, approximately 725 Da, approximately 1,000 Da, approximately 2,000 Da, approximately 2,700 Da, approximately 3,500 Da), poly(DL-lysine) hydrobromide (M w about 1,000-4,000 Da, about 30,000-70,000 Da, about 500-2,000 Da, about 1,000-4,000 Da, about 4,000-15,000 Da, about 15,000-30,000 Da, about 30,000-70,000 Da), poly(D-lysine) hydrobromide (Mw Approximately 1,000-4,000 Da, approximately 4,000-15,000 Da, approximately 15,000-30,000 Da, approximately 30,000-70,000 Da), poly(L-tyrosine), M w is approximately 10,000 to 40,000 Da, poly(L-serine), M w is approximately 5,000-10,000 Da, poly(L-threonine), M w are approximately 5,000-15,000 Da, PAMAM dendrimer G(0)-NH2, ethylenediamine core (surface groups: 4, 8, 16, 32 or 64), PAMAM dendrimer G(2)-OH, ethylenediamine core (surface groups: 16, 32, 64), DAB-AM-4, polypropyleneiminetetraamine dendrimer (surface groups: 4, 8, 16, 32, 64), PAMAM-tris(hydroxymethyl)amidomethane dendrimer, 2nd generation, ethylenediamine core (surface groups: 48), PAMAM-tris(hydroxymethyl)amidomethane dendrimer, 3rd generation, ethylenediamine core (surface groups: 96), PAMAM-succinamic acid dendrimer, ethylenediamine core, 2nd generation (surface groups: 16), amino-dPEG 2™ t-butyl ester, Amino-dPEG4™ t-butyl ester, Amino-dPEG8™ t-butyl ester, Amino-dPEG 12 (trademark) t-butyl ester, amino-dPEG 24 (trademark) t-butyl ester, m-dPEG4 (trademark) amine, m-dPEG 12 (trademark) Amine, m-dPEG 24 (trademark) amine, Hydroxy-dPEG4(trademark) t-butyl ester, Hydroxy-dPEG8(trademark) t-butyl ester, m-dPEG 11 (trademark) Alcohol, dPEG 12 (trademark) diol, mono-Nt-boc-amido-dPEG3(trademark)-amine, mono-Nt-boc-amido-dPEG 11 (trademark)-amine, mono-Nt-CBZ-amide-dPEG3(trademark)-amine, Nt-boc-amide-dPEG4(trademark) alcohol, Nt-boc-amide-dPEG 12(trademark) alcohol, bis-dPEG5™ acid, bis-dPEG7™ acid, bis-dPEG5™ half benzyl half acid, bis-dPEG9™ half benzyl half acid, N-Fmoc-amide-dPEG2™ acid, N-Fmoc-amide-dPEG4™ acid, N-Fmoc-amide-dPEG8™ acid, N-Fmoc-amide-dPEG 12 (trademark) acid, N-Fmoc-amide-dPEG 24 (trademark) acid, N-CBZ-amide-dPEG4(trademark)-acid, N-CBZ-amide-dPEG8(trademark)-acid, N-CBZ-amide-dPEG 12 (trademark)-acid, N-CBZ-amide-dPEG 24 (trademark)-acid, Nt-boc-amide-dPEG4 (trademark)-acid, and the like.

[0210] Non-limiting examples of polymers for use in the present invention include polyesters, polyethers, poly(orthoesters), poly(vinyl alcohols), polyamides, polycarbonates, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyolefins, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidones, polyglycolides, polysiloxanes, polylactides, polyurethanes, polyethylenes, polyanhydrides, polyhydroxy acids, polypropylfumerates, polycaprolactones, polyacetals, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, olefinic polymers derived from metathesis reactions with functionalized monomers, and block polymers or copolymers thereof.

[0211] Non-limiting examples of biopolymers for use in the present invention include polyesters (such as polyhydroxyalkanoates, polylactic acid, etc.); proteins (such as silk, collagen, gelatin, elastin, resilin, adhesives, polyamino acids, soy, zein, wheat gluten, casein, serum albumin, etc.); polysaccharides (such as xanthan, dextran, gellan, levan, curdlan, polygalactosamine, cellulose, pullulan, elsinan, isopropyl alcohol, etc.); These include: starch, agar, alginate, carrageenan, pectin, konjac and various gums (e.g., guar), chitin, chitosan, hyaluronic acid, etc.); lipids / surfactants (acetoglycerides, waxes, emulsions, etc.); polyphenols (lignin, tannin, humic acid, etc.); specialty polymers (shellac, poly-gamma-glutamic acid, natural gums, synthetic gums derived from natural fats, etc.). Also included are chemically modified versions of the above biopolymers (to improve solubility / functionality in drug product formulations, to resist digestion / degradation, to facilitate chemical modification with antagonist synthons, etc.).

[0212] In one aspect of the invention, the polymer is a "charged polymer," in which case the polymer can have one or more charged groups. Charged polymers include polycations and their precursors (e.g., polybases, polyacids, etc.), polyanions and their precursors (e.g., polyacids, polybases, etc.), polymers with multiple anionic and cationic groups (e.g., multiple acidic and basic groups such as those found in various proteins), and polymers with multiple anionic and cationic groups (e.g., multiple acidic and basic groups such as those found in various proteins). Charged polymers can include a wide range of chemical species, including charged polymers (polymers having a charge of 0.1 to 0.5), ionomers (charged polymers in which a small but significant proportion of the building blocks carry a charge), and the like. Usually, the number of charged groups is so great that the polymer is soluble in polar solvents (particularly water) when in an ionically dissociated form (also called a polyion). Some charged polymers have both anionic and cationic groups (e.g., proteins) and may have a net negative charge (e.g., because the anionic groups contribute more charges than the cationic groups, referred to herein as polyanions), a net positive charge (e.g., because the cationic groups contribute more charges than the anionic groups, referred to herein as polycations), or a neutral net charge (e.g., because the cationic and anionic groups contribute equal charges). In this regard, the net charge of a particular charged polymer may vary with the pH of its surrounding environment. Charged polymers that contain both cationic and anionic groups may be classified herein as either polycations or polyanions, depending on the predominance of the groups.

[0213] Specific examples of suitable polycations include, for example, the following, among others: polyamines (including polyamidoamines), poly(amino methacrylates) (including poly(dialkylaminoalkyl methacrylates) such as poly(dimethylaminoethyl methacrylate) and poly(diethylaminoethyl methacrylate)), polyvinylamines, polyvinylpyridines (including quaternary polyvinylpyridines such as poly(N-ethyl-4-vinylpyridine), poly(vinylbenzyltrimethylamine)), polyallylamine (such as poly(allylamine hydrochloride) (PAH)) and poly(diallyldialkylamines) (such as poly(diallyidimethylammonium chloride)), spermine, spermidine, hexadimethrene bromide ... bromides (polybrene), polyimines (including polyalkyleneimines such as polyethyleneimine, polypropyleneimine and ethoxylated polyethyleneimine), basic peptides and proteins (including histone polypeptides, and homopolymers and copolymers containing lysine, arginine, ornithine and combinations thereof, including poly-L-lysine, poly-D-lysine, poly-L,D-lysine, poly-L-arginine, poly-D-arginine, poly-D,L-arginine, poly-L-ornithine, poly-D-ornithine and poly-L,D-ornithine, gelatin, albumin, protamine and protamine sulfate), and polycationic polysaccharides, such as cationic starch and chitosan, as well as copolymers, derivatives and combinations of the above. Preferred polymers for use in the present invention include poly(d-glutamic acid), poly(dl-glutamic acid), poly(l-aspartic acid), poly(d-aspartic acid), poly(dl-aspartic acid), poly(l-lysine), poly(d-lysine), poly(dl-lysine), and copolymers of polyamino acids, and polymers of N-methyl derivatives of amino acids.Other preferred polymers include polyethylene glycol (PEG), as well as poly(2-hydroxyethyl-1-glutamine), chitosan, carboxymethyldextran, hyaluronic acid, human serum albumin, and alginic acid.

[0214] Specific examples of suitable polyanions include, for example, the following, among others: polysulfonates (such as polyvinylsulfonate), poly(styrenesulfonate) (such as poly(sodium styrenesulfonate) (PSS)), sulfonated poly(tetrafluoroethylene), sulfonated polymers (such as those described in U.S. Pat. No. 5,840,387) (such as sulfonated styrene-ethylene / butylene-styrene triblock copolymers, sulfonated styrene homopolymers and copolymers (such as the sulfonated versions of polystyrene-polyolefin copolymers described in U.S. Pat. No. 6,545,097 to Pinchuk et al. (which polymers can be sulfonated using the methods described, for example, in U.S. Pat. Nos. 5,840,387 and 5,468,574), as well as sulfonated versions of various other homopolymers and copolymers), polysulfates (polyvinyl Glycosaminoglycans, sulfated and non-sulfated, and certain proteoglycans, such as heparin, heparin sulfate, chondroitin sulfate, keratan sulfate, dermatan sulfate, polycarboxylates (acrylic acid polymers and their salts, such as ammonium, potassium, sodium, etc.), e.g., Atofina and Polysciences The polysaccharides may be selected from those available from Polysaccharide Corporation, Inc., methacrylic acid polymers and salts thereof (e.g., Eudragit, methacrylic acid and ethyl acrylate copolymers), carboxymethylcellulose, carboxymethyl amylose, and carboxylic acid derivatives of various other polymers, polyanionic peptides and proteins (such as glutamic acid polymers and copolymers, aspartic acid polymers and copolymers), polymers and copolymers of uronic acids (such as mannuronic acid, galacturonic acid and guluronic acid, and salts thereof), alginic acid and sodium alginate, hyaluronic acid, gelatin and carrageenan, polyphosphates (such as phosphoric acid derivatives of various polymers), polyphosphonates (such as polyvinyl phosphonates), polysulfates (such as polyvinyl sulfate), and copolymers, derivatives and combinations of the foregoing.

[0215] Exemplary natural polymers include naturally occurring polysaccharides (e.g., arabinan, fructan, fulcan, galactan, galacturonan, glucan, mannan, xylan (e.g., inulin, etc.), levan, fucoidan, carrageenan, galatocarolose, pectic acid, pectin (including amylose), pullulan, glycogen, amylopectin, cellulose, dextran, dextrin, dextrose, glucose, polyglucose, polydextrose, pustulan, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, alginic acid, xanthan gum, starch, etc.), and various other natural homopolymers or heteropolymers (e.g., the following aldoses, ketoses, acids or amines: erythrose, threose ... and those containing one or more of the following naturally occurring derivatives: sucrose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, dextrose, mannose, gulose, idose, galactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, mannitol, sorbitol, lactose, sucrose, trehalose, maltose, cellobiose, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine, and neuraminic acid, and naturally occurring derivatives thereof. Thus, suitable polymers include, for example, proteins such as albumin, silk, collagen, elastin, resilin, polyamino acids, soy, wheat gluten and casein.

[0216] Non-limiting examples of polyesters include polylactic acid, polyglycolic acid, poly(lactide-co-glycolide), poly(e-caprolactone), polydioxanone, poly(ethylene terephthalate), poly(malic acid), poly(tartronic acid), polyphosphazene, poly(orthoesters), poly(valeric acid), poly(buteric acid), poly Included are hydroxybutyrate, polyhydroxyvalerate, polyanhydrides, and copolymers of the monomers used to synthesize any of the above polymers (e.g., poly(lactic-co-glycolic acid) (PLGA)), or copolymers of polyhydroxybutyrate and hydroxyvaleric acid.

[0217] Non-limiting examples of polyesters include polylactic acid, polyglycolic acid, poly(lactide-co-glycolide), poly(ε-caprolactone), polydioxanone, poly(ethylene terephthalate), poly(malic acid), poly(tartronic acid), polyphosphazenes, poly(orthoesters), poly(valeric acid), poly(butyric acid), polyhydroxybutyrate, polyhydroxyvalerate, polyanhydrides, and polymers synthesized from any of the above polymers. Copolymers of monomers used to form the polymeric polymeric polymers include copolymers of monomers such as poly(lactic-co-glycolic acid) (PLGA) or copolymers of polyhydroxybutyrate and hydroxyvaleric acid.

[0218] Polyethers and poly(orthoesters) can also be used to prepare polymer conjugates for use in the present invention. These polymers can be incorporated into multiple blocks, resulting in block polymers with various degradation rates, mechanical strength, porosity, diffusivity and intrinsic viscosity. Examples of polyethers include polyethylene glycol and polypropylene glycol. An example of a multiple block copolymer is poly(ether ester amide). In addition, triblock copolymers of poly(orthoesters) with various poly(ethylene glycol) contents are useful for stabilizing them in water / oil (w / o) emulsions. Other useful block copolymers include diblock copolymers of poly(lactic acid-co-glycolic acid) and poly(ethylene glycol) (PEG), triblock copolymers of PEG-PLGA-PEG, copolymers of PLGA and polylysine, and poly(ester ether) block copolymers.

[0219] In one aspect of the invention, the polymer is poly(ethylene glycol) (PEG) or a related poly(alkylene glycol). The term PEG includes poly(ethylene glycol) in any of its forms, including linear forms (e.g., alkoxy PEG or bifunctional PEG), branched or multi-arm forms (e.g., forked PEG or PEG attached to a polyol core), pendant PEG, etc. The general formula for PEG is -CH2CHO-(CH2CHO). n -CH2CH2-, where n is from about 0 to about 500, usually from about 2 to about 200. Similar polymers can also be derived from polypropylene glycol and related poly(alkylene) glycols.

