Opioid compounds and uses thereof

Abstract

The invention relates to opioid compounds and uses thereof. The present invention relates to opioid derivatives of Formula I: # imgabs0 # or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R3, R4 and Z are as defined herein in the disclosure. The invention also relates to the use of such compounds for the treatment or prevention of e.g. Pain.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of February 22, 2019, an application number of "201980014458.3", and an invention title of "Novel Opioid Compounds and Their Uses". The original application is the Chinese national phase application of international application PCT / US2019 / 019280. BACKGROUND OF THE INVENTION TECHNICAL FIELD

[0003] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to opioid compounds. BACKGROUND ART

[0004] The primary site of pain control is in the central nervous system (CNS). The three major classes of opioid receptors, μ (mu), κ (kappa), and δ (delta), are distributed throughout the CNS and peripheral regions (Foss, J.F., The American Journal of Surgery 182 (November 2001 Supplement): 19S - 26S (2001)). The primary receptor involved in pain management is the μ-opioid receptor (Foss, J.F., ibid.).

[0005] Opioids (also referred to as opioid agonists) are a group of compounds that bind to the opioid receptors mentioned above and exhibit properties similar to those of opium or morphine. Opioids are widely administered for a variety of medical indications, but they are primarily used as moderate to potent analgesics. Examples of opioid compounds include, but are not limited to, morphine, oxycodone, hydromorphone, oxymorphone, hydrocodone, levophanol, methadone, pethidine, fentanyl, codeine, propoxyphene, buprenorphine, butorphanol, pentazocine, and nalbuphine.

[0006] The use of opioid compounds has been reported to have a variety of potential side effects, including abuse and diversion.

[0007] Attempts have been made to reduce the abuse potential of opioids. For example, various opioid receptor antagonists have been developed to block the action of opioid agonists in cases of overdose. Additionally, in attempts to formulate abuse-deterrent tablets, various formulations containing an opioid receptor agonist in combination with an opioid antagonist have been developed, where the antagonist becomes substantially bioavailable upon fragmentation or tampering with the tablet.

[0008] Other alternatives to reduce the abuse potential of opioids include the use of opioid prodrugs. Opioid prodrugs may exhibit pharmacological properties different from those of opioids, such as those related to absorption, distribution, and elimination. For example, U.S. Patent No. 7,230,005 describes the conversion of opioid analgesics to their poorly absorbed ester prodrugs or other prodrug derivatives; U.S. Patent Application Publication No. 2008 / 0318905 describes the covalent attachment of a prodrug moiety to the amine functionality of an abusable parent drug; U.S. Patent Application Publication No. 2009 / 0192095 describes an opioid prodrug comprising an opioid analgesic covalently bonded via a carbamate linkage to a peptide 1-5 amino acids in length; WO 2011 / 002991 A1 describes a hydrocodone enol-ester conjugate as a prodrug; U.S. Patent Application Publication No. 2017 / 095734 describes hydrocodone and hydromorphone prodrugs; U.S. Patent Application Publication No. 2017 / 015266 describes an oxycodone prodrug; and U.S. Patent Application Publication No. 2017 / 0151228 describes an oxymorphone prodrug.

[0009] There remains a need to provide opioid prodrugs that, when administered to a patient determined to be in need thereof, provide effective analgesia while reducing the potential for abuse or adverse side effects. SUMMARY OF THE INVENTION

[0010] In one aspect, the present disclosure provides compounds represented by the following formulas I, II, III, IV, V, and VI, and pharmaceutically acceptable salts and solvates thereof, which are collectively referred to herein as "disclosed compounds" (each will be referred to individually hereinafter as "compounds of the present disclosure").

[0011] In another aspect, the present disclosure provides the use of the compounds of the present disclosure as modulators of one or more opioid receptors. Specifically, the present disclosure provides the use of the compounds of the present disclosure as modulators of μ, δ, κ, and / or ORL-1 opioid receptors, and particularly as modulators of the μ opioid receptor.

[0012] In another aspect, the present disclosure provides a method of treating, ameliorating, or preventing a disorder in a patient responsive to modulation of one or more opioid receptors, the method comprising administering to the patient an effective amount of a compound of the present disclosure.

[0013] In another aspect, the present disclosure provides the use of the compounds of the present disclosure as analgesics for treating, ameliorating, or preventing pain.

[0014] The present invention further provides a method for treating, ameliorating or preventing pain, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the pain is acute pain, chronic pain (including but not limited to neuropathic pain, postoperative pain and inflammatory pain) and surgical pain. In certain embodiments, the compound of the present disclosure can be used for treating or preventing chronic pain. In a particular embodiment, the administration is via an oral route. In one embodiment, the compound is formulated in a solid oral dosage form. In another embodiment, the compound is formulated in a liquid oral dosage form. In one embodiment, the dosage form is designed for immediate release. In another embodiment, the dosage form is designed for controlled release.

[0015] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable carriers. Such compositions can be used for treating, ameliorating or preventing pain in a patient. In a particular embodiment, the pharmaceutical composition is an oral dosage form. In one embodiment, the pharmaceutical composition is a solid oral dosage form. In another embodiment, the pharmaceutical composition is a liquid oral dosage form. In one embodiment, the dosage form is designed for immediate release. In another embodiment, the dosage form is designed for controlled release.

[0016] In another embodiment, the present invention relates to a method for treating, ameliorating or preventing pain, the method comprising administering to a patient in need of such treatment, amelioration or prevention a pharmaceutical composition of the present invention. In a particular embodiment, the administration is via an oral route. In one embodiment, the compound is in a solid oral dosage form. In another embodiment, the compound is in a liquid oral dosage form. In one embodiment, the dosage form is designed for immediate release. In another embodiment, the dosage form is designed for controlled release.

[0017] In another aspect, the present disclosure provides a compound of the present disclosure for treating, ameliorating or preventing a condition responsive to modulation of one or more opioid receptors. Preferably, the condition is responsive to modulation of the μ-opioid receptor.

[0018] In another aspect, the present disclosure provides a method for effecting such modulation in a patient in need of modulating one or more opioid receptors, the method comprising administering to the patient an effective amount of a compound of the present disclosure.

[0019] In another aspect, the present disclosure provides a compound of the present disclosure for treating, ameliorating or preventing pain in a patient in need of such treatment, amelioration or prevention.

[0020] In another aspect, the present disclosure provides the compounds of the present disclosure for treating, ameliorating or preventing pain in a patient, such as acute pain, chronic pain (including but not limited to neuropathic pain, postoperative pain and inflammatory pain) or surgical pain.

[0021] In another aspect, the present disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for treating, ameliorating or preventing a condition responsive to modulation of one or more opioid receptors.

[0022] In another aspect, the present disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for modulating one or more opioid receptors in a patient. Preferably, the μ or κ opioid receptor is modulated.

[0023] In another aspect, the present disclosure provides the compounds of the present disclosure for use as a medicament.

[0024] In another aspect, the present disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for treating, ameliorating or preventing pain in a patient such as acute pain, chronic pain or surgical pain.

[0025] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure for treating, ameliorating or preventing a condition responsive to modulation of one or more opioid receptors.

[0026] The present disclosure further provides a method for preparing a pharmaceutical composition, the method comprising mixing a compound of the present disclosure and a pharmaceutically acceptable carrier to form the pharmaceutical composition.

[0027] In another aspect, the present invention relates to a kit comprising a sterile container containing an effective amount of a compound of the present disclosure and instructions for therapeutic use.

[0028] In another aspect, the present disclosure further provides a method of slowing the onset of opioid activity in a mammal in need of opioid therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound of the present disclosure or a mixture of compounds of the present disclosure. In one embodiment of this aspect of the present disclosure, the compound of the present disclosure is co-administered with one or more other therapeutic agents. In another embodiment, the method provides for slowing the onset of the analgesic activity of the opioid.

[0029] Additional embodiments and advantages of the present disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the present disclosure. The embodiments and advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0030] It should be understood that the above summary and the following detailed description are merely exemplary and explanatory and do not limit the claimed invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The following drawings are given by way of example only and are therefore not intended to limit the scope of the invention.

[0032] Figure 1A 、 Figure 1B 、 Figure 1C and Figure 1D respectively show the COSY NMR spectrum, partial 1 1H NMR spectrum, 1 1H NMR spectrum and HPLC chromatogram of 6-acetyl oxycodone prepared in Example 1.

[0033] Figure 2A and Figure 2B respectively show the 1 1H NMR spectrum and HPLC chromatogram of 6-PEG oxycodone prepared in Example 2.

[0034] Figure 3A and Figure 3B respectively show the 1 1H NMR spectrum and HPLC chromatogram of 6,14-bis-lauroyl oxycodone prepared in Example 3.

[0035] Figure 4A and Figure 4B respectively show the 1 1H NMR spectrum and HPLC chromatogram of 6-lauroyl oxycodone prepared in Example 4.

[0036] Figure 5A and Figure 5B respectively show the 1 1H NMR spectrum and HPLC chromatogram of 6,14-bis-valeryl oxycodone prepared in Example 5.

[0037] Figure 6 shows the hydrolysis results of 6-acetyl oxycodone described in Example 6 in different media.

[0038] Figure 7A and Figure 7B respectively show the 1 1H NMR spectrum and HPLC chromatogram of 6,14-bis-acetyl oxycodone prepared in Example 7.

[0039] Figure 8 shows the hydrolysis results of 6-acetyl hydrocodone described in Example 9 in different media.

[0040] Figure 9Shows the hydrolysis results of 6,14-bis-PEG-oxycodone described in Example 11 in different media.

[0041] Figure 10 Shows the RP flash chromatogram obtained by separating 14-lauroyl oxycodone from a mixture of 6,14-bis-lauroyl oxycodone and 14-lauroyl oxycodone as described in Example 14.

[0042] Figure 11 Shows the RP flash chromatogram obtained by purifying 14-lauroyl oxycodone from a mixture of 14-lauroyl oxycodone and oxycodone as described in Example 14. Detailed Description

[0043] One aspect of the present invention provides a compound of the present disclosure represented by Formula I:

[0044]

[0045] And pharmaceutically acceptable salts and solvates thereof, wherein:

[0046] R 1 Is H; alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl; -PEG-R 7 ; Or a hydroxyl protecting group PG selected from the group consisting of: alkyl, arylalkyl, heterocyclic, (heterocyclic)alkyl, acyl, silyl and carbonate, any of which groups is optionally substituted;

[0047] Z is C-OR 2 Or C(=O);

[0048] Is a single bond or a double bond, provided that when Z is C(=O), Is a single bond, and when Z is C-OR 2 When, Is a double bond;

[0049] R 2 Is -C(=O)R 5 Or -PEG-R 7 Where

[0050] R 5 Is selected from the group consisting of: unsubstituted C 1-12 Alkyl, unsubstituted C 2-12 Alkenyl, unsubstituted C 2-12 Alkynyl, -CH2-O-(CH2CH2O) m -R7 、 -O-(CH2CH2O) n -R 7 、 -NH-(CH2CH2O) p -R 7 、 phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6 - membered heterocycle and (5 - or 6 - membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted by 1, 2 or 3 substituents, and the substituents are each independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl; and wherein the 6 - membered heterocyclic group is attached to the carbonyl carbon of R 2 through a carbon atom or through a nitrogen atom;

[0051] R 3 is hydrogen, OH, -Y-PEG-R 7 or -OC(=O)R 6 , wherein

[0052] Y is a covalent bond or a linker;

[0053] R 6 is selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、 -O-(CH2CH2O) n -R 7 、 -NH(CH2CH2O) p -R 7 、 phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6 - membered heterocycle and (5 - or 6 - membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted by 1, 2 or 3 substituents, and the substituents are each independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl; and wherein the 6 - membered heterocyclic group is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom;

[0054] provided that when Z is C(=O), R 3 is -OC(=O)R 6 ;

[0055] R 7 is selected from the group consisting of hydrogen, C 1-6Alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which groups is optionally substituted;

[0056] R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, any of which groups is optionally substituted with 1, 2, or 3 substituents, each of which is independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl;

[0057] m is an integer between 1 and 9 (i.e., selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9); and

[0058] n and p are each independently an integer between 1 and 20 (i.e., selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20); and

[0059] provided that R 2 and R 3 at least one of which is -C(=O)R 5 and -OC(=O)R 6 .

[0060] In another embodiment, a compound of the present disclosure is a compound of formula II:

[0061]

[0062] and pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , R 3 and R 4 are as defined above for formula I.

[0063] In another embodiment, a compound of the present disclosure is a compound of formula I or formula II and pharmaceutically acceptable salts and solvates thereof, provided that:

[0064] 1) The compound is not

[0065]

[0066] 2) When R 1 is unsubstituted alkyl, R 3 is hydrogen and R 4 is unsubstituted C 1-6 alkyl, then R 5 is not optionally substituted phenyl or optionally substituted pyridyl; or

[0067] 3) When R1 is an unsubstituted alkyl, R 4 is an unsubstituted C 1-6 alkyl and R 3 is -OC(=O)R 6 then R 5 and R 6 are both not an optionally substituted pyridyl group.

[0068] In another embodiment, the compounds of the present disclosure are compounds of formula I and their pharmaceutically acceptable salts and solvates, provided that:

[0069] 4) The compound is not

[0070]

[0071] In another embodiment, the compounds of the present disclosure are compounds represented by formula III:

[0072]

[0073] and their pharmaceutically acceptable salts and solvates, wherein R 1 、R 2 、R 3 and R 4 are as defined for formula I.

[0074] In another embodiment, the compounds of the present disclosure are compounds represented by formula IV:

[0075]

[0076] and their pharmaceutically acceptable salts and solvates, wherein R 31 is hydrogen or OH, and R 1 、R 4 and R 5 are as defined for formula I.

[0077] In another embodiment, the compounds of the present disclosure are compounds of formula IV and their pharmaceutically acceptable salts and solvates, provided that:

[0078] 1) The compound is not

[0079] or

[0080] 2) When R 1 is an unsubstituted alkyl, R 31 is hydrogen and R 4 is an unsubstituted C 1-6 alkyl, then R 5 is not an optionally substituted phenyl group or an optionally substituted pyridyl group.

[0081] In another embodiment, the compounds of the present disclosure are compounds of Formula I or Formula II, wherein R 2 is -C(=O)R 5 and R 3 is -OC(=O)R 6 and R 5 and R 6 are the same and are represented by Formula V:

[0082]

[0083] and their pharmaceutically acceptable salts and solvates, wherein R 1 R 4 and R 5 are as defined for Formula I.

[0084] In another embodiment, the compounds of the present disclosure are compounds of Formula V and their pharmaceutically acceptable salts and solvates, provided that:

[0085] 1) The compound is not

[0086] or

[0087] 2) When R 1 is an unsubstituted alkyl group and R 4 is an unsubstituted C 1-6 alkyl group, then R 5 is not an optionally substituted pyridyl group.

[0088] In yet another embodiment, the compounds of the present disclosure are compounds represented by Formula VI:

[0089]

[0090] and their pharmaceutically acceptable salts and solvates, wherein R 3 is -OC(=O)R 6 and R 1 R 4 and R 6 are as defined for Formula I.

[0091] In another embodiment, the compounds of the present disclosure are compounds of Formula VI and their pharmaceutically acceptable salts and solvates, provided that:

[0092] 4) The compound is not

[0093]

[0094] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 1 is H or an alkyl group optionally substituted with 1, 2, or 3 substituents, each of which is independently selected from the group consisting of hydroxyl, halogen, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy, and alkoxycarbonyl. In another embodiment, R 1 is H, unsubstituted C 1-10 alkyl, or C 1-10 alkyl substituted with 1 or 2 substituents, each of which is independently selected from the group consisting of hydroxyl, halogen, halo(C 1-6 )alkyl, amino, (C 1-6 alkyl)amino, di(C 1-6 )alkylamino, carboxyl, C 1-6 alkoxy, and C 1-6 alkoxycarbonyl. In another embodiment, R 1 is H, unsubstituted C 1-6 alkyl, or C 1-6 alkyl substituted with 1 or 2 substituents, each of which is independently selected from the group consisting of hydroxyl, halogen, halo(C 1-4 )alkyl, amino, (C 1-4 alkyl)amino, di(C 1-4 )alkylamino, carboxyl, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl, and is preferably substituted with 1 or 2 substituents, each of which is independently selected from the group consisting of hydroxyl, halogen, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxyl, methoxy, ethoxy, methoxycarbonyl, and ethoxycarbonyl.

[0095] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 1 is H or unsubstituted C 1-6 alkyl. In another embodiment, R 1 is H. In another embodiment, R 1 is unsubstituted C 1-4 alkyl. In another embodiment, R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl. In another embodiment, R 1 is unsubstituted methyl.

[0096] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 1 is -PEG-R 7. As used herein, "PEG" refers to a single ethylene oxide unit or an oligomer having two or more ethylene oxide subunits. As used herein, "oligomer" refers to a molecule having from about 2 to about 50 monomers. In certain embodiments, PEG is -(CH2CH2O) q -, where q varies from 1 to 50. In another embodiment, q varies from 1 to 10. In another embodiment, q varies from 1 to 5. In another embodiment, q is 1, 2, 3, 4, or 5. In another embodiment, R 7 is hydrogen, methyl, ethyl, or benzyl. In another embodiment, R 7 is methyl.