[0220] Multi-armed or branched PEG molecules, such as those described in US Patent No. 5,932,462, can also be used as PEG polymers.Generally speaking, multi-armed, branched, or star-shaped or dendritic polymers have two or more polymer arms extending from a central branch point that is covalently bonded directly or indirectly through an intervening connecting atom to one or more active moieties, such as opioid agonists, antagonists or digestive enzyme inverting substrates.It is understood by those skilled in the art that the term poly(ethylene glycol) or PEG refers to or includes all of the above forms of PEG or poly(alkylene glycol).

[0221] Preferred scaffolds selected from those listed above that are most useful in constructing the polymatrix of the present invention are: (i) readily commercially available; (ii) contain a sufficient number and type of chemically available functional groups (e.g., carboxylate, amine, thiol, alcohol, isocyanate, etc.); (iii) efficiently undergo the coupling chemistry required to attach the desired number of S1, S2 and optionally S3 subunits; and (iv) result in polymatrix products with desirable physicochemical (e.g., solubility, stability, release of opioid antagonist in vitro upon chemical tampering, etc.) and biological (e.g., selective enzymatic release of opioid agonist in vivo, protection against overdose by enzyme saturation, release of opioid antagonist in systemic circulation, etc.) profiles. Compounds of the Invention

[0222] In some embodiments, the compounds of the invention have the formula: [ka] (In the formula, S1 is a non-opioid releasing enzyme substrate or inhibitor; S2 is an opioid agonist releasing enzyme substrate; S3 is an on-demand opioid antagonist releasing moiety; Z is a linker moiety as previously described, n is an integer ranging from 1 to 10; m is an integer ranging from 1 to 10; p and r are each independently an integer ranging from 0 to 10. has.

[0223] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; R 1 and R 2 are each independently R or R′, or R 1 and R 2 can be linked to form an optionally substituted spirocyclic ring; R 3 is R″ or R 3 is R 1 Or R 2 and linked to form an optionally substituted heterocyclic ring, Each R is independently hydrogen, methyl, or alkyl, e.g., lower alkyl, and each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, a natural or unnatural amino acid side chain, an amino acid side chain mimetic, -Z-(S2) n , or -Z-(S x ) n and Z is a linking moiety, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, -Z-(S2) n Or -Z-(S x ) n and Z is a linking moiety, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; R 4is hydrogen, methyl, -C(=NR)-NR2 (wherein each R is independently hydrogen or methyl), or a group of the formula: [ka] and each A2 is independently an amino acid side chain or an amino acid side chain mimetic capable of being recognized by a digestive enzyme; n is an integer ranging from 1 to 10; and r is an integer ranging from 1 to 6.

[0224] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; R 1 , R 2 and R 3 can be R', or R 2 and R 3 can be linked to form an optionally substituted spirocyclic ring; R 2 Or R 3 is R 1 can be linked to form an optionally substituted heterocyclic ring, R 2 Or R 3 can be joined with R' to form an optionally substituted ring, or R' can be linked with a geminal R' to thereby form an optionally substituted spirocyclic ring; Each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyethylene glycol, or a polyethylene glycol-containing moiety, or a linking moiety Z, or -Z-(S2).n Or -Z-(S x ) n and Z is as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0225] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0226] In some embodiments, A2 directs the site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. 2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0227] Each of the compounds of the invention can contain various numbers of S1, S2, or S3 subunits, as described throughout. In some embodiments, the molar ratio of S1 to S2 ranges from 1 to 2, 1 to 4, 1 to 8, or 1 to 10, and an S1 subunit is derived from each of the S2 subunits. However, one of skill in the art will recognize that compounds of the invention having various ratios of S1 to S2 and S3 can be readily achieved and are within the scope of the invention.

[0228] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; A2 is an amino acid side chain or an amino acid side chain mimetic that can be recognized by a digestive enzyme; Each Z is independently a linking moiety.

[0229] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; A2 is an amino acid side chain or amino acid side chain mimic that can be recognized by digestive enzymes. It is an imitation, Each Z is independently a linking moiety; R is cyclopropylmethyl or allyl; R' is each or independently hydrogen or methyl.

[0230] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; A2 is an amino acid side chain or an amino acid side chain mimetic capable of being recognized by a GI enzyme, Each Z is a linking moiety, R'' is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or one or more amino acids or structural or functional mimetics thereof).

[0231] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; S3 is an opioid antagonist releasing moiety, A2 is an amino acid side chain or an amino acid side chain mimetic that can be recognized by a digestive enzyme; R is cyclopropylmethyl or allyl; Each Z is a linking moiety, R'' is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or one or more amino acids or structural or functional mimetics thereof).

[0232] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; each S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; A2 is an amino acid side chain or an amino acid side chain mimetic that can be recognized by a digestive enzyme; Each Z is a linking moiety.

[0233] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; A2 is an amino acid side chain or an amino acid side chain mimetic that can be recognized by a digestive enzyme; R″ is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or one or more amino acids or structural or functional mimetics thereof; Each Z is a linking moiety.

[0234] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; S3 is an opioid antagonist releasing moiety, A2 is an amino acid side chain or an amino acid side chain mimetic that can be recognized by a digestive enzyme; R is cyclopropylmethyl or allyl; Each Z is a linking moiety, R' is each or independently hydrogen or methyl.

[0235] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; A2 is an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme, and Z is each a linking moiety.

[0236] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; Each Z is independently a linking moiety; Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0237] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is each independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10, r is each or independently an integer from 1 to 6, n is an integer from 0 to 10, R''' is hydrogen, methyl, or -C(=NR)-NR2, and R is each or independently hydrogen or methyl; [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0238] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0239] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; S3 is an opioid antagonist releasing moiety, R is cyclopropylmethyl or allyl; Each Z is independently a linking moiety; Each R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyethylene glycol or a polyethylene glycol-containing moiety, or a linking moiety Z, or -Z-(S2). n Or -Z-(S x ) n and Z is as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0240] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0241] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0242] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; S3 is an opioid antagonist releasing moiety, R is cyclopropylmethyl or allyl; Each Z is independently a linking moiety; A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0243] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing acyl, -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0244] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0245] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit, respectively; Each Z is independently a linking moiety; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x )n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0246] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0247] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0248] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; S3 is an opioid antagonist releasing moiety, Each Z is independently a linking moiety; X is OH or hydrogen; R is cyclopropylmethyl or allyl; R' is each and independently hydrogen or methyl; Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0249] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0250] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0251] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit; Z is a linking moiety, Each A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0252] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0253] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0254] In another embodiment, the composition of the present invention comprises a compound of the formula: [ka] (In the formula, S1 is a non-opioid releasing enzyme substrate or inhibitor; S2 is an opioid agonist releasing enzyme substrate; S3 is an on-demand opioid antagonist releasing moiety; M is a covalent scaffold; Z is a linker moiety as previously described, r, m, and n each independently represent an integer ranging from 1 to 10, 1 to 100, 1 to 1,000, 1 to 100,000, 1 to 1,000,000, or 1 to 1,000,000,000; p is an integer in the range of 0-10, 0-100, 0-1,000, 0-100,000, 0-1,000,000, or 0-1,000,000,000. It is represented by:

[0255] In some embodiments, M is carboxymethylcellulose or a functionalized cellulose derivative, chitosan, or a poly[amino acid].

[0256] In some embodiments, the compounds of the invention are represented by the following structure: [ka] (In the formula, each S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; each S2 is independently an opioid agonist-releasing GI enzyme substrate; S3 is an on-demand opioid antagonist releasing substrate, Each R is independently -H or -CHCOOH; Each Z is independently a linking moiety as previously defined; R' is -OR1 or -NR1R2, where R1 and R2 are each or independently hydrogen, methyl, lower alkyl, or terminally functionalized polyethylene glycol; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9.

[0257] In some embodiments, the carboxymethyl cellulose polymer scaffold can have a molecular weight in the range of about 50-1000 kDa. In some embodiments, the scaffold comprises between 100-10,000, e.g., between 300-6,000 anhydroglucose subunits. In some embodiments, the scaffold has a degree of substitution of 0.65-0.85 carboxymethyl groups per anhydroglucose unit, e.g., a total of about 100-6,000 carboxymethyl substituted monomeric units. The number of S1 substituted monomeric units, n, can be about 1-10, 20, 30, 40, or 50% of the total number of carboxymethyl substituted monomeric units. The number of S2 substituted monomeric units, m, can be about 1-10, 20, 30, 40, or 50% of the total number of carboxymethyl substituted monomeric units. The number of S3 substituted monomeric units, r, can be about 0-10, 20, 30, 40, or 50% of the total number of carboxymethyl substituted monomeric units. The number of R' substituted monomeric units, x, can be about 0 to 10, 20, 30, 40, 50, or 90% of the total number of carboxymethyl substituted monomeric units. In a preferred embodiment, the covalent attachment of the S1, S2, S3, and R' bonds to the defined functional groups contained in the monomeric units of the polymer scaffold occurs regiochemically random, resulting in a random distribution of the S1, S2, S3, and R' bonds of the polymer scaffold.

[0258] In some embodiments, the compounds of the invention are represented by the following structure: [ka] (In the formula, each S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; each S2 is independently an opioid agonist-releasing GI enzyme substrate; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit, respectively; Each Z is independently a linking moiety as previously defined; R' is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or one or more amino acids or structural mimetics thereof; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9.

[0259] In some embodiments, the scaffold can have a molecular weight in the range of about 30-300 kDa. In some embodiments, the scaffold comprises between about 100 and about 3,000 glucosamine subunits, for example, about 150 to about 2,000 glucosamine subunits. The number of S1 substituted monomer units, n, can be about 1-50% of the total number of glucosamine monomer units. The number of S2 substituted monomer units, m, can be about 1-50% of the total number of glucosamine monomer units. The number of S3 substituted monomer units, r, can be about 0-50% of the total number of glucosamine monomer units. The number of R' substituted monomer units, x, can be about 0-90% of the total number of glucosamine monomer units. In a preferred embodiment, the covalent attachment of the S1, S2, S3 and R' bonds to defined functional groups contained in the monomer units of the polymer scaffold occurs regiochemically random, resulting in a random distribution of the S1, S2, S3 and R' bonds of the polymer scaffold.

[0260] In some embodiments, the compounds of the invention are represented by the following structure: [ka] (In the formula, each S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; each S2 is independently an opioid agonist-releasing GI enzyme substrate; S3 is an opioid antagonist releasing substrate, Each Z is independently a linking moiety as previously defined; R' is -OR1 or -NR1R2, where R1 and R2 are each or independently hydrogen, methyl, lower alkyl, or terminally functionalized polyethylene glycol; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9.

[0261] In some embodiments, the scaffold can have a molecular weight in the range of about 200-1000 kDa. In some embodiments, the scaffold comprises polyglutamic acid subunits in the range of about 1,000-7,000. The number of S1 substituted monomer units, n, can be about 1-50% of the total number of polyglutamic acid monomer units. The number of S2 substituted monomer units, m, can be about 1-50% of the total number of polyglutamic acid monomer units. The number of S3 substituted monomer units, r, can be about 0-50% of the total number of polyglutamic acid monomer units. The number of R' substituted monomer units, x, can be about 0-90% of the total number of polyglutamic acid monomer units. In a preferred embodiment, the covalent linkage of the S1, S2, S3 and R' bonds to the defined functional groups contained in the monomer units of the polymer scaffold occurs regiochemically random, resulting in a random distribution of the S1, S2, S3 and R' bonds of the polymer scaffold.

[0262] In some embodiments, the compounds of the invention are represented by the following structure: [ka] (In the formula, each S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; each S2 is independently an opioid agonist-releasing GI enzyme substrate; S3 is an opioid antagonist releasing substrate, Each Z is independently a linking moiety as previously defined; R' is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or one or more amino acids or structural mimetics thereof; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9.

[0263] The starting polylysine polymer can have a molecular weight in the range of about 30-300 kDa containing lysine subunits in the range of 150-2,000. The number of S1 substituted lysine monomer units, n, can be about 1-50% of the total number of lysine monomer units. The number of S2 substituted monomer units, m, can be about 1-50% of the total number of lysine monomer units. The number of S3 substituted monomer units, r, can be about 0-50% of the total number of lysine monomer units. The number of R' substituted monomer units, x, can be about 0-90% of the total number of lysine monomer units. In a preferred embodiment, the covalent linkage of the S1, S2, S3 and R' bonds to the defined functional groups contained in the monomer units of the polymer scaffold occurs regiochemically random, resulting in a random distribution of the S1, S2, S3 and R' bonds of the polymer scaffold.

[0264] In some embodiments, the compounds of the invention are represented by the following structure: [ka] (In the formula, each S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; each S2 is independently an opioid agonist-releasing GI enzyme substrate; S3 is an opioid antagonist releasing substrate, Each Z is independently a linking moiety as previously defined; R is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, an amino acid side chain or a structural mimetic of an amino acid side chain; X can be oxygen or nitrogen; R' is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyethylene glycol-containing alkyl, or one or more amino acids; n is an integer from 1 to 10, m is an integer from 1 to 10; r is an integer from 0 to 10; where x is an integer from 0 to 10.