[0097] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 1 is a hydroxyl protecting group PG selected from the group consisting of alkyl, arylalkyl, heterocyclic group, (heterocyclic group)alkyl, acyl, silyl, and carbonate group, any of which groups is optionally substituted.

[0098] In view of the present disclosure, it will be apparent to those of ordinary skill in the art that certain groups included in the definition of PG overlap with other definitions of R 1 such as methyl, tert-butyl, etc., and thus, as described herein, certain compounds of the present disclosure having groups that serve as hydroxyl protecting groups and having R 1 groups may have pharmaceutical activity.

[0099] In another embodiment, the hydroxyl protecting group PG is alkyl, typically an optionally substituted C 1-6 alkyl, and suitably an unsubstituted methyl or tert-butyl.

[0100] In another embodiment, the hydroxyl protecting group PG is arylalkyl. Suitable arylalkyls include, for example, unsubstituted benzyl, substituted benzyl such as p-methoxybenzyl, and naphthylmethyl.

[0101] In another embodiment, the hydroxyl protecting group PG is a heterocyclic group, such as unsubstituted tetrahydropyranyl or optionally substituted tetrahydropyranyl.

[0102] In another embodiment, the hydroxyl protecting group PG is (heterocyclic group)alkyl. Suitable (heterocyclic group)alkyls include, for example, 4-morpholinyl(C 1-4 )alkyl, such as 2-(4-morpholinyl)ethyl.

[0103] In another embodiment, the hydroxyl protecting group PG is silyl. The term "silyl" as used herein refers to a group having the following structure:

[0104] wherein R 8 , R 9 and R 10 are each independently selected from the group consisting of alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl or arylalkyl, any of said groups being optionally substituted. In one embodiment, the silyl group is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl.

[0105] In another embodiment, the hydroxy protecting group PG is an acyl group. As used herein, the term "acyl group" refers to the following structure:

[0106] wherein R 11 is alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl or arylalkyl, any of said groups being optionally substituted. The acyl group can be, for example, C 1-4 alkylcarbonyl (such as, for example, acetyl), arylcarbonyl (such as, for example, benzoyl), acetylpropionyl or pivaloyl. In another embodiment, the acyl group is benzoyl.

[0107] In another embodiment, the hydroxy protecting group is a carbonate group. As used herein, the term "carbonate group" refers to the following structure:

[0108] wherein R 12 is alkyl, alkenyl, cycloalkyl, aryl, (cycloalkyl)alkyl or arylalkyl, any of said groups being optionally substituted. Generally, R 12 is C 1-10 alkyl (such as, for example, 2,4-dimethylpent-3-yl), C 2-6 alkenyl (such as, for example, vinyl or prop-2-enyl, i.e., allyl), C 3-12 cycloalkyl (such as, for example, adamantyl), phenyl or benzyl. In one embodiment, the carbonate group is benzyloxycarbonyl.

[0109] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I to VI, wherein R 1 is PG, where said PG is selected from the group consisting of methyl, tert-butyl, optionally substituted benzyl, optionally substituted benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and triisopropylsilyl.

[0110] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I to III, wherein R 3 is hydrogen and R 2 is -C(=O)R 5 , wherein R 5 is as defined for Formula I.

[0111] In another embodiment, a compound of the present disclosure is a compound of any one of Formulas I to III, wherein R 3 is OH and R 2 is -C(=O)R 5 wherein R 5 is as defined for Formula I.

[0112] In another embodiment, a compound of the present disclosure is a compound of any one of Formulas I to III, wherein R 3 is -Y-PEG-R 7 and R 2 is -C(=O)R 5 wherein Y, PEG, R 7 and R 5 are as defined above for Formula I.

[0113] In one embodiment, Y is a covalent bond. In another embodiment, Y is a linker. Suitable linkers include ethers, amides, urethanes, amines, thioethers, ureas, or carbon-carbon bonds. In certain embodiments, the linker Y is selected from the group consisting of: -O-, -O-CH2-, -CH2-O-, -NH-, -S-, -C(=O)-, -C(=O)O-, and -OC(=O)-. In certain embodiments, Y is selected from the group consisting of: -O-, -O-CH2-, -CH2-O-, and -NH-. In certain embodiments, Y is -O-. In another embodiment, R 7 is hydrogen, methyl, ethyl, or benzyl. In another embodiment, R 7 is methyl.

[0114] In another embodiment, a compound of the present disclosure is a compound of any one of Formulas I to III and VI, wherein R 3 is -OC(=O)R 6 wherein R 6 is selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7 , -NH-(CH2CH2O) p -R 7, phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; wherein the 6-membered heterocycle is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom; R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic group, any of which is optionally substituted; m is an integer between 1 and 9; and n and p are each independently an integer between 1 and 20. In certain embodiments, R 7 is hydrogen, methyl, ethyl, or benzyl. In another embodiment, R 7 is methyl.

[0115] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I to III and VI, wherein R 3 is -OC(=O)R 6 , wherein R 6 is selected from the group consisting of unsubstituted C 1-6 alkyl, unsubstituted C 7-12 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, -CH2-O-(CH2CH2O) m -CH3, -O-(CH2CH2O) n -CH3, -NH-(CH2CH2O) p -CH3, phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; m is 1, 2, 3, 4, or 5; n and p are each independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and wherein the 6-membered heterocycle is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom. In another embodiment, R 6 is selected from the group consisting of unsubstituted C 1-6 alkyl, unsubstituted C 7-12 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C2-6 Alkynyl, -CH2-O-(CH2CH2O) m -CH3, -O-(CH2CH2O) n -CH3, -NH-(CH2CH2O) p -CH3, phenyl, benzyl, phenethyl, pyridyl, C 3-6 Cycloalkyl, (C 3-6 Cycloalkyl)(C 1-4 )alkyl, C 3-6 Cycloalkenyl, (C 3-6 Cycloalkenyl)(C 1-4 )alkyl, 6-membered heterocycle and (5-membered or 6-membered heterocycle)(C 1-4 )alkyl, wherein the phenyl, pyridyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl and the heterocyclic moiety are optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of C 1-4 Alkyl, hydroxy, halo, halo(C 1-4 )alkyl, amino, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, carboxyl, C 1-4 Alkoxy and C 1-4 Alkoxycarbonyl, and preferably optionally substituted with 1 or 2 substituents, each substituent independently selected from the group consisting of methyl, hydroxy, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxyl, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl; m is 1, 2 or 3; n and p are each independently selected from the group consisting of 1, 2, 3, 4, 5 and 6; and wherein the 6-membered heterocycle is attached to the carbonyl carbon through a carbon atom.

[0116] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I to III and VI, wherein R 3 is -OC(=O)R 6 , and R 6 is unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl or C 2-6 alkynyl. In another embodiment, R 6 is unsubstituted C 1-4 alkyl. In another embodiment, R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In another embodiment, R 6 is methyl. In another embodiment, R 6 is ethyl, propyl or n-butyl.

[0117] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to III and VI, wherein R 3 is -OC(=O)R 6 , and R 6 is unsubstituted C 7-12 alkyl. In another embodiment, R 6 is heptyl, octyl, nonyl, decyl, undecyl or dodecyl. In another embodiment, R 6 is undecyl.

[0118] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to III and VI, wherein R 3 is -OC(=O)R 6 , and R 6 is -CH2-O-CH2CH2O-CH3, -CH2-O-CH2CH2O-CH2CH2O-CH3, -CH2-O-(CH2CH2O)3-CH3, -O-CH2CH2O-CH3, -O-CH2CH2O-CH2CH2O-CH3 or -O-(CH2CH2O)3-CH3. In another embodiment, R 6 is -CH2-O-CH2CH2O-CH2CH2O-CH3.

[0119] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is hydrogen.

[0120] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is alkyl, alkenyl, alkynyl, cycloalkyl and (cycloalkyl)alkyl, any one of said groups being optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl.

[0121] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl or C 3-6 (cycloalkyl)(C 1-6 )alkyl, any one of said groups being optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of hydroxy, halo, halo(C 1-6)Alkyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, carboxyl, C 1-6 alkoxy and C 1-6 alkoxycarbonyl.

[0122] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl(C 1-4 )alkyl, any one of said groups being optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxyl, C 1-4 alkoxy and C 1-4 alkoxycarbonyl.