[0265] In some embodiments, the polypeptide scaffold can be comprised of a range of 2-40 natural or unnatural amino acid monomer units. The number of S1 substituted monomer units, n, can be about 1-50% of the total number of monomer units. The number of S2 substituted monomer units, m, can be about 1-50% of the total number of monomer units. The number of S3 substituted monomer units, r, can be about 0-50% of the total number of monomer units. The number of R' substituted monomer units, x, can be about 0-50% of the total number of monomer units. In a preferred embodiment, the S1, S2, S3 and R' substituted monomer units can be regiochemically randomly distributed.

[0266] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate subunit or a GI enzyme inhibitor, respectively; S3 is an opioid antagonist releasing moiety, R is cyclopropylmethyl or allyl; Each Z is a linking moiety, R″ is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or one or more amino acids or structural or functional mimetics thereof; R' is H or -CH2COOH; W can be oxygen or nitrogen; R''' is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyethylene glycol-containing alkyl, or one or more amino acids; A2 is an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme, for example, A2 can be the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine or a structural / functional mimic thereof; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9.

[0267] In some embodiments, the carboxymethylcellulose scaffold can have a molecular weight in the range of about 50-1000 kDa. In some embodiments, the scaffold comprises anhydroglucose subunits in the range of 300-6,000. In some embodiments, the scaffold has a degree of substitution of 0.65-0.85 carboxymethyl groups per anhydroglucose unit, resulting in a total of about 100-6,000 carboxymethyl-substituted monomeric units. The number of substituted monomeric units, n, can be about 1-50% of the total number of carboxymethyl-substituted monomeric units. The number of substituted monomeric units, m, can be about 1-50% of the total number of carboxymethyl-substituted monomeric units. The number of substituted monomeric units, r, can be about 0-50% of the total number of carboxymethyl-substituted monomeric units. The number of substituted monomeric units, x, can be about 0-90% of the total number of carboxymethyl-substituted monomeric units. In a preferred embodiment, the covalent attachment of the defined bonds to the monomeric units of the polymeric scaffold occurs regiochemically random, resulting in a random distribution of bonds in the polymeric scaffold.

[0268] In some embodiments, the compounds of the invention are represented by the following structure: [ka] (In the formula, R' is H or -CH2COOH; R is cyclopropylmethyl or allyl; X is OH or hydrogen; Each Z is independently a linking moiety as previously defined; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9; A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0269] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0270] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0271] The carboxymethylcellulose scaffold can have a molecular weight in the range of about 50-1000 kDa. In some embodiments, the scaffold comprises anhydroglucose subunits in the range of 300-6,000. In some embodiments, the scaffold has a degree of substitution of 0.65-0.85 carboxymethyl groups per anhydroglucose unit, resulting in a total of about 100-6,000 carboxymethyl-substituted monomeric units. The number of substituted monomeric units, n, can be about 1-50% of the total number of carboxymethyl-substituted monomeric units. The number of substituted monomeric units, m, can be about 1-50% of the total number of carboxymethyl-substituted monomeric units. The number of substituted monomeric units, r, can be about 0-50% of the total number of carboxymethyl-substituted monomeric units. The number of R″-substituted monomeric units, x, can be about 0-90% of the total number of carboxymethyl-substituted monomeric units. In a preferred embodiment, the defined functional groups contained in the monomeric units of the polymer scaffold are The covalent attachment of the Z and R'' bonds to the groups occurs regiochemically random, resulting in a random distribution of bonds in the polymer scaffold.

[0272] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; each S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; S3 is an opioid antagonist releasing moiety, R is cyclopropylmethyl or allyl; Each Z is a linking moiety, R″ is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or one or more amino acids or structural or functional mimetics thereof; R' is each and independently hydrogen or methyl; A2 is an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme, for example, A2 can be the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine or a structural / functional mimic thereof; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9.

[0273] The chitosan scaffold can have a molecular weight in the range of about 30-300 kDa containing glucosamine subunits in the range of 150-2,000. The number of substituted monomer units, n, can be about 1-50% of the total number of glucosamine monomer units. The number of substituted monomer units, m, can be about 1-50% of the total number of glucosamine monomer units. The number of substituted monomer units, r, can be about 0-50% of the total number of glucosamine monomer units. The number of R″ substituted monomer units, x, can be about 0-90% of the total number of glucosamine monomer units. In a preferred embodiment, the covalent linkage of S1, S2, S3 and R″ bonds to the defined functional groups contained in the monomer units of the polymer scaffold occurs regiochemically random, resulting in a random distribution of bonds in the polymer scaffold.

[0274] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, R' is each and independently hydrogen or methyl; R is cyclopropylmethyl or allyl; Each Z is independently a linking moiety as previously defined; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9; A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0275] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by digestive enzymes leading to site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit, including but not limited to the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or structural / functional mimics thereof; R'' is as defined above. It can be said that:

[0276] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0277] The chitosan polymer scaffold can have a molecular weight in the range of about 30-300 kDa containing a range of 150-2,000 glucosamine subunits. The number of substituted monomer units, n, can be about 1-50% of the total number of glucosamine monomer units. The number of substituted monomer units, m, can be about 1-50% of the total number of glucosamine monomer units. The number of substituted monomer units, r, can be about 0-50% of the total number of glucosamine monomer units. The number of R″ substituted monomer units, x, can be about 0-90% of the total number of glucosamine monomer units. R′ is each or independently hydrogen or methyl. In a preferred embodiment, the covalent linkage of Z and R″ bonds to the defined functional groups contained in the monomer units of the polymer scaffold occurs regiochemically random, resulting in a random distribution of bonds in the polymer scaffold.

[0278] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; each S1 is independently a non-opioid releasing GI enzyme substrate or a GI enzyme inhibitor; S3 is an opioid antagonist releasing moiety, R is cyclopropylmethyl or allyl; Each Z is a linking moiety, R″ is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or one or more amino acids or structural or functional mimetics thereof; A2 is an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme, for example, A2 can be the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine or a structural / functional mimic thereof; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9.

[0279] The polyglutamic acid polymers can have molecular weights ranging from about 200 to 1000 kDa, containing polyglutamic acid subunits ranging from about 1000 to 7,000. The number of substituted monomer units, n, can be about 1-50% of the total number of polyglutamic acid monomer units. The number of substituted monomer units, m, can be about 1-50% of the total number of polyglutamic acid monomer units. The number of substituted monomer units, r, can be about 0-50% of the total number of polyglutamic acid monomer units. The number of R″ substituted monomer units, x, can be about 0-90% of the total number of polyglutamic acid monomer units. In a preferred embodiment, the covalent linkage of Z and R″ bonds to the defined functional groups contained in the monomer units of the polymer scaffold occurs regiochemically random, resulting in a random distribution of bonds in the polymer scaffold.

[0280] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, X is OH or hydrogen; Each Z is independently a linking moiety as previously defined; W is hydrogen or -OH, X' is -OH, -OR'', or -NH2 or -NHR'' or -N(R'')2; R is cyclopropylmethyl or allyl; R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9; A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0281] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by digestive enzymes leading to site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit, including but not limited to the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or structural / functional mimics thereof; R'' is as defined above. It can be said that:

[0282] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0283] The polyglutamic acid polymer can have a molecular weight in the range of about 200-1000 kDa containing polyglutamic acid subunits in the range of about 1000-7,000. The number of substituted monomer units, n, can be about 1-50% of the total number of polyglutamic acid monomer units. The number of substituted monomer units, m, can be about 1-50% of the total number of polyglutamic acid monomer units. The number of substituted monomer units, r, can be about 0-50% of the total number of polyglutamic acid monomer units. The number of R″ substituted monomer units, x, can be about 0-90% of the total number of polyglutamic acid monomer units. In a preferred embodiment, the covalent linkage of Z and R″ bonds to the defined functional groups contained in the monomer units of the polymer scaffold occurs regiochemically random, resulting in a random distribution of bonds in the polymer scaffold.

[0284] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, Each Z is independently a linking moiety as previously defined; R' is each and independently hydrogen or methyl; X is hydrogen or -OH; R is cyclopropylmethyl or allyl; R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; n is an integer such that n / (m+n+r+x) is between 0.01 and 0.5; m is an integer such that m / (m+n+r+x) is between 0.01 and 0.5; r is an integer such that r / (m+n+r+x) is between 0 and 0.5; x is an integer such that x / (m+n+r+x) is between 0 and 0.9; A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0285] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0286] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0287] The polylysine scaffold can have a molecular weight ranging from about 30-300 kDa containing lysine subunits ranging from 150-2,000. The number of substituted lysine monomer units, n, can be about 1-50% of the total number of lysine monomer units. The number of substituted monomer units, m, can be about 1-50% of the total number of lysine monomer units. The number of substituted monomer units, r, can be about 0-50% of the total number of lysine monomer units. The number of R″ substituted monomer units, x, can be about 0-90% of the total number of lysine monomer units. In a preferred embodiment, the covalent linkage of Z and R″ to the defined functional groups contained in the monomer units of the polymer scaffold occurs regiochemically random, resulting in a random distribution of bonds in the polymer scaffold.

[0288] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, D is an opioid agonist, for example, where D is morphone, codon, or morphine; X is OH or hydrogen; S1 is a non-opioid releasing GI enzyme substrate or GI enzyme inhibitor subunit, respectively; S3 is an opioid antagonist releasing moiety, R is cyclopropylmethyl or allyl; Each Z is a linking moiety, R″ is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or one or more amino acids or structural or functional mimetics thereof; R' is hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, an amino acid side chain or a structural mimetic of an amino acid side chain; W is OH, O-alkyl, NH, NHR or N(R); A2 is an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme, for example, A2 can be the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine or a structural / functional mimic thereof; n is an integer from 1 to 10, m is an integer from 1 to 10; r is an integer from 0 to 10; where x is an integer from 0 to 10.

[0289] In some embodiments, the polypeptide scaffold can be comprised of between 2 and 40 natural or unnatural amino acid monomeric units. The number of substituted monomeric units, n, can be between about 1 and 50% of the total number of monomeric units. The number of substituted monomeric units, m, can be between about 1 and 50% of the total number of monomeric units. The number of substituted monomeric units, r, can be between about 0 and 50% of the total number of monomeric units. The number of R' substituted monomeric units, x, can be between about 0 and 50% of the total number of monomeric units. All possible regiochemical distributions of Z and R' containing bonds in the peptide backbone are encompassed within the scope of the present invention.

[0290] In some embodiments, the compounds of the invention are represented by one of the following structures: [ka] (In the formula, Each Z is independently a linking moiety as previously defined; X is hydrogen or -OH; R is cyclopropylmethyl or allyl; R' is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or Z, a linker moiety as previously defined; Each R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each S x (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; A2 is independently an amino acid side chain or an amino acid side chain mimic that can be recognized by a digestive enzyme).

[0291] In some embodiments, A2 is: [ka] (In the formula, R is each or independently hydrogen or methyl, and R″ is independently hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, acyl, substituted acyl group, polyethylene glycol-containing acyl, polyethylene glycol-containing alkyl, or a natural or unnatural amino acid, amino acid mimetic, or -Z-(S2) n Or -Z-(S x ) n and Z is a linker moiety as previously defined, Each x is independently 1 or 3 (whereby each Sx (represented as S1 or S3 subunits), n is an integer ranging from 1 to 10; each r is independently an integer from 1 to 6; n is an integer from 0 to 10, R''' is hydrogen, methyl or -C(=NR)-NR2, where R is each or independently hydrogen or methyl; or [ka] and A2 is a natural or unnatural amino acid side chain or amino acid side chain mimic that can be recognized by a digestive enzyme leading to site-specific hydrolysis of the S2 substrate prior to release of the bound opioid agonist from the S2 subunit, including but not limited to, the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimic thereof, and R″ is as defined above. It can be said that:

[0292] In some embodiments, A2 directs site-specific hydrolysis of the S2 substrate before the bound opioid agonist is released from the S2 subunit. In some embodiments, A2 is the amino acid side chain of arginine, homoarginine, lysine, homolysine, ε-N-methyllysine, ornithine, or a structural / functional mimetic thereof.

[0293] In some embodiments, the polypeptide scaffold can be comprised of between 2 and 20 natural or unnatural amino acid monomeric units. The number of substituted monomeric units, n, can be between about 1 and 50% of the total number of monomeric units. The number of substituted monomeric units, m, can be between about 1 and 50% of the total number of monomeric units. The number of substituted monomeric units, r, can be between about 0 and 50% of the total number of monomeric units. The number of R' substituted monomeric units, x, can be between about 0 and 50% of the total number of monomeric units. All possible regiochemical distributions of Z and R' bonds on the peptide backbone are encompassed within the scope of the present invention.

[0294] In certain embodiments, the present disclosure provides compounds in which an opioid agonist is covalently attached to a GI enzyme inhibitor or substrate to reduce the effect of the opioid agonist. The opioid agonist may be covalently attached to a GI enzyme inhibitor through a scaffold, such as an optionally substituted alkyl scaffold or an optionally substituted heteroalkyl scaffold. In certain embodiments, the scaffold comprises 1-100 atoms, such as about 5-50 atoms. In certain embodiments, there is no scaffold and the opioid agonist is directly attached to the GI enzyme inhibitor. In certain embodiments, the compounds of the present disclosure have the structure of formula (I): [ka] or a salt thereof, wherein Q is independently selected from optionally substituted heteroalkyl and optionally substituted alkyl; L 1 is independently at each occurrence absent, a cleavable linker or a non-cleavable linker; L 2 is independently at each occurrence absent, a cleavable linker or a non-cleavable linker; R 1 is independently selected from GI enzyme substrates and GI enzyme inhibitors for each occurrence, R 2is an opioid agonist covalently bound to a GI enzyme substrate, m and n are independently selected at each occurrence from 1 to 1,000,000.

[0295] In some embodiments, with respect to compounds or salts of Formula (I), Q is an optionally substituted heteroalkyl group.

[0296] In some embodiments, with respect to compounds or salts of Formula (I), Q is an optionally substituted peptide.

[0297] In certain embodiments, with respect to a compound or salt of formula (I), Q is an optionally substituted heteroalkyl group. Heteroalkyl includes an alkyl chain interrupted by one or more heteroatoms, such as O, N, or S. The heteroalkyl chain can include from about 4 to about 100 atoms. The heteroalkyl chain can be optionally substituted with one or more substituents. In certain embodiments, the heteroalkyl is a peptide, such as -ala-gly- or -arg-ala-.

[0298] In some embodiments, for compounds or salts of formula (I), Q is an optionally substituted peptide having 1-500 amino acids. In some embodiments, for compounds or salts of formula (I), Q is an optionally substituted peptide having 1-50 amino acids. In some embodiments, for compounds or salts of formula (I), Q is an optionally substituted peptide having 1-10 amino acids. In some embodiments, for compounds or salts of formula (I), Q is an optionally substituted peptide having 1-3 amino acids.

[0299] In some embodiments, the compound or salt of formula (I) has the structure of formula (IA), (IB) or (IC): [ka] wherein W is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, and optionally substituted alkoxycarbonyl. It is represented by:

[0300] In some embodiments, the compound or salt of formula (I) has the structure of formula (ID), (IE) or (IF): [ka] It is represented by:

[0301] In some embodiments, R 1 is independently selected at each occurrence from a GI enzyme inhibitor. 1 Q, at each occurrence, with respect to a compound or salt of Formula (I), is a serine protease inhibitor.

[0302] In some embodiments, with respect to the compound or salt of formula (I), R 1 -L 1 is the following: [ka] (In the formula, Y is independently selected from amidine, guanidine, benzylamine, alkyl-substituted amidine, alkyl-substituted guanidine, alkyl-substituted benzylamine, benzylguanidine, alkyl-substituted benzylamidine, or alkyl-substituted benzyl; Z is independently selected from hydrogen, cyano, nitro, halogen, alkyl and alkoxy. are independently selected for each occurrence from

[0303] In some embodiments, with respect to compounds or salts of Formula (I), Y is an amidine.

[0304] In some embodiments, with respect to the compound or salt of formula (I), R1 -L 1 is the expression: [ka] It is represented by:

[0305] In some embodiments, with respect to the compound or salt of formula (I), L 1 Each occurrence is selected from a cleavable or non-cleavable linker containing 2 to 15 atoms.

[0306] In some embodiments, with respect to the compound or salt of formula (I), L 1 is -O-CH2-CH2-NH- or -O-CH2-CH2-O-.

[0307] In some embodiments, with respect to a compound or salt of formula (I), n is selected from 1 to 20. In some embodiments, with respect to a compound or salt of formula (I), n is selected from 1 to 10. In some embodiments, with respect to a compound or salt of formula (I), n is selected from 1 to 3.

[0308] In some embodiments, with respect to the compound or salt of formula (I), R 2 -L 2 is the following: [ka] (In the formula, D is an opioid agonist, R 101 and R 102 are independently selected from optionally substituted alkyl, amino acid side chains, and amino acid side chain mimetics. are independently selected for each occurrence from

[0309] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It is understood that "substituted" or "substituted by" includes the implicit proviso that such substitution is subject to the permissible valences of the atom and substituent being replaced, as well as the implicit proviso that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permissible substituents can be one or more and can be the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of such heteroatoms.

[0310] In some embodiments, a substituent may be any substituent described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazino (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -Rb -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a)2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2), optionally substituted by R a are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl; R a Each of these is, allowing valence, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(Ra )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2), optionally substituted by R b are each independently selected from a direct bond, or a straight or branched alkylene, alkenylene, or alkynylene chain; R c are each a straight or branched alkylene, alkenylene or alkynylene chain.

[0311] In certain embodiments, the linker L 1 or L 2 is selected from in vitro or in vivo cleavable linkers. Cleavable linkers may include chemically or enzymatically unstable or degradable linkages. The cleavable linkers described herein rely on gastrointestinal processes, such as exposure to acidic conditions and exposure to GI enzymes, to cleave the linker. Cleavable linkers generally incorporate one or more chemical bonds that are either chemically or enzymatically cleavable, while the remaining portion of the linker is non-cleavable.

[0312] In certain embodiments, the linker L 1 or L 2is selected from non-cleavable linkers. In certain embodiments, non-cleavable linkers are not cleaved by gastrointestinal processes. Exemplary linkers of the present disclosure include the following: [ka] wherein Each F is independently [ka] and During the ceremony, each R is independently hydrogen, methyl, lower alkyl, aryl, or arylalkyl; X can be carbon, oxygen or nitrogen; L can be a linear, branched or polyvalent scaffold comprised of alkyl, aryl, substituted alkyl, substituted aryl, heteroalkyl, substituted heteroalkyl, polyalkylene glycol, polypeptide, polyamide, polycarbamate, polyurea, polycarbonate or combinations thereof. Preparation of the Compounds of the Invention

[0313] The compounds of the invention can be synthesized using techniques and materials known to those skilled in the art, such as, for example, those described in Smith and March, MARCH'S ADVANCED ORGANIC CHEMISTRY: Reactions, Mechanisms, and Structure, 5th Edition, (Wiley-Interscience, 2001), Vogel, A TEXTBOOK OF PRACTICAL ORGANIC CHEMISTRY, Including Qualitative Organic Analysis, 4th Edition, New York, (Longman, 1978), Carey and Sundberg, ADVANCED ORGANIC CHEMISTY, 3rd Edition, Volumes A and B (Plenum 1992), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2nd Edition (Wiley 1991). Starting materials for the compounds of the invention can be obtained using standard techniques and commercially available precursor materials, such as those available from Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo.), Lancaster Synthesis (Ward Hill, MA), Apin Chemicals, Ltd. (New Brunswick, NJ), Ryan Scientific (Columbia, SC), Maybridge (Cornwall, England) and Trans World Chemicals (Rockville, Md.).

[0314] The procedures described herein for synthesizing the compounds of the present invention may include one or more steps of protection and deprotection (e.g., formation and removal of suitable protecting groups). In addition, the synthetic procedures disclosed below may include various purification techniques, such as column chromatography, flash chromatography, thin layer chromatography (TLC), recrystallization, distillation, high pressure liquid chromatography (HPLC), dialysis, size exclusion chromatography, and the like. Similarly, proton and carbon-13 nuclear magnetic resonance ( 1 H and 13 Various techniques well known in the chemical arts for identification and quantification of chemical reaction products can likewise be used, such as C NMR, infrared and ultraviolet spectroscopy (IR and UV), X-ray crystallography, elemental analysis (EA), HPLC and mass spectroscopy (MS), and multi-angle light scattering (MALS). Methods of protection and deprotection, purification, and identification and quantification are well known in the chemical arts.

[0315] In some embodiments, the synthetic methods use a polymer scaffold with multiple repeating functional groups that can react with complementary functional groups Z on the S1, S2 or S3 substrate subunits, resulting in a covalently linked unimolecular polysubstrate construct. The functional groups of the polymer scaffold can be, for example, carboxylic acids, esters, aldehydes, alcohols, amines, isocyanates, epoxides, etc.

[0316] The compounds of the present invention can be collected and purified by using methods known in the art.Generally, the compounds of the present invention described herein can be purified by any of the means known in the art, including chromatographic means such as high performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography and ion exchange chromatography, size exclusion chromatography, etc.Any suitable stationary phase can be used, including normal phase and reverse phase, and ionic resin.See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, LR Snyder and JJ Kirkland, eds., John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl, eds., Springer-Verlag, New York, 1969.

[0317] The compounds of the invention described herein may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Thus, stereomerically pure forms (e.g., geometrically pure, enantiomerically pure or diastereomerically pure), as well as mixtures of enantiomers or stereoisomers, may be used. All possible enantiomers and stereoisomers of the compounds of the present invention, including those of the enantiomers ... 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O and the like. Compounds can exist in non-solvated form and solvated form, including hydrated form. Generally, compounds can be hydrated or solvated. Certain compounds can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of this disclosure.

[0318] Representative synthetic routes useful for preparing exemplary compounds of the invention are illustrated below in the Schemes below.

[0319] Scheme A: [ka]

[0320] Scheme B: [ka]

[0321] Scheme C: [ka]

[0322] Scheme D: [ka]

[0323] Scheme E: [ka]

[0324] Scheme F: [ka] Specific synthetic routes used to prepare exemplary compounds of the present invention are illustrated below in the Schemes below. [ka]

[0325] Preparation of Compound B

[0326] 2-Bromoisonicotinic acid (20.2 g, 100 mmol) was dissolved in DMF (500 mL) at ambient temperature. Cs2CO3 (32.6 g, 100 mmol) was added in one portion, followed by MeI (6.3 mL, 100 mmol). The mixture was stirred at ambient temperature for 15 h, then water (500 mL) was added. The mixture was extracted with EtOAc (500 mL). The organic layer was washed with water (500 mL), brine (500 mL), and then dried over Na2SO4. The organic layer was then filtered and concentrated to give a white solid (18.3 g, 84.7 mmol). LC-MS: [M+H] 217.1 (C7H6BrNO2+H, calculated: 216.1). The crude product was used directly without further purification.

[0327] The crude product from the previous reaction was dissolved in DMF (100 mL) and then Zn(CN)2 (3.42 g, 29.11 mmol) was added in one portion. The mixture was degassed using nitrogen and then Pd(PPh3)4 (2.82 g) was added. The mixture was degassed again and then heated in an oil bath (120 °C). After 2.5 h, the reaction was cooled to ambient temperature and water (120 mL) was added. The mixture was stirred for 30 min and then filtered through a frit. The collected solid was washed with water (2 x 60 mL) and then dried under vacuum to give an off-white solid (5.2 g, 32.6 mmol). LC-MS: [M+H] 163.3 (C8H6N2O2+H, calculated: 163.1). The crude product was used directly without further purification.

[0328] The crude product from the previous reaction (8.0 g, 49.36 mmol) was dissolved in EtOH (200 mL). To the reaction mixture was added Pd / 5% on barium sulfate (2.4 g) and 4N HCl (in 1,4-dioxane; 20 mL). The mixture was hydrogenated at 55 psi in a Parr hydrogenation apparatus for 4 h. The mixture was then filtered through a Celite pad, which was then washed with MeOH (3×50 mL). The combined filtrate was then concentrated, and the residue was partitioned between EtOAc (120 mL) and water (50 mL). The organic layer was washed with 10% citric acid (20 mL) and brine (20 mL), then dried over Na2SO4. The mixture was then filtered and concentrated to give compound B in 86% yield (10.5 g, 40.2 mmol). LC-MS: [M+H] 266.7 (C 13 H 18 N2O4+H, calculated value: 266.1). Compound B was used directly without further purification.

[0329] Preparation of Compound C

[0330] To a solution of Boc-Arg(Pbf)-OH (6.31 g, 12.0 mmol), compound B (2.30 g, 11.4 mmol) and HATU (4.43 g, 12.56 mmol) in DMF (120 mL) was added DIPEA (8.0 mL, 45.66 mmol) dropwise over 5 min at 5° C. The reaction mixture was allowed to warm to ambient temperature and stirring was continued for an additional hour. Upon completion of the reaction, DMF was removed under vacuum and the reaction mixture was then diluted with DCM. The organic layer was washed with 1N HCl, saturated NaHCO3, brine and then dried over MgSO4. The organic layer was then filtered and concentrated to give an off-white solid. (7.18 g, 10.6 mmol) LC-MS: [M+H] 675.9 (C 32 H 46 N6O8S+H, calculated: 675.41). The crude product was used directly without further purification.

[0331] The crude product of the previous reaction (7.0 g, 10.36 mmol) was dissolved in DCM (50 mL) and treated with a solution of 4 M hydrogen chloride in 1,4-dioxane (50 mL). After 1 h, the solvent was removed under vacuum until approximately 50 mL remained. Diethyl ether (approximately 500 mL) was added to the reaction mixture, which produced a fine white precipitate. The precipitate was filtered off, washed with ether (3×150 mL) and dried under vacuum to give a fine white solid. (6.42 g, 9.9 mmol) LC-MS: [M+H] 575.7 (C 27 H 38 N6O6S+H, calculated value: 575.26). The crude product was used directly without further purification.

[0332] The crude product of the previous reaction (6.2 g, 9.6 mmol) was dissolved in DMF and to this solution was added SuO-Gly-NAc (2.05 g, 9.6 mmol) at 5° C. and DIPEA (5.2 mL, 30 mmol) was added dropwise over 5 min. The temperature of the reaction mixture was allowed to rise to ambient temperature and stirring was continued for an additional hour. Upon completion of the reaction, DMF was removed under high vacuum and the reaction mixture was diluted with DCM (200 mL) and washed with 1N HCl (300 mL), followed by saturated NaHCO3 (300 mL) and brine (500 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The oily product was dried under high vacuum overnight to give compound C as a yellow oil in 92.1% yield (5.93 g, 8.8 mmol). LC-MS: [M+H] 674.7 (C 31 H 43 N7O8S+H, calculated value: 674.29).