[0123] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl(C 1-2 )alkyl, any one of said groups being optionally substituted with 1 or 2 substituents, each of said substituents being independently selected from the group consisting of: hydroxy, halo, halo(C 1-2 )alkyl, amino, C 1-2 alkylamino, di(C 1-2 )alkylamino, carboxyl, C 1-2 alkoxy and C 1-2 alkoxycarbonyl, and preferably optionally substituted with 1 or 2 substituents, each of said substituents being independently selected from the group consisting of: hydroxy, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxyl, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl.

[0124] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is unsubstituted C 1-6 alkyl, and advantageously unsubstituted C 1-4Alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl). In another embodiment, R 4 is methyl or ethyl. In another embodiment, R 4 is methyl.

[0125] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is C 3-6 (cycloalkyl)(C 1-4 )alkyl, such as cyclopropyl(C 1-4 )alkyl, cyclobutyl(C 1-4 )alkyl, cyclopentyl(C 1-4 )alkyl or cyclohexyl(C 1-4 )alkyl, the groups being optionally substituted with 1, 2 or 3 substituents, each independently selected from the group consisting of: hydroxyl, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxyl, C 1-4 alkoxy and C 1-4 alkoxycarbonyl, and preferably optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of: hydroxyl, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxyl, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl. In another embodiment, R 4 is unsubstituted cyclopropyl(C 1-4 )alkyl. In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is unsubstituted (cyclopropyl)methyl, 2-(cyclopropyl)ethyl or 3-(cyclopropyl)propyl.

[0126] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is C 1-6 alkyl substituted with 1, 2 or 3 substituents, and preferably is C 1-4 alkyl, the substituents each independently selected from the group consisting of: halo (such as fluorine) and halo(C 1-4 )alkyl (such as, for example, trifluoro(C 1-2 )alkyl).

[0127] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to VI, wherein R 4 is unsubstituted or substituted with 1, 2 or 3 substituents of C 2-6 alkenyl (for example C 2-4alkenyl), and the substituents are each independently selected from the group consisting of: halo (such as fluoro) and halo(C 1-4 )alkyl (such as, for example, trifluoro(C 1-2 )alkyl).

[0128] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to III, wherein R 2 is -C(=O)R 5 , and R 5 is selected from the group consisting of: unsubstituted C 1-6 alkyl, unsubstituted C 7-12 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7 , -NH-(CH2CH2O) p -R 7 , phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, and the substituents are each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy, and alkoxycarbonyl; wherein the 6-membered heterocycle is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom; R 7 is selected from the group consisting of: hydrogen, C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic group, any of which is optionally substituted; m is an integer between 1 and 9; and n and p are each independently an integer between 1 and 20. In certain embodiments, R 7 is hydrogen, methyl, ethyl, or benzyl. In another embodiment, R 7 is methyl.

[0129] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas I to III, wherein R 2 is -C(=O)R 5 , and R 5 is selected from the group consisting of: unsubstituted C 1-6 alkyl, unsubstituted C 7-12 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, -CH2-O-(CH2CH2O) m-CH3, -O-(CH2CH2O) n -CH3, -NH-(CH2CH2O) p -CH3, phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; m is 1, 2, 3, 4, or 5; n and p are each independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and wherein the 6-membered heterocycle is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom. In another embodiment, R 5 is selected from the group consisting of unsubstituted C 1-6 alkyl, unsubstituted C 7-12 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, -CH2-O-(CH2CH2O) m -CH3, -O-(CH2CH2O) n -CH3, -NH-(CH2CH2O) p -CH3, phenyl, benzyl, phenethyl, pyridyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)(C 1-4 )alkyl, C 3-6 cycloalkenyl, (C 3-6 cycloalkenyl)(C 1-4 )alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)(C 1-4 )alkyl, wherein the phenyl, pyridyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of C 1-4 alkyl, hydroxy, halo, halo(C 1-4 )alkyl, amino, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy, and C 1-4an alkoxycarbonyl group and preferably optionally substituted with one or two substituents each independently selected from the group consisting of methyl, hydroxy, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxyl, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl; m is 1, 2 or 3; n and p are each independently selected from the group consisting of 1, 2, 3, 5, 5 and 6; and wherein said 6-membered heterocycle is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom.

[0130] In another embodiment, a compound of the present disclosure is a compound of any one of Formulas I to III, wherein R 2 is -C(=O)R 5 and R 5 is unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl or C 2-6 alkynyl. In another embodiment, R 5 is unsubstituted C 1-4 alkyl. In another embodiment, R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In another embodiment, R 5 is unsubstituted C 1-4 alkyl. In another embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl, propyl or n-butyl.

[0131] In another embodiment, a compound of the present disclosure is a compound of any one of Formulas I to III, wherein R 2 is -C(=O)R 5 and R 5 is unsubstituted C 7-12 alkyl. In another embodiment, R 5 is heptyl, octyl, nonyl, decyl, undecyl or dodecyl. In another embodiment, R 5 is undecyl.

[0132] In another embodiment, a compound of the present disclosure is a compound of any one of Formulas I to III, wherein R 2 is -C(=O)R 5 and R 5is -CH2-O-CH2CH2O-CH3, -CH2-O-CH2CH2O-CH2CH2O-CH3, -CH2-O-(CH2CH2O)3-CH3, -O-CH2CH2O-CH3, -O-CH2CH2O-CH2CH2O-CH3 or -O-(CH2CH2O)3-CH3. In another embodiment, R 5 is -CH2-O-CH2CH2O-CH2CH2O-CH3.

[0133] In another embodiment, the compounds of the present disclosure are compounds of formula IV, wherein R 5 is selected from the group consisting of: unsubstituted C 1-6 alkyl, unsubstituted C 7-12 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 、-NH-(CH2CH2O) p -R 7 、phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle and (5- or 6-membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl; wherein the 6-membered heterocycle is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom; R 7 is selected from the group consisting of: hydrogen, C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclic group, any of which groups is optionally substituted; m is an integer between 1 and 9; and n and p are each independently an integer between 1 and 20. In certain embodiments, R 7 is hydrogen, methyl, ethyl or benzyl. In another embodiment, R 7 is methyl.

[0134] In another embodiment, the compounds of the present disclosure are compounds of formula IV, wherein R 5 is selected from the group consisting of: unsubstituted C 1-6 alkyl, unsubstituted C 7-12 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, -CH2-O-(CH2CH2O)m -CH3, -O-(CH2CH2O) n -CH3, -NH-(CH2CH2O) p -CH3, phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)alkyl, where the phenyl, pyridyl, cycloalkyl, cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; m is 1, 2, 3, 4, or 5; n and p are each independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and where the 6-membered heterocycle is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom. In another embodiment, R 5 is selected from the group consisting of unsubstituted C 1-6 alkyl, unsubstituted C 7-12 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, -CH2-O-(CH2CH2O) m -CH3, -O-(CH2CH2O) n -CH3, -NH-(CH2CH2O) p -CH3, phenyl, benzyl, phenethyl, pyridyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)(C 1-4 )alkyl, C 3-6 cycloalkenyl, (C 3-6 cycloalkenyl)(C 1-4 )alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)(C 1-4 )alkyl, where the phenyl, pyridyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of C 1-4 alkyl, hydroxy, halo, halo(C 1-4 )alkyl, amino, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy, and C 1-4an alkoxycarbonyl group, and preferably optionally substituted with one or two substituents each independently selected from the group consisting of methyl, hydroxy, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl; m is 1, 2 or 3; n and p are each independently selected from the group consisting of 1, 2, 3, 5, 5 and 6; and wherein said 6-membered heterocycle is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom.

[0135] In another embodiment, a compound of the present disclosure is a compound of formula IV, wherein R 5 is an unsubstituted C 1-6 alkyl, an unsubstituted C 2-6 alkenyl or a C 2-6 alkynyl. In another embodiment, R 5 is an unsubstituted C 1-4 alkyl. In another embodiment, R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In another embodiment, R 5 is an unsubstituted C 1-4 alkyl. In another embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl, propyl or n-butyl.

[0136] In another embodiment, a compound of the present disclosure is a compound of formula IV, wherein R 5 is an unsubstituted C 7-12 alkyl. In another embodiment, R 5 is heptyl, octyl, nonyl, decyl, undecyl or dodecyl. In another embodiment, R 5 is undecyl.

[0137] In another embodiment, a compound of the present disclosure is a compound of formula IV, wherein R 5 is -CH2-O-CH2CH2O-CH3, -CH2-O-CH2CH2O-CH2CH2O-CH3, -CH2-O-(CH2CH2O)3-CH3, -O-CH2CH2O-CH3, -O-CH2CH2O-CH2CH2O-CH3 or -O-(CH2CH2O)3-CH3. In another embodiment, R 5 is -CH2-O-CH2CH2O-CH2CH2O-CH3.

[0138] In another embodiment, a compound of the present disclosure is a compound of any one of formulas I to III, wherein R 2is -C(=O)R 5 , R 3 is -OC(=O)R 6 , and R 5 and R 6 are the same, being a compound of formula V, wherein R 5 is as defined above, provided that the compound is not

[0139] In another embodiment, in the compound of formula V, each R 5 is butyl or undecyl. In another embodiment, each R 5 is -CH2-O-CH2CH2O-CH2CH2O-CH3.

[0140] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I to III, wherein R 3 is -OC(=O)R 6 , and R 5 and R 6 are different.

[0141] In another embodiment, the compound of the present disclosure is a compound of formula II or formula III, wherein

[0142] R 1 is H or unsubstituted C 1-6 alkyl;

[0143] R 2 is -C(O)(C 1-6 )alkyl;

[0144] R 3 is H or OH; and

[0145] R 4 is unsubstituted C 1-6 alkyl,

[0146] provided that the compound is not

[0147]

[0148] In another embodiment, the compound of the present disclosure is a compound of formula II or formula III, which is oxycodone enol ester and its pharmaceutically acceptable salts and solvates, wherein R1 is methyl, R 3 is OH, R 4 is methyl, and R 2 is -C(=O)R 5 , wherein R 5As defined above for Formula II. In another embodiment, the compounds of the present disclosure are compounds of Formula II or Formula III having the following structures, respectively

[0149] and their pharmaceutically acceptable salts and solvates. Alternatively, these oxycodone enol esters and their pharmaceutically acceptable salts and solvates are compounds of Formula IV, wherein R1 is methyl, R 31 is OH, R 4 is methyl, and R 2 is -C(=O)R 5 wherein R 5 is as defined above for II.

[0150] In another embodiment, the compounds of the present disclosure are compounds of Formula II or Formula III, which are oxymorphone enol esters and their pharmaceutically acceptable salts and solvates, wherein R1 is hydrogen, R 3 is OH, R 4 is methyl, and R 2 is -C(=O)R 5 wherein R 5 is as defined above for Formula II. Alternatively, these oxymorphone enol esters and their pharmaceutically acceptable salts and solvates are compounds of Formula IV, wherein R1 is hydrogen, R 31 is OH, R 4 is methyl, and R 5 is as defined above for Formula II.

[0151] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas II to IV, which are hydrocodone enol esters and their pharmaceutically acceptable salts and solvates, wherein R1 is methyl, R 3 / R 31 is H, R 4 is methyl, R 2 is -C(=O)R 5 and R 5 is as defined above for Formula II, provided that the compound is not

[0152]

[0153] In another embodiment, the compounds of the present disclosure are compounds of any one of Formulas II to IV, which are hydromorphone enol esters and their pharmaceutically acceptable salts and solvates, wherein R1 is hydrogen, R 3 / R 31 is H, R 4 is methyl, and R 2 is -C(=O)R 5 and R 5As defined above for Formula II, provided that the compound is not

[0154]

[0155] In another embodiment, the compounds of the present disclosure include:

[0156] and pharmaceutically acceptable salts and solvates thereof.

[0157] In another embodiment, the compounds of the present disclosure include:

[0158]

[0159]

[0160] and pharmaceutically acceptable salts and solvates thereof.

[0161] The optional substituents attached to the aryl, phenyl and heteroaryl rings each replace a hydrogen atom that would otherwise be present at any position on the aryl, phenyl or heteroaryl ring.

[0162] Available halo or halogen groups include fluorine, chlorine, bromine and iodine.

[0163] Available alkyl groups are selected from straight-chain and branched-chain C 1-12 alkyl groups. Typical C 1-12 alkyl groups include methyl (Me), ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, dodecyl, isopropyl, sec-butyl, tert-butyl, isobutyl, isopentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl and 3,3-dimethylheptyl and so on. In one embodiment, the available C 1-12 alkyl groups are straight-chain C 1-12Alkyl. In another embodiment, the available alkyls are selected from straight-chain and branched C 1-10 alkyls, namely straight-chain C 1-10 alkyls and branched C 3-10 alkyls. In another embodiment, the available alkyls are selected from straight-chain and branched C 1-6 alkyls, namely straight-chain C 1-6 alkyls and branched C 3-6 alkyls. Typical C 1-6 alkyls include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 3-pentyl, hexyl, and the like. In one embodiment, the available alkyls are selected from straight-chain and branched C 1-4 alkyls, namely straight-chain C 1-4 alkyls and branched C 3-4 alkyls. Typical C 1-4 alkyls include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl. Typical C 1-2 alkyls include methyl and ethyl. In the present application, C 1-6 alkyl refers to straight-chain and branched C 1-6 alkyls, and C 1-4 alkyl refers to straight-chain and branched C 1-4 alkyls, as defined above in this paragraph. In another embodiment, the available alkyls are selected from straight-chain and branched C 7-12 alkyls.

[0164] The available alkenyls are selected from straight-chain and branched C 2-12 alkenyls. As used herein, the term "C 2-12 alkenyl", when used by itself or as part of another group, refers to straight-chain and branched acyclic hydrocarbons having 2 to 12 carbon atoms and including at least one carbon-carbon double bond. Representative typical C 2-12 alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like. In one embodiment, the available C 2-12 alkenyl is C 2-10 alkenyl. In another embodiment, the available C 2-12 alkenyl is C 2-6 alkenyl. Typical C 2-6 alkenyls include ethenyl (i.e., vinyl), allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, and 3-hexenyl. Typical C2-4 Alkenyl includes vinyl, propenyl, isopropenyl, butenyl, and sec-butenyl.

[0165] Available alkynyls are selected from straight-chain and branched-chain C 2-12 alkynyl. As used herein, the term "C 2-12 alkynyl", when used by itself or as part of another group, refers to straight-chain and branched-chain acyclic hydrocarbons having 2 to 12 carbon atoms and including at least one carbon-carbon triple bond. Representative straight-chain and branched-chain C 2-12 alkynyls include ethynyl (alkynyl), propynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, 3-methylbut-1-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, and the like. In one embodiment, the C 2-12 alkynyl is C 2-10 alkynyl. In another embodiment, the C 2-12 alkynyl is C 2-6 alkynyl. Typical C 2-6 alkynyls include ethynyl (acetylenyl) (i.e., ethynyl (alkynyl)), propynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, 3-methylbut-1-ynyl, pent-4-ynyl, and hex-1-ynyl. In another embodiment, the C 2-10 alkynyl is C 2-4 alkynyl. Typical C 2-4 alkynyls include ethynyl, propynyl, but-1-ynyl, and but-2-ynyl.

[0166] Available haloalkyls include any of the above-mentioned C 1-12 alkyls substituted with one or more fluorine, chlorine, bromine, or iodine atoms, preferably any of the above-mentioned C 1-6 alkyls, and preferably any of the above-mentioned C 1-4 alkyls (e.g., fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl).

[0167] Available cycloalkyls are selected from saturated cyclic hydrocarbon groups having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C 3-12 cycloalkyl) or the specified number of carbon atoms, containing 1, 2, or 3 rings. In one embodiment, the cycloalkyl has one or two rings. Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, and adamantyl. In another embodiment, the cycloalkyl is C 3-6Cycloalkyl. Typical C 3-6 Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0168] Available cycloalkenyls are selected from cyclic hydrocarbon groups having 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C4-C 12 cycloalkenyl) or partially unsaturated (i.e., containing one or two double bonds) with the specified number of carbon atoms, having 1, 2, or 3 rings. In one embodiment, the cycloalkenyl has one or two rings. In another embodiment, the cycloalkenyl is C 3-8 cycloalkenyl. In another embodiment, the cycloalkenyl is C 3-7 cycloalkenyl. In another embodiment, the cycloalkenyl is C 3-6 cycloalkenyl. In one embodiment, the cycloalkenyl contains one double bond. Exemplary cycloalkenyls containing one double bond include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl. In another embodiment, the cycloalkenyl contains two double bonds. Preferably, the cycloalkenyl containing two double bonds has 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C5-C 12 cyclodienyl). Exemplary cycloalkenyls having two double bonds include cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclononadienyl, and cyclodecadienyl.

[0169] Available alkoxy groups include oxygen substituted with any of the C 1-12 alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, and dodecyloxy), preferably substituted with any of the C 1-6 alkyl groups, and more preferably substituted with any of the C 1-4 alkyl groups.

[0170] Available halo(C 1-6 )alkoxy groups include oxygen substituted with any of the halo(C 1-6 )alkyl groups mentioned above (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy).

[0171] Available (cycloalkyl)alkyl groups include any of the C 1-12 alkyl groups mentioned above substituted with any of the cycloalkyl groups mentioned above, and preferably any of the C 1-6 alkyl groups mentioned above (e.g., (cyclopropyl)methyl, 2-(cyclopropyl)ethyl, (cyclopropyl)propyl, (cyclobutyl)methyl, (cyclopentyl)methyl, and (cyclohexyl)methyl).