[0333] Preparation of Compound D

[0334] To a solution of compound C (4.40 g, 6.53 mmol) in MeOH (50 mL) under nitrogen was added 10% Pd / C (250 mg), 10% Pt / C (200 mg) and 1,1,2-trichloroethane (729 mL, 7.8 mmol, 1.2 equiv). The reaction mixture was stirred overnight at 65 psi. Upon completion, the reaction mixture was filled with a Celite pad and cooled to 37° C. The mixture was filtered through a glass frit and washed with MeOH (3×20 mL). The filtrate was concentrated under vacuum to a volume of approximately 10 mL and diethyl ether (300 mL) was added. The resulting fine white precipitate was filtered, washed with ether (2×100 mL) and dried under high vacuum. This gave an off-white solid (3.78 g, 81%). LC-MS: [M+H] 680.6 (C 31 H 49 N7O8S+H, calculated: 680.3). The crude product was used directly without further purification.

[0335] The crude product of the previous reaction (3.5 g, 4.89 mmol) was dissolved in ethanol (100 mL) and then Boc2O (1.07 g, 4.89) was added. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was then evaporated in vacuo to give a thick light yellow oil (3.8 g, 4.86 mmol, 99%). LC-MS [M+H] 780.7 (C 36 H 57 N7O 10 S+H, calculated: 780.4. The crude product was used directly without further purification.

[0336] To the crude product of the previous reaction (3.8 g, 4.86 mmol) in methanol (75 mL) was added an aqueous solution of LiOH (0.29 g, 12 mmol) (20 mL) at 5° C. The temperature of the reaction mixture was allowed to rise to ambient temperature and stirring was continued for an additional 4 h. Upon completion of the reaction, the reaction mixture was neutralized to pH 7.0 with 1N HCl. Methanol was then evaporated under vacuum to give an oily liquid which was dried under high vacuum to give compound D in 79.9% yield (2.98 g, 3.88 mmol). LC-MS, [M+H] 766.8 (C 35 H 55 N7O 10 S+H, calculated value: 766.4).

[0337] Preparation of Compound F

[0338] A solution of compound E (mesylate salt, purchased from PCI, catalog number A1193; 10.0 g, 35.5 mmol), 4-(2-((tert-butoxycarbonyl)amine)ethoxy)benzoic acid (10.0 g, 35.5 mmol) and DCC (11.0 g, 53.3 mmol) in pyridine (100 mL) was stirred overnight. The solvent was evaporated in vacuo. The residue was then dissolved in 4N hydrogen chloride in 1,4-dioxane (100 mL). After 1 h, the solvent was removed under vacuum until approximately 50 mL remained. Diethyl ether (approximately 500 mL) was added to the reaction mixture, which produced an off-white / light tan precipitate. The precipitate was filtered off, washed with ether (3×150 mL) and dried under vacuum to give an off-white solid. The crude product was triturated in acetone, then MTBE, filtered and dried to give an off-white / light tan precipitate (11.1 g, 74%). LC-MS, [M+H] 350.4 (C 20 H 19 N3O3+H, calculated: 350.1). The crude product was used without further purification.

[0339] The crude product of the previous reaction (10.0 g, 24.2 mmol) was dissolved in DMF and to this solution was added SuO-Lys(Boc)-NCBZ (11.6 g, 24.2 mmol) at 5° C. and DIPEA (17.4 mL, 100 mmol) was added dropwise over 5 min. The temperature of the reaction mixture was allowed to rise to ambient temperature and stirring was continued for an additional hour. Once the reaction was complete, DMF was removed under high vacuum and the reaction mixture was diluted with DCM (300 mL) and washed with 1N HCl (500 mL), then saturated NaHCO3 (500 mL) and brine (750 mL). The organic phase was dried over MgSO4, filtered and the solvent was evaporated. The oily product was dissolved in 4N hydrogen chloride in 1,4-dioxane (50 mL). After 1 hour, the solvent was removed under vacuum until approximately 10 mL remained. Diethyl ether (approximately 500 mL) was added to the reaction mixture, which produced an off-white / light tan precipitate. The precipitate was filtered off, washed with ether (3×150 mL), and dried under vacuum to give compound F (15.04 g, 91%). LC-MS, [M+H] 611.7 (C 34 H 37 N5O6+H, calculated value: 611.3). The crude product was obtained without further purification. was used.

[0340] Preparation of Compound G

[0341] To a solution of compound F (1.96 g, 2.86 mmol), compound D (2.19 g, 2.86 mmol) and HATU (1.30 g, 3.43 mmol) in DMF (200 mL) was added NMM (0.94 mL, 9 mmol) dropwise over 5 min at -20°C. The reaction mixture was allowed to warm to ambient temperature and stirring was continued for an additional hour. Upon completion of the reaction, DMF was removed under vacuum and the reaction mixture was then diluted with DCM. The organic layer was washed with 1N HCl, saturated NaHCO3, brine and then dried over MgSO4. The organic layer was then filtered and concentrated to give an off-white solid. (4.11 g) LC-MS: [M+H] 1360.0 (C 69 H 90 N 12 O 15S+H, calculated: 1359.6). The crude product was dissolved in 4N hydrogen chloride in 1,4-dioxane (50 mL). After 1 h, the solvent was removed under vacuum until approximately 10 mL remained. Diethyl ether (approximately 500 mL) was added to the reaction mixture, which produced an off-white / light tan precipitate. The precipitate was filtered off, washed with ether (3×150 mL), and dried under vacuum to give a solid (compound F′) (3.12 g, 82%). LC-MS, [M+H] 1259.9 (C 64 H 82 N 12 O 13 S+H, calculated: 1259.6). The crude product (compound F') was used directly without further purification.

[0342] Preparation of Activated Hydrocodone

[0343] A solution of hydrocodone free base (7.6 g, 25.36 mmol) in THF (200 mL) was cooled to -78°C and then a 0.5 M solution of KHMDS in toluene (50.7 mL, 25.36 mmol) was added dropwise over 5 minutes under nitrogen. The reaction mixture was stirred for 30 minutes and then a solution of 4-nitrophenyl chloroformate (5.1 g, 25.4 mmol) in THF (100 mL) was added dropwise over 5 minutes under nitrogen and cooling with dry ice / acetone. Upon completion, the reaction mixture was diluted with 2 M KHMDS in diethyl ether and cooled with acetone. HCl (100 mL) and ether (400 mL) were added dropwise to form a fine white precipitate. The precipitate was filtered through a glass frit and washed with ether (3×200 mL). The solid was dried under high vacuum overnight, then dissolved in 5% aqueous KH2PO4 (800 mL) and extracted with DCM (2×200 mL). The organic phase was dried over Na2SO4 (anhydrous), filtered and the solvent was concentrated under vacuum to a volume of about 10 mL. To this mixture was added a solution of 2M HCl in diethyl ether (80 mL) and ether (400 mL). The resulting fine white precipitate was filtered off, washed with ether (2×200 mL) and dried under high vacuum to give the activated hydrocodone in 67% yield (8.4 g, 16.8 mmol). LC-MS [M+H]: 465.3 (C 25 H 24 N2O7+H, calculated value: 464.2).

[0344] Compound F' (2.0 g, 1.5 mmol) and activated hydrocodone (750 mg, 1.5 mmol) were dissolved in DMF (40 mL) and DIPEA (0.780 mL, 4.5 mmol) was added. The reaction mixture was stirred at 40° C. overnight. Upon completion of the reaction, DMF was evaporated and the resulting oily product was dissolved in DCM (700 mL). The mixture was then washed with 5% sodium phosphate (2×100 mL), 0.1 N aqueous HCl (100 mL) and brine (150 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The oily product was dried under high vacuum overnight to give crude compound G in 88.7% yield. (2.15 g, 1.33 mmol) LC-MS: [M+H] 1585.1 (C 83 H 101 N 13 O 17 S+H, calculated: 1584.7). The crude reaction mixture was then purified by preparative HPLC to give the desired product (compound G) in 61% yield (1.51 g, 0.91 mmol).

[0345] Preparation of Compound 1

[0346] To a solution of compound G (1.50 g, 0.91 mmol) in MeOH (25 mL) was added 10% Pd / C (150 mg), 4N hydrogen chloride (1,4-dioxane, 2 mL) under nitrogen. The reaction mixture was stirred at 40 psi for 3 h. Upon completion, the reaction mixture was filtered through a glass frit packed with a Celite pad and washed with MeOH (3×20 mL). The filtrate was concentrated under vacuum to a volume of about 10 mL and diethyl ether (200 mL) was added. The resulting fine white precipitate was filtered, washed with ether (2×50 mL) and the resulting solution was evaporated under vacuum and dried under high vacuum overnight to give a light yellow solid (1.39 g). LC-MS: [M+H] 1451.1 (C 75 H 95 N 13 O 15 S+H, calculated: 1450.7). The crude solid was dissolved in DCM (30 mL) and to this mixture was added NMM (1.0 mL, 5.5 mmol) followed by acetic anhydride (0.18 mL, 0.91 mmol). The reaction was stirred at ambient temperature for 1 h. The reaction was then concentrated and to the crude reaction mixture was added 5% cresol in TFA (15 ml). The reaction was stirred at room temperature for 4 h. Upon completion, the reaction mixture was concentrated and dissolved in 20% ACN / H2O (20 mL) and purified by preparative HPLC to give compound 1 (890 mg, 0.63 mmol, 69.7% yield over 3 steps) as a white solid. LC-MS: [M+H] 1331.9 (C 32 H 43 N3O8+H, calculated value: 1331.6). [ka]

[0347] Preparation of compound 2

[0348] To compound G (1.2 g, 0.741 mmol) was added 5% cresol in TFA (10 ml). The reaction was stirred at room temperature for 4 h. Upon completion, the reaction mixture was concentrated, dissolved in 20% ACN / HO (20 mL) and purified by preparative HPLC to give compound 2 (0.73 g, 0.52 mmol, 70.2% yield) as an off-white solid. LC-MS: [M+H] 1332.9 (C 70 H 85 N 13 O 14 +H, calculated value: 1332.6). [ka]

[0349] Preparation of compound 3

[0350] Compound F' (3.0 g, 4.0 mmol) was dissolved in EtOH (40 mL). To the reaction mixture was added 10% Pd(OH)2 / C (0.3 g) and 4N HCl (in 1,4-dioxane; 3 mL). The mixture was hydrogenated at 40 psi for 4 h in a Parr hydrogenation apparatus. The mixture was then filtered through a Celite pad, which was then washed with MeOH (3 x 10 mL). The reaction was concentrated under vacuum. The crude reaction mixture was then dissolved in DMF (25 mL) and to this solution was added SuO-Lys(Boc)-NAc (1.91 g, 4.0 mmol) at 5°C, followed by the dropwise addition of DIPEA (2.08 mL, 12 mmol) over 5 min. The reaction mixture was allowed to warm to ambient temperature and stirring was continued for an additional 1 h. Upon completion of the reaction, DMF was removed under high vacuum and the reaction mixture was diluted with DCM (100 mL) and washed with 1N HCl (100 mL), then aqueous NaHCO3 (100 mL) and brine (250 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated to give an off-white solid (3.10 g, 3.3 mmol). LC-MS: [M+H] 940.8 (C 50 H 65 N7O 11+H, calculated: 940.5). The crude product was used directly without further purification.

[0351] The crude product of the previous reaction (3.10 g, 3.3 mmol) was dissolved in EtOH (100 mL). To this reaction mixture was added 10% Pd(OH)2 / C (0.3 g) and 4N HCl (in 1,4-dioxane; 4 mL). The mixture was hydrogenated at 40 psi in a Parr hydrogenation apparatus for 4 h. The mixture was then filtered through a Celite pad, which was then washed with MeOH (3×25 mL). The reaction was concentrated under vacuum. The crude reaction mixture was then dissolved in DMF (25 mL) and to this solution was added SuO-Lys(Boc)-NAc (1.57 g, 3.3 mmol) at 5° C. DIPEA (2.42 mL, 14 mmol) was then added dropwise over 5 min. The reaction mixture was allowed to warm to ambient temperature and stirring was continued for an additional 2 h. Upon completion of the reaction, DMF was removed under high vacuum and the reaction mixture was diluted with DCM (300 mL) and washed with 1N HCl (200 mL), then aqueous NaHCO3 (200 mL) and brine (250 mL). The organic phase was dried over Na2SO4, filtered and the solvent evaporated to give an off-white solid. (3.85 g, 3.3 mmol) LC-MS: [M+H] 1168.9 (C 61 H 85 N9O 14 +H, calculated: 1168.6). The crude product was used directly without further purification.

[0352] The crude product of the previous reaction (3.85 g, 3.3 mmol) was dissolved in DCM (100 mL) and treated with a solution of 4 M hydrogen chloride in 1,4-dioxane (15 mL). After 1 h, the solvent was removed under vacuum until approximately 50 mL remained. Diethyl ether (approximately 300 mL) was added to the reaction mixture, which produced a fine white precipitate. The precipitate was filtered off, washed with ether (3×75 mL), and dried under vacuum to give compound H as a fine white solid. (3.3 g, 3.3 mmol) LC-MS: [M+H] 868.8 (C46 H 61 N9O8+H, calculated: 868.5). The crude compound H was used directly without further purification.

[0353] To a solution of compound H (2.1 g, 2.0 mmol), compound D (4.81 g, 6.3 mmol) and HATU (2.87 g, 7.56 mmol) in DMF (40 mL) at -20°C, DIPEA (3.95 mL, 22.7 mmol) was added dropwise over 5 min. The reaction mixture was allowed to warm to ambient temperature and stirring was continued for an additional hour. Upon completion of the reaction, DMF was removed under vacuum and the reaction mixture was then diluted with DCM. The organic layer was washed with 1N HCl, saturated NaHCO3, brine and then dried over MgSO4. The organic layer was then filtered and concentrated to give an off-white solid. (6.68 g) LC-MS: [M+H] 2939.9 (C 145 H 211 N 27 O 32 S3+H, calculated: 2939.5). The crude product was dissolved in 4N hydrogen chloride in 1,4-dioxane (50 mL). After 1 h, the solvent was removed in vacuo until approximately 10 mL remained. Diethyl ether (approximately 500 mL) was added to the reaction mixture, which produced an off-white / light tan precipitate. The precipitate was filtered off, washed with ether (3×100 mL), and dried under vacuum to give a solid (compound H′) in 84% yield (4.67 g, 1.68 mmol) over two steps. LC-MS: [M+H] 2639.7 (C 130 H 187 N 27 O 26 S+H, calculated: 2639.3). The crude product (compound H') was used directly without further purification.

[0354] Compound H' (3.0 g, 1.08 mmol) and activated hydrocodone (1.62 g, 3.23 mmol) were dissolved in DMF (40 mL) and DIPEA (1.68 mL, 9.7 mmol) was added. The reaction mixture was stirred at 40° C. overnight. Upon completion of the reaction, DMF was evaporated and the resulting oily product was dissolved in DCM (200 mL). The mixture was then washed with 5% sodium phosphate (2×200 mL), 0.1 N aqueous HCl (500 mL) and brine (250 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The oily product was dried under high vacuum overnight to give crude compound I in 89.5% yield. (3.75 g, 0.967 mmol) LC-MS: [M+H] 3885.8 (C 187 H 248 Cl4IN 30 O 38 S3+H, calculated: 3885.5). The crude reaction mixture was then purified by preparative HPLC to give the desired product (compound I) in 62% yield (2.51 g, 0.67 mmol).

[0355] Compound I (1.50 g, 0.40 mmol) was added with 5% cresol in TFA (10 ml). The reaction was stirred at room temperature for 4 h. Upon completion, the reaction mixture was concentrated, dissolved in 20% ACN / H2O (20 mL) and purified by preparative HPLC to give the compound. Compound 3 was obtained as an off-white solid in 83% yield (1.03 g, 0.33 mmol). LC-MS: [M+H] 578.6 (C 32 H 43 N3O8+H, calculated value: 578.7). Pharmaceutical Compositions

[0356] Similarly, pharmaceutical compositions comprising one or more of the compounds described above in combination with one or more non-toxic pharma- ceutically acceptable carriers and / or excipients and / or adjuvants (collectively referred to herein as "carrier" materials), and, if desired, other active ingredients, are encompassed by the present invention. The compounds and compositions of the present invention can be administered orally, preferably in the form of pharmaceutical compositions adapted for oral administration, in a dose effective for preventing or treating pain.

[0357] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, soft gelatin (softgel) capsule, hard gelatin capsule, suspension, or liquid.

[0358] The amount and dosage regimen of each of the therapeutically active compounds administered to treat or prevent pain using the compounds and / or compositions of the present invention will depend on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound used, and therefore may vary widely. The pharmaceutical composition may contain a compound of the present invention in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 1000 mg, and most preferably between about 1 to 500 mg. A daily dose of about 0.01 to 100 mg / kg body weight, preferably between about 0.1 to about 50 mg / kg body weight, and most preferably between about 0.5 to about 20 mg / kg body weight may be appropriate. The daily dose may be administered in one to four, six, eight or more divided doses per day.

[0359] For therapeutic purposes, the compound of the present invention is usually combined with one or more additives suitable for the indicated administration route.The compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, gum acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets can contain controlled release formulations, which can be provided in the dispersion of active compound in hydroxypropylmethylcellulose.

[0360] The pharmaceutical composition of the present invention can be prepared by uniformly mixing predetermined amounts of the active ingredient, an absorption aid, and, if necessary, a base, etc., in a stirrer or a grinding mill, if necessary.

[0361] The pharmaceutical compositions disclosed herein contain a compound of the invention disclosed herein together with a suitable amount of a pharma- ceutically acceptable vehicle so as to provide the form for proper administration to a subject.

[0362] Suitable pharmaceutical vehicles include additives such as starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk powder, glycerol, propylene, glycol, water, ethanol, etc. The pharmaceutical compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. In addition, auxiliary, stabilizing, thickening, gelling, lubricating and coloring agents, and / or agents designed to deter oral and parenteral abuse (e.g., gelling agents and / or stimulants) may be used.

[0363] The pharmaceutical compositions can be manufactured by conventional mixing, dissolving, granulating, dragee-making, micronizing, emulsifying, encapsulating, entrapping or lyophilizing processes.The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, excipients, additives or auxiliaries that facilitate the processing of the compositions and compounds disclosed herein into preparations that can be used as pharmaceuticals.

[0364] The pharmaceutical composition can be in the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, liquid-containing capsule, powder, sustained release formulation, emulsion, suspension, or any other form suitable for use known to those skilled in the art.In some embodiments, the pharmaceutically acceptable vehicle is a capsule (see, for example, Grosswald et al., U.S. Pat. No. 5,698,155).Other examples of suitable pharmaceutical vehicles are described in the art (see Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 19th Edition, 1995).

[0365] Pharmaceutical compositions for oral delivery can be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, slurries, suspensions, or elixirs. Orally administered compositions may contain one or more optional agents, such as sweeteners, such as fructose, aspartame, or saccharin, flavoring agents, such as peppermint, wintergreen oil, or cherry coloring agents, and preservatives, to obtain a medicamentously palatable preparation.

[0366] Furthermore, when in tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period of time. Oral compositions may contain standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, sucrose, sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP), granulating agents, binders, and disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate), and the like.

[0367] Methods involving oral administration of the compounds disclosed herein can also be carried out using a number of different dosage forms that achieve sustained release.

[0368] In some embodiments, the dosage form comprises beads that upon dissolution or diffusion release the compositions and / or compounds disclosed herein over an extended period of time, preferably at least 6 hours, more preferably at least 8 hours, even more preferably at least 12 hours, and most preferably at least 24 hours. The beads can have a central composition or core that includes the compounds disclosed herein and a pharma- ceutically acceptable vehicle, including lubricants, antioxidants, and buffers as required. The beads can be medical preparations with a diameter of about 1 to about 2 mm. Each individual bead can contain a dose of the compounds disclosed herein. The beads, in some embodiments, are formed from non-crosslinked materials to enhance their evacuation from the gastrointestinal tract. The beads can be coated with a release rate controlling polymer that provides a sustained release profile.

[0369] The sustained release beads may be made into tablets for therapeutically effective administration. The beads may be made into matrix tablets by direct compression of a plurality of beads that are coated with acrylic resin and blended with additives such as hydroxypropylmethylcellulose. The manufacture of beads has been disclosed in the art (Lu, Int. J. Pharm. 1994, Vol. 112, pp. 117-124; Pharmaceutical Sciences by Remington, 14th Edition, pp. 1626-1628 (1970); Fincher, J. Pharm. Sci. 1968, Vol. 57, pp. 1825-1835; Benedikt, U.S. Patent No. 4,083,949), as has the manufacture of tablets (Pharmaceutical Sciences, by Remington, 17th Edition, Chapter 90, pp. 1603-1625 (1985)).

[0370] In other embodiments, oral sustained release pumps may be used (Langer, supra; Sefton, 1987, CRC Crit Ref Biomed. Eng. vol. 14: p. 201; Saudek et al., 1989 , N. Engl. J Med. 321:574).

[0371] In still other embodiments, polymeric materials can be used (see, Medical Applications of Controlled Release, Langer and Wise, eds., CRC Press., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball, eds., Wiley, New York (1984); Langer et al., 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). In some embodiments, polymeric materials are used for oral sustained release delivery. Such polymers include, for example, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose (most preferred is hydroxypropylmethylcellulose). Other cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5(3) 1-9). Factors affecting drug release are discussed in detail in the literature. These methods are well known to those skilled in the art and have been described in the art (Bamba et al., Int. J. Pharm. 1977). 9, Vol. 2, p. 307).

[0372] In yet another embodiment, enteric coated preparations can be used for oral sustained release administration. Coating materials include, for example, polymers whose solubility is pH dependent (i.e., pH controlled release), polymers whose swelling, dissolution or erosion rate is slow or pH dependent (i.e., time controlled release), polymers that are degraded by enzymes (i.e., enzyme controlled release), and polymers that form a film layer that is destroyed by increased pressure (i.e., pressure controlled release).

[0373] In yet another embodiment, drug-releasing lipid matrix can be used for oral sustained release administration.For example, the solid microparticles of the compositions and / or compounds disclosed herein can be coated with a thin controlled release layer of lipid (e.g., glyceryl behenate and / or glyceryl palmitostearate) as disclosed in Farah et al., U.S. Pat. No. 6,375,987 and Joachim et al., U.S. Pat. No. 6,379,700.The lipid-coated particles can be compressed to form tablets, if necessary.Another controlled release lipid-based matrix material suitable for sustained release oral administration includes polyglycolized glycerides as disclosed in Roussin et al., U.S. Pat. No. 6,171,615.

[0374] In yet another embodiment, wax can be used for oral sustained release administration.Examples of suitable sustained release waxes are disclosed in Cain et al., U.S. Patent No. 3,402,240 (carnauba wax, candelilla wax, esparto wax and ulic acid wax); Shtohryn et al., U.S. Patent No. 4,820,523 (hydrogenated vegetable oil, beeswax, carnauba wax, paraffin, candelillia, ozokerite and mixtures thereof); and Walters, U.S. Patent No. 4,421,736 (mixtures of paraffin and castor oil wax).

[0375] In yet other embodiments, osmotic delivery systems are used for oral sustained release administration (Verma et al., Drug Dev. Ind. Pharm. 2000, 26:695-708). In embodiments, the OROS® system made by Alza Corporation (Mountain View, Calif.) is used in an oral sustained release delivery device (Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899).

[0376] In yet another embodiment, the dosage form comprises a compound disclosed herein coated onto a polymeric substrate. The polymer can be an erodible or non-erodible polymer. The coated substrate can be folded to provide a bilayer polymeric drug dosage form. For example, the compound disclosed herein can be coated onto a polymer such as a polypeptide, collagen, gelatin, polyvinyl alcohol, polyorthoester, polyacetyl or polyorthocarbonate, and the coated polymer can be folded to provide a double-layered dosage form. In operation, the bioerodible dosage form erodes at a controlled rate to dispense the compound over a sustained release period. Representative biodegradable polymers include members selected from the group consisting of biodegradable poly(amides), poly(amino acids), poly(esters), poly(lactic acid), poly(glycolic acid), poly(carbohydrates), poly(orthoesters), poly(orthocarbonates), poly(acetyls), poly(anhydrides), biodegradable poly(dihydropyrans), and poly(dioxinones), all of which are known in the art (Rosoff, Controlled Release of Drugs, Chapter 2, pp. 53-95 (1989); Heller et al., U.S. Pat. No. 3,811,444; Michaels, U.S. Pat. No. 3,962,414; Capozza, U.S. Pat. No. 4,066,747; Schmitt, U.S. Pat. No. 4,070,347; Choi et al., U.S. Pat. No. 4,079,038; Choi et al., U.S. Pat. No. 4,093,709).

[0377] In other embodiments, the dosage form comprises a compound disclosed herein loaded onto a polymer that releases the drug(s) by diffusion through the polymer, or by influx through pores, or by rupture of the polymer matrix. The drug delivery polymer dosage form comprises a concentration of 10 mg to 2500 mg uniformly contained within or on the surface of the polymer. The dosage form comprises at least one exposed surface at the start of delivery of the dose. The non-exposed surface, if present, is coated with a pharma- ceutically acceptable material that is impermeable to the passage of the drug. The dosage form may be manufactured by procedures known in the art. One example of obtaining the dosage form includes blending a pharma- ceutically acceptable carrier, such as polyethylene glycol, with a known dose of the composition and / or compound disclosed herein at an elevated temperature (e.g., 37°C), and adding this to a silastic medical grade elastomer with a crosslinker, such as octanoate, and then casting in a mold. This step is repeated for each successive layer as necessary. The system is allowed to cure for about 1 hour to obtain the dosage form. The representative polymer for producing this dosage form comprises the member selected from the group consisting of olefin and vinyl polymer, addition polymer, condensation polymer, carbohydrate polymer and silicone polymer (as represented by polyethylene, polypropylene, polyvinyl acetate, polymethyl acrylate, polyisobutyl methacrylate, polyalginate, polyamide and polysilicone).Polymer and the procedure for producing them are described in the art (Coleman et al., Polymers 1990, vol. 31, pp. 1187-1231; Roerdink et al., Drug Carrier Systems 1989, vol. 9, pp. 57-10; Leong et al., Adv. Drug Delivery Rev. 1987, vol. 1, pp. 199-233; Roff et al., Handbook of Common Polymers 1971, CRC Press; Chien et al., U.S. Patent No. 3,992,518).