[0172] Usable (cycloalkenyl)alkyls include any of the above-mentioned C-alkyls substituted with any of the above-mentioned cycloalkenyls, and preferably any of the above-mentioned C-alkyls 1-12 (e.g., (cyclobutenyl)methyl, 2-(cyclobutenyl)ethyl, (cyclobutenyl)propyl, (cyclopentenyl)methyl, (cyclohexenyl)methyl, and (cyclopentadienyl)methyl). 1-6 (e.g., (cyclobutenyl)methyl, 2-(cyclobutenyl)ethyl, (cyclobutenyl)propyl, (cyclopentenyl)methyl, (cyclohexenyl)methyl, and (cyclopentadienyl)methyl).

[0173] Usable aryls are C-aryls, especially C-aryls 6-14 (e.g., phenyl (Ph), naphthyl, phenanthryl, anthryl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl, more preferably phenyl, naphthyl, and biphenyl). 6-10 (e.g., phenyl (Ph), naphthyl, phenanthryl, anthryl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl, more preferably phenyl, naphthyl, and biphenyl). 6-14 (e.g., phenyl (Ph), naphthyl, phenanthryl, anthryl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl, more preferably phenyl, naphthyl, and biphenyl).

[0174] Usable arylalkyls include any of the above-mentioned C-alkyls substituted with any of the above-mentioned aryls, and preferably any of the above-mentioned C-alkyls 1-12 (e.g., benzyl and phenethyl). 1-6 (e.g., benzyl and phenethyl).

[0175] Usable arylalkenyls include any of the above-mentioned C-alkenyls substituted with any of the above-mentioned aryls (e.g., styryl). 2-6 (e.g., styryl).

[0176] Usable arylalkynyls include any of the above-mentioned C-alkynyls substituted with any of the above-mentioned aryls (e.g., phenylacetylenyl). 2-6 (e.g., phenylacetylenyl).

[0177] Usable aryloxys include oxygen substituted with any of the above-mentioned aryls (e.g., phenoxy).

[0178] Usable arylalkoxys or aryloxyalkyls include oxygen substituted with any of the above-mentioned arylalkyls (e.g., benzyloxy).

[0179] Usable (aryloxyalkoxy)carbonyls include carbonyl substituted with any of the above-mentioned aryloxyalkyls (e.g., (benzyloxy)carbonyl).

[0180] The terms "heterocyclic" and "heterocyclic group" are used herein to mean a saturated or partially unsaturated 3- to 7-membered monocyclic or 7- to 10-membered bicyclic ring system, said ring system consisting of carbon atoms and one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocycles is fused to a benzene ring, and wherein the heterocycle may be substituted on a carbon atom or a nitrogen atom if the resulting compound is stable. In one embodiment, the 3- to 7-membered monocyclic heterocycle is a saturated or unsaturated non-aromatic ring. The 3-membered heterocycle contains 1 heteroatom, the 4-membered heterocycle may contain up to 2 heteroatoms, the 5-membered heterocycle may contain up to 4 heteroatoms, the 6-membered heterocycle may contain up to 4 heteroatoms, and the 7-membered heterocycle may contain up to 5 heteroatoms. Each heteroatom is independently selected from: nitrogen, which may be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The 3- to 7-membered heterocycle may be linked through a nitrogen or carbon atom. The 7- to 10-membered bicyclic heterocycle contains 1 to 4 heteroatoms independently selected from: nitrogen, which may be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The 7- to 10-membered bicyclic heterocycle may be linked through a nitrogen or carbon atom. Examples of heterocycles include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, 2-oxaoxazolidinyl, tetrahydrothienyl, imidazolinyl, hexahydropyrimidinyl, and benzodiazepine In one embodiment, the heterocycle is a 5- or 6-membered heterocycle. Typical 5-membered heterocyclic groups include pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, oxazolidinyl, 2-oxaoxazolidinyl, tetrahydrothienyl, and imidazolidinyl. Typical 6-membered heterocyclic groups include piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, and hexahydropyrimidinyl.

[0181] Usable (heterocyclic group)alkyl or (heterocyclic)alkyl includes any of the above-mentioned C 1-10 alkyls substituted by any of the above-mentioned heterocyclic groups or heterocyclic moieties, and preferably any of the above-mentioned C 1-6 alkyls (e.g., (pyrrolidin-2-yl)methyl, (pyrrolidin-1-yl)methyl, (piperidin-1-yl)methyl, (morpholin-4-yl)methyl, (2-oxooxazolidin-4-yl)methyl, 2-(2-oxooxazolidin-4-yl)ethyl, (2-oxoimidazolin-1-yl)methyl, (2-oxoimidazolin-1-yl)ethyl, and (2-oxoimidazolin-1-yl)propyl).

[0182] As used herein, the term "heteroaryl" refers to a group having from 5 to 14 ring atoms, sharing 6, 10 or 14 π electrons in a cyclic array and containing carbon atoms and 1, 2 or 3 heteroatoms of oxygen, nitrogen or sulfur or 4 nitrogen atoms. In one embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In one embodiment, the heteroaryl is a 5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, N and S. Examples of heteroaryl include thienyl, furyl, pyranyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolinyl, quinolinyl, pyrimidinyl, thiazolyl, isothiazolyl and isoxazolyl. The 5-membered heteroaryl may contain up to 4 heteroatoms. The 6-membered heteroaryl may contain up to 3 heteroatoms.

[0183] As used herein, the term "amino" or "amino group" refers to -NH2.

[0184] Suitable aminoalkyls include any of the above-mentioned C 1-112 alkyls substituted with one or more amino groups, and preferably any of the above-mentioned C 1-6 alkyls, and more preferably any of the above-mentioned C 1-4 alkyls.

[0185] Suitable alkylamino and dialkylamino are -NHR 13 and -NR 13 R 14 respectively, where R 13 and R 14 are each independently selected from C 1-10 alkyl, preferably C 1-6 alkyl, and more preferably C 1-4 alkyl.

[0186] As used herein, the term "aminocarbonyl" refers to -C(=O)NH2.

[0187] Suitable alkylcarbonyls include a carbonyl group substituted with any of the above-mentioned C 1-10 alkyls, i.e., -C(=O)-.

[0188] Suitable arylcarbonyls include a carbonyl group substituted with any of the above-mentioned aryls (e.g., benzoyl).

[0189] Suitable alkylcarbonyloxy or acyloxy includes an oxygen atom substituted with any of the above-mentioned alkylcarbonyls.

[0190] Suitable alkylcarbonylamino or acylamino includes any of the above-mentioned alkylcarbonyls attached to the amino nitrogen, such as methylcarbonylamino.

[0191] As used herein, the term "carboxamido" refers to a group of the formula -C(=O)NR 15 R 16 wherein R 15 and R 16 are each independently hydrogen, optionally substituted C 1-10 alkyl or optionally substituted aryl. Exemplary carboxamidos include -CONH2, -CON(H)CH3, -CON(CH3)2 and -CON(H)Ph.

[0192] As used herein, the term "sulfonamido" refers to a group of the formula -SO2NR 17 R 18 wherein R 17 and R 18 are each independently hydrogen, optionally substituted C 1-10 alkyl or optionally substituted aryl. Exemplary sulfonamidos include -SO2NH2, -SO2N(H)CH3 and -SO2N(H)Ph.

[0193] As used herein, the term "thiol" refers to -SH.

[0194] Available mercaptoalkyls include any of the above-mentioned C 1-12 alkyls substituted with an -SH group, and preferably any of the above-mentioned C 1-6 alkyls.

[0195] As used herein, the term "carboxyl" refers to -COOH.

[0196] Available carboxyalkyls include any of the above-mentioned C 1-12 alkyls substituted with a -COOH group, and preferably any of the above-mentioned C 1-6 alkyls.

[0197] As used herein, the term "hydroxyl (hydroxyl or hydroxy)" refers to -OH.

[0198] Available hydroxyalkyls include any of the above-mentioned C 1-12 alkyls substituted with one or more hydroxyl groups, preferably any of the above-mentioned C 1-6 alkyls, and preferably any of the above-mentioned C 1-4 alkyls. Representative hydroxy(C 1-6 )alkyls include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl and 1,3-dihydroxypropan-2-yl.

[0199] As used herein, the term "cyano" means -CN.

[0200] As used herein, the term "nitro" means -NO2.

[0201] As used herein, the term "ureido" means -NH-C(=O)-NH2.

[0202] As used herein, the term "azido" means -N3.