[0378] In another embodiment, the dosage form comprises a plurality of small pills. The small sustained release pills provide several individual doses to provide various time doses that provide a sustained release drug delivery profile over an extended period of time, up to 24 hours. The matrix comprises a hydrophilic polymer selected from the group consisting of polysaccharides, agar, agarose, natural gums, alkaline alginates including sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, gum arabic, gum ghatti, gum karaya, gum tragacanth, locust bean gum, pectin, amylopectin, gelatin, and hydrophilic colloids. The hydrophilic matrix comprises a plurality of 4-50 small pills, each small pill comprising a dose population of 10 ng, 0.5 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 5.0 mg, etc. The small pills contain a release rate controlling wall having a thickness of 0.001 mm up to 10 mm to provide sustained release of the drug(s). Exemplary wall forming materials include triglyceryl esters selected from the group consisting of glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl laureate, glyceryl didecenoate and glyceryl tridenoate. Other wall forming materials include polyvinyl acetate, phthalate, methylcellulose phthalate and microporous olefins. Procedures for producing small pills are disclosed in Urquhart et al., U.S. Pat. No. 4,434,153; Urquhart et al., U.S. Pat. No. 4,721,613; Theeuwes, U.S. Pat. No. 4,853,229; Barry, U.S. Pat. No. 2,996,431; Neville, U.S. Pat. No. 3,139,383; and Mehta, U.S. Pat. No. 4,752,470.

[0379] In other embodiments, the dosage form comprises an osmotic dosage form, comprising a semi-permeable wall surrounding a therapeutic composition comprising a compound disclosed herein. In use within a subject, an osmotic dosage form comprising a homogeneous composition absorbs fluid through the semi-permeable wall into the dosage form in response to a concentration gradient on both sides of the semi-permeable wall. The therapeutic composition in the dosage form generates an osmotic pressure differential that causes the therapeutic composition to be administered from the dosage form through an outlet port for an extended period of time up to 24 hours (or in some cases, up to 30 hours), resulting in a controlled and sustained release. These delivery platforms can achieve a substantially zero-order delivery profile, as opposed to the spiked profiles of immediate release formulations.

[0380] In another embodiment, the dosage form comprises a wall surrounding a compartment, the wall comprising a semipermeable polymer composition that is permeable to the passage of fluids and substantially impermeable to the passage of the compound disclosed herein present in the compartment, a drug-containing layer composition within the compartment, a hydrogel push layer composition within the compartment comprising an osmotic formulation for absorbing and incorporating fluids to expand in size to push the drug composition layer out of the dosage form, and another osmotic dosage form with at least one flow channel in the wall for releasing the composition. The method delivers the compound disclosed herein by imbibing fluid through the semipermeable wall, causing the push layer to expand at a rate of fluid absorption determined by the permeability of the semipermeable wall and the osmotic pressure across the semipermeable wall, thereby delivering the compound disclosed herein from the dosage form through the outlet flow channel to the subject over an extended period of time (up to 24 hours, or even 30 hours). The composition of the hydrogel layer is a polyalkylene oxide having a weight average molecular weight of 1,000,000 to 8,000,000 (this is The hydrogel may comprise 10 mg to 1000 mg of a member selected from the group consisting of polyethylene oxide of a weight average molecular weight of 1,000,000 to 6,000,000, polyethylene oxide of a molecular weight of 2,000,000, polyethylene oxide of a molecular weight of 4,000,000, polyethylene oxide of a molecular weight of 5,000,000, polyethylene oxide of a molecular weight of 7,000,000, and polypropylene oxide of a weight average molecular weight of 1,000,000 to 8,000,000, or 10 mg to 1000 mg of an alkali carboxymethylcellulose (such as sodium carboxymethylcellulose or potassium carboxymethylcellulose) of a weight average molecular weight of 10,000 to 6,000,000. The hydrogel expansion layer contains, in this production, 0.0 mg to 350 mg; in this production, 0.1 mg to 250 mg of hydroxyalkyl cellulose (e.g., hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose or hydroxypentyl cellulose) having a weight average molecular weight of 7,500 to 4,500,000; 1 mg to 50 mg of an osmotic pressure adjusting agent selected from the group consisting of sodium chloride, potassium chloride, potassium phosphate, tartaric acid, citric acid, raffinose, magnesium sulfate, magnesium chloride, urea, inositol, sucrose, glucose and sorbitol; 0 to 5 mg of a coloring agent such as ferric oxide; hydroxypropyl ethyl cellulose, hydroxypropyl pentyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl ... 0 mg to 30 mg of hydroxypropyl alkylcellulose having a number average molecular weight of 9,000 to 225,000 selected from the group consisting of cellulose and hydropropyl butyl cellulose, in this production, 0.1 mg to 30 mg of ascorbic acid, butylated hydroxyanisole, butylated hydroxyquinone, butylated hydroxyanisole, hydroxycoumarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl hydroxybenzoate, trihydroxybutyrophenone, dimethyl and 0.00 to 1.5 mg of an antioxidant selected from the group consisting of phenol, dibutylphenol, vitamin E, lecithin, and ethanolamine; and 0.0 mg to 7 mg of a lubricant selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, magnesium oleate, calcium palmitate, sodium suberate, potassium laurate, salts of fatty acids, salts of alicyclic acids, salts of aromatic acids, mixtures of stearic acid, oleic acid, palmitic acid, salts of fatty acids, alicyclic acids, or aromatic acids, and salts of fatty acids, alicyclic acids, or aromatic acids.

[0381] In osmotic dosage forms, the semipermeable wall comprises a composition that is permeable to the passage of fluids and impermeable to the passage of the compounds disclosed herein. The wall is non-toxic and comprises a polymer selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate. The wall comprises 75% (weight percent) to 100% by weight of a cellulose acid wall-forming polymer. Alternatively, the wall can further comprise 0.01% to 80% by weight of polyethylene glycol or 1% to 25% by weight of a cellulose ether selected from the group consisting of hydroxypropylcellulose or hydroxypropyl alkylcellulose (such as hydroxypropylmethylcellulose). The sum of the weight percents of all components comprising the wall equals 100% by weight. The internal compartment comprises a drug-containing composition alone or layered with an expandable hydrogel composition. The expandable hydrogel composition in the compartment increases in size by absorbing fluid through the semipermeable wall, which causes the hydrogel to expand and occupy space within the compartment, which forces the drug composition out of the dosage form. The therapeutic layer and the expansion layer work together during the operation of the dosage form to release the compounds disclosed herein to a subject over time. The dosage form includes a flow passage in the wall that connects the exterior of the dosage form to the internal compartment. The osmotic powder dosage form can be made to deliver drug from the dosage form to a subject with a zero-order release rate over a period of up to about 24 hours.

[0382] The expression "flow passage" as used herein includes means and methods suitable for metered release of the compounds disclosed herein from the compartment of the dosage form. The outlet means includes at least one flow passage, including orifices, holes, gaps, pores, porous elements, hollow fibers, capillaries, channels, porous overlays, or porous elements that provide osmotic controlled release of the compounds disclosed herein. The flow passage includes materials that erode or flow out of the wall in the fluid environment of use to create at least one flow passage of a dimension that provides controlled release. Exemplary materials suitable for forming a flow passage or multiple flow passages include flowable poly(glycolic) acid or poly(lactic) acid polymers, gelatinous filaments, poly(vinyl alcohol), flowable polysaccharides, salts, and oxides in the wall. A pore flow passage or more than one pore flow passage can be formed by flowing out a flowable compound, such as sorbitol, from the wall. The flow passage has controlled release dimensions, such as circular, triangular, square and elliptical, for metered release of the composition and / or drug from the dosage form. The dosage form may be constructed such that one or more flow passages are in spaced relationship to one another on a single surface of the wall, or on more than one surface. The expression "fluid environment" refers to aqueous or biological fluids, such as in a human patient, including the gastrointestinal tract. Flow passages and devices for forming flow passages are disclosed in Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899; Saunders et al., U.S. Pat. No. 4,063,064; Theeuwes et al., U.S. Pat. No. 4,088,864, and Ayer et al., U.S. Pat. No. 4,816,263. Flow passages formed by flowing are disclosed in Ayer et al., U.S. Pat. No. 4,200,098 and Ayer et al., U.S. Pat. No. 4,285,987.

[0383] To reduce dosing frequency and to increase convenience to the subject and improve subject compliance, the sustained release oral dosage form (regardless of the specific form of the sustained release dosage form) preferably provides therapeutic concentrations of the compounds disclosed herein in the blood of a patient for a period of at least about 6 hours, more preferably for a period of at least about 8 hours, even more preferably for a period of at least about 12 hours, and most preferably for a period of at least about 24 hours.

[0384] For example, in the case of oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, additives or excipients include water, physiological saline, alkylene glycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol), oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g., acetates, citrates, ascorbates, between about 5 mM and about 50 mM), etc. Furthermore, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, etc. may be added.

[0385] When used to treat and / or prevent disease, the compounds disclosed herein and / or pharmaceutical compositions thereof may be administered alone or in combination with other pharmaceutical agents, including the compounds disclosed herein and / or pharmaceutical compositions thereof. The compounds disclosed herein may be administered or applied alone or as a pharmaceutical composition.

[0386] The amount of the compounds disclosed herein and / or pharmaceutical compositions thereof that will be effective to treat or prevent a disease in a patient will depend on the specific nature of the condition and can be determined by standard clinical techniques known in the art. The amount of the compounds disclosed herein and / or pharmaceutical compositions thereof administered will, of course, depend on the subject being treated, the subject's weight, the severity of the disorder, and the judgment of the prescribing physician, among other factors.

[0387] In certain embodiments, the compounds disclosed herein and / or pharmaceutical compositions thereof can be used in combination therapy with at least one other therapeutic agent. The compounds disclosed herein and / or pharmaceutical compositions thereof and the therapeutic agent can act additively, or more preferably, synergistically. In some embodiments, the compounds disclosed herein and / or pharmaceutical compositions thereof are administered simultaneously with the administration of another therapeutic agent. For example, the compounds disclosed herein and / or pharmaceutical compositions thereof may be administered together with another therapeutic agent (e.g., including but not limited to, peripheral opioid antagonists, laxatives, non-opioid analgesics, etc.). In other embodiments, the compounds disclosed herein and / or pharmaceutical compositions thereof are administered before or after the administration of the other therapeutic agent.

[0388] Thus, in one aspect of the present invention, the oral dosage form can contain one or more compounds of the present invention and non-opioid drugs.Such non-opioid drugs preferably provide additional analgesic and / or anti-inflammatory effects, and include, for example, aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs ("NSAIDs") (e.g. naproxen, ibuprofen, ketoprofen, etc.), N-methyl-D-aspartic acid (NMDA) receptor antagonists (e.g. morphinans such as dextromethorphan or dextrorphan), or ketamine, cyclooxygenase-II inhibitors ("COX-II inhibitors"), and / or glycine receptor antagonists.

[0389] All printed patents and publications mentioned in this application are hereby incorporated by reference in their entirety. While the preferred embodiment of the invention has been illustrated and described, it will be understood that various changes can be made therein without departing from the spirit and scope of the invention. Pharmacokinetic and pharmacodynamic measurements

[0390] Pharmacokinetic and pharmacodynamic data can be obtained by various experimental techniques. The components of the pharmacokinetic and pharmacodynamic profile that are appropriate for describing a particular composition may vary in different subjects due to the variability of drug metabolism. Pharmacokinetic and pharmacodynamic profiles can be based on determining the average parameters of a group of subjects. The group of subjects includes any reasonable number of subjects suitable for determining a representative average, for example, 5 subjects, 10 subjects, 15 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more. This average is determined by calculating the average of all subjects' measurements for each parameter measured.