[0203] As used herein, the term "ambient temperature" means the surrounding temperature. The ambient temperature indoors is the same as the room temperature and is about 20 °C to about 25 °C.

[0204] As used herein, the term "about" when used in connection with a measured quantity means the normal variation of that measured quantity as would be expected by a person of ordinary skill in the art making the measurement and exercising a level of care commensurate with the precision of the measurement goal and the measuring equipment. Generally, the term "about" includes the recited numerical value ± 10%. Thus, "about 10" means 9 to 11. As used herein, the term "optionally substituted" means that a group can be unsubstituted or substituted.

[0205] When not otherwise specified, the optional substituents on an optionally substituted group include one or more groups, typically 1, 2, or 3 groups, independently selected from the group consisting of: the halogen groups mentioned above, halo(C 1-6 )alkyl, aryl, heterocycle, cycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, cycloalkyl(C 1-6 )alkyl, heterocycle(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, amino(C 1-6 ), carboxy(C 1-6 )alkyl, alkoxy(C 1-6 )alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino, hydroxy, mercapto, alkylcarbonyloxy, aryloxy, ar(C 1-6 )alkoxy, carboxamido, sulfonamido, azido, C 1-6 alkoxy, halo(C 1-6 )alkoxy, carboxy, aminocarbonyl, (=O) and mercapto(C 1-6 )alkyl. Preferred optional substituents include halogen, halo(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, hydroxy, nitro, C1-6 alkyl, C 1-6 alkoxy, halo(C 1-6 )alkoxy, and amino.

[0206] The compounds of the present disclosure encompass all salts of the compounds of any one of Formulas I-VI. The present invention preferably includes all non-toxic pharmaceutically acceptable salts of the compounds of the present disclosure. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salts, potassium salts, cesium salts, etc.; alkaline earth metals such as calcium salts, magnesium salts, etc.; organic amine salts such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.; inorganic acid salts such as hydrochloride salts, hydrobromide salts, phosphate salts, sulfate salts, etc.; organic acid salts such as citrate salts, lactate salts, tartrate salts, maleate salts, fumarate salts, mandelate salts, acetate salts, dichloroacetate salts, trifluoroacetate salts, oxalate salts, formate salts, etc.; sulfonate salts such as methanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate salts, etc.; and amino acid salts such as arginine salts, asparagine salts, glutamate salts, etc.

[0207] Acid addition salts can be formed by mixing a solution of a specific compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, etc. Basic salts can be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, etc.

[0208] The compounds of the present disclosure also encompass solvates of any of the compounds of Formulas I - VI. Solvates generally do not significantly alter the physiological activity or toxicity of the compound and can thus be used as pharmacologically equivalent substances. As used herein, the term "solvate" refers to the combination, physical association, and / or fusion of a compound of the invention with solvent molecules, such as, for example, a disolvate, a monosolvate, or a hemisolvate, wherein the ratio of solvent molecules to the compound of the invention is approximately 2:1, approximately 1:1, or approximately 1:2, respectively. Such physical associations involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be isolated, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolable solvates. The compounds of the present disclosure can exist in the form of solvates with pharmaceutically acceptable solvents (such as water, methanol, ethanol, etc.), and it is intended that the invention includes both solvate and non-solvate forms of the compounds of any one of Formulas I - VI. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates wherein the solvent molecule is water. Solvates are generally useful as pharmacologically equivalent substances. The preparation of solvates is known in the art. See, for example, M. Caira et al., J. Pharmaceut. Sci., 93(3):601 - 611 (2004), which describes the preparation of a solvate of fluconazole with ethyl acetate and water. E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004) and A.L. Bingham et al., Chem. Commun.:603 - 604 (2001) describe similar preparations of solvates, hemisolvates, hydrates, etc. Typical non-limiting methods for preparing solvates will include dissolving a compound of any one of Formulas I - VI in the desired solvent (organic, aqueous, or a mixture thereof) at a temperature above about 20°C to about 25°C, followed by cooling the solution at a rate sufficient to form crystals, and separating the crystals by known methods such as filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in the solvate crystals.

[0209] The compounds of the present disclosure can be isotopically labeled (i.e., radioactively labeled). Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S,18 F and 36 Cl, and preferably 3 H, 11 C and 14 C. In view of the present disclosure, the isotopically labeled compounds of the present invention can be prepared by methods known in the art. For example, the tritiated compounds of the present disclosure can be prepared by introducing tritium into a specific compound by catalytic dehalogenation with tritium. The method can include reacting a suitable halogen-substituted precursor of the compounds of the present disclosure with tritium gas in the presence of a base in the presence of a suitable catalyst such as Pd / C. Other suitable methods for preparing tritiated compounds can be found in Filer, Isotopes in the Physical and Biomedical Sciences, Volume 1, Labeled Compounds (Part A), Chapter 6 (1987). 14 11C-carbon labeled compounds can be prepared using starting materials having 14 11C-carbon.

[0210] The isotopically labeled compounds of the present disclosure, their pharmaceutically acceptable salts and solvates, can be used as radioligands to test the binding of compounds to opioid receptors. For example, the radiolabeled compounds of the present disclosure can be used to characterize the specific binding of test or candidate compounds to the receptor. Binding assays using such radiolabeled compounds can provide an in vitro alternative to animal testing for evaluating structure-activity relationships. For example, receptor assays can be performed in a competitive assay with a fixed concentration of the radiolabeled compound of the present disclosure and increasing concentrations of the test compound. In one non-limiting embodiment, the present invention provides a method for screening the ability of a candidate compound to bind to an opioid receptor, the method comprising: a) introducing a fixed concentration of the radiolabeled compound into a receptor under conditions that allow the radiolabeled compound of the present disclosure to bind to the receptor to form a complex; b) titrating the complex with the candidate compound; and c) determining the binding of the candidate compound to the receptor.

[0211] Some of the compounds disclosed herein may contain one or more asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms, such as epimers. The present invention is intended to cover all such possible forms, as well as their racemic and resolved forms and the use of their mixtures. In view of the present disclosure, individual enantiomers can be separated according to methods known to those of ordinary skill in the art. When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, they are intended to include both E geometric isomers and Z geometric isomers unless otherwise specified. All tautomers are also intended to be covered by the present invention.

[0212] As used herein, the term "stereoisomer" is a general term for all isomers of an individual molecule, the isomers differing only in the orientation of their atoms in space. It includes enantiomers and isomers of a compound having more than one chiral center that are not mirror images of each other (diastereomers).

[0213] The term "chiral center" refers to a carbon atom that is attached to four different groups.

[0214] The term "epimer" refers to a diastereomer in which only one of two or more tetrahedral stereocenters present in the corresponding molecular entity has an opposite configuration.

[0215] The term "stereocenter" is a group bearing atoms such that an interchange of any two groups results in a stereoisomer.

[0216] The term "enantiomer" or "enantiomeric" refers to molecules that are non-superimposable on their mirror images and are thus optically active, where an enantiomer rotates the plane of polarized light in one direction and its mirror-image compound rotates the plane of polarized light in the opposite direction.

[0217] The term "racemic" refers to a mixture of equal parts of enantiomers and the mixture is not optically active.

[0218] The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.

[0219] The term "a" or "an" means one or more.

[0220] The term "treatment" refers to the administration of a therapy in an amount, manner, or mode that is effective to ameliorate a condition, symptom, or parameter associated with a disorder or to prevent progression of a disorder to a statistically significant degree or to a degree detectable by one of ordinary skill in the art. The effective amount, manner, or mode can vary depending on the subject and can be tailored to the patient.

[0221] Open-ended terms such as "comprising," "including," "containing," and "having" mean "including."

[0222] The term "effective amount" or "therapeutically effective amount" of a compound of the present disclosure means the amount of a compound of the present disclosure that is capable of delivering a therapeutically effective dose of the parent opioid when administered as indicated.

[0223] Suitable hydroxy protecting groups for PG are well known and include, for example, any suitable hydroxy protecting group disclosed in Wuts, P.G.M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, 4th Edition, pages 16 - 430 (J. Wiley & Sons, 2007), which is incorporated herein by reference in its entirety. As used herein, the term "hydroxy protecting group" refers to a group that blocks (i.e., protects) the hydroxy functionality when reacting on other functional groups or a part of a molecule. Those skilled in the art will be familiar with the selection, attachment, and cleavage of protecting groups and will understand that many different protecting groups are known in the art and the suitability of one or another protecting group depends on the particular synthetic scheme planned. Suitable hydroxy protecting groups are generally capable of being selectively introduced and removed using mild reaction conditions that do not interfere with other parts of the subject compound. These protecting groups can be introduced or removed at appropriate stages using methods known in the art. The chemical nature of such groups, their methods of introduction and removal are known in the art and can be found, for example, in Greene, T.W. and Wuts, P.G.M. supra. Additional hydroxy protecting groups can be found, for example, in U.S. Patent No. 5,952,495, U.S. Patent Application Publication No. 2008 / 0312411, WO 2006 / 035195, and WO 98 / 02033, which are incorporated herein by reference in their entirety. Suitable hydroxy protecting groups include methoxymethyl, tetrahydropyranyl, tert - butyl, allyl, tert - butyldimethylsilyl, tert - butyldiphenylsilyl, acetyl, pivaloyl, benzoyl, benzyl (Bn), and p - methoxybenzyl.