[0391] The dose can be adjusted to achieve a desired pharmacokinetic or pharmacodynamic profile, such as a desired or effective blood profile as described herein. The compounds of the present invention can be administered in the form of a single dose of about 1 mg to about 2000 mg, about 5 mg to about 1000 mg, about 10 mg to about 500 mg, about 50 mg to about 250 mg, about 100 mg to about 200 mg, about 1 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mg to about 350 mg, about 350 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 900 mg, about 900 mg to about 1000 mg, about 900 mg to about 1200 mg, about 900 mg to about 1300 mg, about 900 mg to about 1400 mg, about 900 mg to about 1500 mg, about 900 mg to about 1600 mg, about 900 mg to about 1700 mg, about 900 mg to about 1800 mg, about 900 mg to about 2000 mg, about 900 mg to about 2100 mg, about 900 mg to about 2200 mg, about 900 mg to about 2300 mg, about 900 mg to about 2400 mg, about 900 mg to about 250 mg, about 900 mg to In order to better characterize the in vitro enzymatic kinetics of the compounds of the present invention, the K of the monomolecular entity can be present in the composition in the range of about 450 mg to about 500 mg, about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1000 mg. m and V max The following can be written:

[0392] The outcome of treating a human subject with a combination therapy can be measured by calculating pharmacodynamic and pharmacokinetic parameters. Non-limiting examples of pharmacodynamic and pharmacokinetic parameters that can be used to determine the efficacy of treating a subject with a composition of the present disclosure include: a) the amount of opioid agonist drug delivered, which can be expressed as dose D; b) the dosing interval, which can be expressed as τ; c) the volume of distribution V d (V d =D / C0), d) the apparent volume into which the drug is distributed, C0 or C ss (C0 or C ss = D / Vd), e) the amount of drug in a given volume of plasma, t 1 / 2 (t 1 / 2 =ln(2) / k e ), f) how quickly the drug is eliminated from the body e (k e =ln(2) / t 1 / 2 =CL / V d ), g) The injection rate K required to equilibrate the equation in (K in =C ss .CL), h)AUC 0-∞ (in this case,

number

number

number

number

number

[0393] The pharmacokinetic parameters can be any suitable parameters to describe the plasma profile of the opioid agonist delivered by the compound of the present invention. For example, the pharmacokinetic profile of the opioid agonist delivered by the compound of the present invention can be, for example, about 0 minutes, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, about 40 minutes, about 41 minutes, about 42 minutes, about 43 minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 75 minutes, about 76 minutes, about 77 minutes , about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, about 40 minutes, about 41 minutes, about 42 minutes, about 43 minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, 60 minutes, 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours The antibody can be obtained at about 13.5 hours, about 14 hours, about 14.5 hours, about 15 hours, about 15.5 hours, about 16 hours, about 16.5 hours, about 17 hours, about 17.5 hours, about 18 hours, about 18.5 hours, about 19 hours, about 19.5 hours, about 20 hours, about 20.5 hours, about 21 hours, about 21.5 hours, about 22 hours, about 22.5 hours, about 23 hours, about 23.5 hours, or about 24 hours.

[0394] The pharmacokinetic parameters can be any parameters suitable for describing the opioid agonist or agonist delivered from the compounds of the present invention. maxis, for example, about 1 ng / mL or more, about 5 ng / mL or more, about 10 ng / mL or more, about 15 ng / mL or more, about 20 ng / mL or more, about 25 ng / mL or more, about 50 ng / mL or more, about 75 ng / mL or more, about 100 ng / mL or more, about 200 ng / mL or more, or any other C suitable for describing the pharmacokinetic profile of the opioid agonists described herein. max It can be said that C max can be, for example, about 1 ng / mL to about 5 ng / mL, about 1 ng / mL to about 10 ng / mL, about 1 ng / mL to about 30 ng / mL, about 1 ng / mL to about 50 ng / mL, about 1 ng / mL to about 75 ng / mL, about 1 μg / mL to about 100 ng / mL, about 1 ng / mL to about 150 ng / mL, about 1 ng / mL to about 200 ng / mL, or about 1 ng / mL to about 300 ng / mL.

[0395] AUC of the compounds of the invention described herein or of the opioid agonists or agonists delivered therefrom (0-inf) or AUC (0-·) may be, for example, about 10 ng·hr / mL or more, about 25 ng·hr / mL or more, about 50 ng·hr / mL or more, about 100 ng·hr / mL or more, about 150 ng·hr / mL or more, about 200 ng·hr / mL or more, about 300 ng·hr / mL or more, about 350 ng·hr / mL or more, about 400 ng·hr / mL or more, about 500 ng·hr / mL or more, about 600 ng·hr / mL or more, about 700 ng·hr / mL or more, about 800 ng·hr / mL or more, about 900 ng·hr / mL or more, about 1000 ng·hr / mL or more, about 2000 ng·hr / mL or more, about 3000 ng·hr / mL or more, about 4000 ng·hr / mL, or any other AUC suitable to describe the pharmacokinetic profile of the unimolecular polysubstrate entities described herein, or the opioid agonists or agonists delivered therefrom. (0-inf) It can be said that: EXAMPLES

[0396] Example 1 In Vitro Characterization of the Mechanism of Protection Against Overdose by Compounds of the Present Disclosure

[0397] This example describes the in vitro experiments using the compounds of the present disclosure to provide a mechanism of protection against overdose.Specifically, this study was designed to evaluate whether increasing concentrations of compounds 2 and 3 can gradually inhibit trypsin activity.

[0398] A commercially available trypsin substrate, N α The effect of increasing concentrations of compounds 2 and 3 on the rate and extent of trypsin-catalyzed hydrolysis of 4-benzoyl-L-arginine 4-nitroanilide hydrochloride was evaluated in vitro in the presence of trypsin (2,000 BAEE activity) in phosphate buffer at pH 7.4 at 37°C. Both buffer alone (i.e., no trypsin present) and trypsin (i.e., no compounds 2 or 3 present) controls were run simultaneously. The data are presented below in the table below and clearly demonstrate that compounds 2 and 3 are able to gradually inhibit trypsin in a concentration-dependent manner in terms of concentration gradient versus inhibition relationship. Based on this data, compounds 2 and 3 are able to inhibit trypsin in a concentration-dependent manner in terms of concentration gradient versus inhibition relationship. It is reasonable to hypothesize that when multiple doses are co-ingested, they may rapidly self-attenuate trypsin-mediated release of the opioid agonist to which they are bound in vivo. [Table 1] [Table 2]

[0399] Example 2 In vivo demonstration of non-linear pharmacokinetics (i.e., protection against overdose) by compounds of the present disclosure

[0400] This example demonstrates the efficacy of compounds of the present disclosure in vivo to demonstrate protection against overdose. In vivo experiments are described (i.e., nonlinear pharmacokinetics of delivered hydrocodone).

[0401] The effect of increasing the oral dose of compounds 2 and 3 on the pharmacokinetics of delivered hydrocodone (i.e., measured plasma hydrocodone concentration versus time) was evaluated in dogs. Specific pharmacokinetic parameters of delivered opioids were calculated (e.g., Cmax, Tmax, AUC) and are shown below in the following table. This data clearly demonstrates that increasing the oral dose of compounds 2 and 3 of the present invention can gradually attenuate the release of hydrocodone in vivo. [Table 4]

[0402] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) A composition comprising at least one GI enzyme-sensitive opioid-releasing subunit capable of releasing an opioid agonist upon action of a GI enzyme, wherein said at least one GI enzyme-sensitive opioid agonist-releasing subunit is covalently linked to at least one non-opioid agonist-releasing GI enzyme subunit capable of being cleaved by said GI enzyme. (Section 2) A composition comprising at least one GI enzyme-sensitive opioid agonist-releasing subunit capable of releasing an opioid agonist upon action of a GI enzyme, said at least one GI enzyme-sensitive opioid agonist-releasing subunit being covalently linked to at least one GI enzyme inhibitor subunit capable of inhibiting said GI enzyme. (Section 3) The composition according to item 1, wherein the at least one GI enzyme-sensitive opioid-releasing subunit and the at least one non-opioid-releasing GI enzyme subunit are covalently linked via a scaffold moiety. (Section 4) The composition according to item 2, wherein the at least one GI enzyme-sensitive opioid-releasing subunit and the at least one GI enzyme inhibitor subunit are covalently linked via a scaffold moiety. (Section 5) 4. The composition according to claim 3, wherein the scaffold portion comprises a polypeptide or a polysaccharide. (Section 6) 5. The composition according to item 4, wherein the scaffold portion comprises a polypeptide or a polysaccharide. (Section 7) Item 2. The composition according to item 1, wherein the at least one non-opioid releasing GI enzyme subunit is a reverse substrate. (Section 8) Item 2. The composition according to item 1, wherein the GI enzyme is trypsin. (Section 9) Item 2. The composition according to item 1, wherein the GI enzyme is chymotrypsin. (Section 10) Item 2. The composition according to item 1, wherein the GI enzyme-sensitive opioid-releasing subunit releases the opioid agonist in the presence of the GI enzyme. (Section 11) The composition according to any one of claims 1 to 10, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, tapentadol, buprenorphine, and pharma- ceutically acceptable salts, prodrugs and mixtures thereof. (Section 12) Item 12. The composition according to item 11, wherein the opioid agonist is oxycodone. (Section 13) 12. The composition according to claim 11, wherein the opioid agonist is hydrocodone. (Section 14) Item 12. The composition according to item 11, wherein the opioid agonist is morphine. (Section 15) Item 2. The composition according to item 1, wherein the non-opioid agonist releasing subunit is capable of saturating or inhibiting the GI enzyme. (Section 16) Item 3. The composition according to item 2, wherein the GI enzyme inhibitor subunit is capable of inhibiting the GI enzyme. (Section 17) The composition according to paragraph 15 or 16, wherein the non-opioid agonist releasing subunits can reduce the expected systemic exposure of the delivered opioid agonist when a dose of the opioid agonist exceeding the prescribed dose is orally administered. (Section 18) The following formula:

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Claims

1. Structure of Formula (I): 【Chemistry 1】 or a salt thereof (wherein Q is an alkylene or an optionally substituted peptide, which, if substituted, is substituted on the N-terminus of said optionally substituted peptide with alkyl or -C(O)-R', where R' is selected from alkyl, aryl, substituted aryl, natural amino acid, unnatural amino acid, alkoxy, and aralkoxy; L １ is independently at each occurrence absent, a cleavable linker or a non-cleavable linker; Here, R １ -L １ is the following formula: 【Chemistry 2】 It is expressed as L ２ -R ２ may be independently determined for each occurrence: 【Chemistry 18】 where: D is an opioid agonist; R １０１ is selected from an amino acid side chain and an amino acid side chain mimetic, and R″ is selected from acetyl, a natural amino acid, and an unnatural amino acid; and m and n are independently selected from 1 to 1,000,000.

2. 2. The compound of claim 1, or a salt thereof, wherein Q is an optionally substituted peptide.

3. 3. The compound of claim 2, or a salt thereof, wherein Q is an optionally substituted peptide having 1 to 500 amino acids.

4. 4. The compound of claim 3, or a salt thereof, wherein Q is an optionally substituted peptide having 1 to 50 amino acids.

5. 5. The compound of claim 4, or a salt thereof, wherein Q is an optionally substituted peptide having 1 to 10 amino acids.

6. 6. The compound of claim 5, or a salt thereof, wherein Q is an optionally substituted peptide having 1 to 3 amino acids.

7. R １ -L １ But the formula: 【Chemistry 12】 2. The compound of claim 1, represented by:

8. L １ Each occurrence of the linker is a cleavable or non-cleavable linker containing 2 to 15 atoms.

2. The compound according to claim 1, or a salt thereof, selected from the group consisting of aryl, ... and aryl groups.

9. L １ But -O-CH ２ -CH ２ The compound or salt thereof according to claim 7, which is -NH-.

10. The compound according to claim 1, or a salt thereof, wherein n is selected from 1 to 20.

11. The compound according to claim 10, wherein n is selected from 1 to 10, or a salt thereof.

12. The compound according to claim 11, or a salt thereof, wherein n is selected from 1 to 3.

13. R １０１ 2. The compound of claim 1, or a salt thereof, wherein R is selected from an amino acid side chain and R" is acetyl or a natural amino acid.

14. R １０１ 2. The compound of claim 1, or a salt thereof, wherein R is selected from an arginine side chain or a lysine side chain, and R″ is acetyl, N-acetylglycine, or N-acetylalanine.

15. R １０１ 15. The compound of claim 14, or a salt thereof, wherein R is selected from an arginine side chain or a lysine side chain, and R" is N-acetylglycine.

16. 2. The compound of claim 1, or a salt thereof, wherein D is selected from morphine linked through a phenolic functional group, morphine linked through an alcohol functional group, hydromorphone linked through a phenolic functional group, hydromorphone linked through an enol functional group, oxycodone linked through an enol functional group, oxycodone linked through an alcohol functional group, codeine linked through an alcohol functional group, levorphanol linked through a phenolic functional group, methadone linked through an enol functional group, oxymorphone linked through a phenolic functional group, oxymorphone linked through an enol functional group, oxymorphone linked through an alcohol functional group, dihydrocodeine linked through an alcohol functional group, tramadol linked through an alcohol functional group, tapentadol linked through a phenolic functional group, and buprenorphine linked through a phenolic functional group.

17. D is of the formula: 【Chemistry 23】 2. The compound of claim 1, represented by:

18. The compound according to claim 1, wherein m is selected from 1 to 20, or a salt thereof.

19. The compound according to claim 18, wherein m is selected from 1 to 10, or a salt thereof.

20. The compound or salt thereof according to claim 19, wherein m is 1 to 3.

21. The compound has the following formula: 【Chemical 27】 2. The compound of claim 1, represented by:

22. The compound has the following formula: 【Chemistry 28】 2. The compound of claim 1, represented by:

23. The compound has the following formula: 【Chemical 29】 2. The compound of claim 1, represented by:

24. The compound has the following formula: 【Chemistry 30】 2. The compound of claim 1, represented by:

25. 13. A pharmaceutical formulation comprising a compound of claim 1 and a pharma- ceutically acceptable excipient.

26. 26. The formulation of claim 25, further formulated as an oral dosage unit, wherein the compound is present in the dosage unit in an amount effective to provide a defined pharmacokinetic (PK) profile of the opioid agonist after ingestion of a prescribed dose.

27. 27. The formulation of claim 26, wherein the PK profile of the opioid agonist comprises at least one PK parameter value that demonstrates delayed or reduced dose-normalized exposure of released opioid agonist relative to a prescribed dose when a dose in excess of the prescribed dose is taken.

28. 28. The formulation of claim 27, wherein the PK parameter value is selected from a Cmax value, an AUC exposure value, and a Tmax value.

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