[0224] As used herein, the term "delayed onset" or "delayed onset" refers to an increase in the onset time of the post - administration therapeutic effect provided by certain compounds of the present disclosure when acting as prodrugs, compared to the corresponding amount of the parent compound (e.g., the expected bioactive moiety) via the same route of administration over the same length of time.

[0225] As used herein, the terms "reduced abuse potential", "reduced abuse potential", etc. refer to a reduced potential for improper non - medical and / or recreational administration of certain compounds of the present disclosure compared to the parent compound, yet the compounds are still capable of delivering the desired therapeutic effect when administered as directed.

[0226] The terms used with respect to the potential for abuse or overdose, such as "decreased", "reduced", "diminished", or "lowered", mean at least about a 10% decrease in the potential for abuse or overdose as measured by one or more standard measures of such potential for abuse or overdose known in the art, with greater percentage changes being preferred for decreases in the potential for abuse and overdose. For example, the decrease can be greater than 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, or 99%.

[0227] As used herein, the term "opioid" refers to a compound that binds to opioid receptors, particularly to mu (μ), kappa (κ), delta (δ), and ORL1 receptors. Opioid compounds for use in this application include opioid agonists, opioid partial agonists, and opioid antagonists, such as oxycodone, hydromorphone, oxymorphone, buprenorphine, and hydrocodone. In one embodiment, the opioid compound (or parent compound) for use in this application is oxycodone or hydrocodone. In another embodiment, the opioid compound (or parent compound) is oxycodone.

[0228] As used herein, a compound that binds to a receptor and mimics the regulatory action of an endogenous ligand is defined as an "agonist". A compound that binds to a receptor and is only partially effective as an agonist is defined as a "partial agonist". A compound that binds to a receptor but does not produce a regulatory action, but rather blocks the binding of a ligand to the receptor, is defined as an "antagonist". (Ross and Kenakin, "Chapter 2: Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug Concentration and Effect", pages 31 - 32, Goodman & Gilman's the Pharmacological Basis of Therapeutics, 10th Edition (J.G. Hardman, L.E. Limbird, and A. Goodman - Gilman eds., 2001)).

[0229] As used herein, the term "opioid therapy" refers to the administration of an opioid to a subject for the treatment or prevention of a disorder for which an opioid compound has been shown to be effective in treating, improving, or preventing.

[0230] In certain embodiments, opioid therapy is used for pain management (e.g., treating, improving, or preventing pain). In another embodiment, opioid therapy is used to treat, prevent, or mitigate opioid-induced adverse pharmacodynamic responses such as euphoria, bowel dysfunction (e.g., constipation, reduced gastric emptying, abdominal colic, cramps, bloating, delayed gastrointestinal transit), nausea, vomiting, somnolence, dizziness, respiratory depression, headache, dry mouth, sedation, sweating, fatigue, hypotension, restlessness, delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence, and tolerance. In a separate embodiment, opioid therapy can be used to treat diarrhea, cough, anxiety (e.g., caused by shortness of breath), and opioid dependence. In another embodiment, opioid therapy can be used to treat, prevent, or mitigate opioid withdrawal.

[0231] As used herein, the term "Oxy" refers to oxycodone.

[0232] Synthesis of the Compounds of the Present Disclosure

[0233] In view of the present disclosure, the compounds of the present disclosure can be prepared using methods known to those skilled in the art or by the illustrative methods shown in the following schemes. For example, the compounds of the present disclosure can be prepared as shown in Scheme A and Scheme B below. Other synthetic methods are described and illustrated in the working examples set forth below.

[0234] Scheme A

[0235]

[0236] A compound of formula IV (wherein R 31 is hydrogen or OH and R 1 , R 4 and R 5 are as defined above for formula I) can be prepared by first mixing compound A (wherein R 31 is hydrogen or OH and R 1 and R 4 are as defined above for formula I) with lithium bis(trimethylsilyl)amide in a suitable polar aprotic solvent such as tetrahydrofuran (THF) at about -70 °C to about -80 °C, and preferably at about -78 °C. The reaction mixture is then allowed to warm to room temperature and stirred at room temperature for about 30 minutes to about 1 hour. The reaction mixture is then re-cooled to a temperature of about -70 °C to about -80 °C, and preferably to about -78 °C, and a suitable acid anhydride of formula (R 5 CO)2O or a reagent of formula R 5 C(=O)X is added to the mixture, wherein R 5 is as defined above for formula I and X is a suitable leaving group such as Cl.

[0237] In another embodiment, a compound of formula IV (wherein R 31 is hydrogen) is prepared by the method of Scheme A. In another embodiment, a compound of formula IV (wherein R 31 is OH) is prepared by the method of Scheme A.

[0238] In another embodiment, in Scheme A, compound A is oxycodone. In another embodiment, the acid anhydride in step 2) is acetic anhydride to obtain 6-acetyl oxycodone.

[0239] A compound of formula I (wherein R 2 is -C(=O)R 5 , and R 3 is -OC(=O)R 6 , where R 5 and R 6 are the same and are as defined above for formula I) can be prepared as shown in Scheme B below to obtain a compound of formula V.

[0240] Scheme B

[0241]

[0242] In Scheme B, R 1 , R 4 and R 5 are as defined above for formula I. Thus, a compound of formula V can be prepared by reacting compound B with an acid anhydride of the appropriate formula (R 5 CO)2O or a reagent of the formula R 5 C(=O)X, where X is a suitable leaving group such as Cl.

[0243] For example, as described in WO 2011 / 088140, compounds of any of formulas I-III comprising substituents containing PEG can be prepared.

[0244] In some non-limiting embodiments, compounds of formulas I-VI are converted to their salts using techniques commonly known to those of ordinary skill in the art. In other embodiments, the salts are pharmaceutically acceptable salts.

[0245] Administration of the compounds of the present disclosure

[0246] The compounds of the present disclosure can act as prodrugs and thereby exhibit one or more advantages over the parent opioid drugs. For example, when inadvertently orally administered at a dose higher than the prescribed dose, the compounds of the present disclosure can be used to prevent accidental overdose by exhibiting a delayed onset of pharmacological activity. In some embodiments, when administered by a non-oral route (e.g., parenteral) that may be employed by abusers, the compounds of the present disclosure can deter abuse by substantially maintaining their prodrug chemical form. Thus, when administered by a parenteral route commonly used for illicit purposes, particularly intravenous, intranasal, and / or inhalation routes, the compounds of the present disclosure deter abuse by reducing the extractability and solubility of the active opioid molecule in an aqueous or alcoholic medium and thereby reducing the availability of the active opioid molecule.

[0247] In some embodiments, the compounds of the present disclosure have little or a different affinity for the μ-opioid receptor compared to the affinity of the parent opioid. Under the acidic conditions of the stomach, the compounds of the present disclosure cannot be converted from the prodrug form to the parent opioid. Instead, under the conditions of the intestine, the compounds of the present disclosure can be converted from the prodrug form to the parent opioid via enzyme-assisted hydrolysis. Compared to directly orally administering the parent opioid, the gradual conversion of the compounds of the present disclosure to the parent opioid upon oral administration to a mammal should result in a gradual but delayed systemic exposure to the parent opioid.

[0248] Opioid prodrugs that provide a gradual conversion to the parent opioid may be less attractive to substance abusers or non-medical recreational users of opioids who seek drugs to provide a rapid euphoria. Since the conversion from the compounds of the present disclosure to the parent opioid will be slower, the onset of euphoria will likewise be slower, thereby making the compounds of the present invention appear less attractive to those who would attempt such non-medical use of the drug.

[0249] In many cases, opioid abuse via the oral route involves immediate-release drugs, or drugs that have been tampered with using controlled-release materials for delaying the release and absorption of the opioid from the dosage form. Immediate-release opioids generally provide a pharmacologically relevant plasma concentration, the onset of a therapeutic effect, and in the case of recreational drug users, the onset of euphoria within about 15 to 180 minutes, 15 to 120 minutes, or 15 to 90 minutes after oral administration.

[0250] The gradual conversion of the compounds of the present invention to the parent opioid in the GI tract can delay the time to reach a pharmacologically relevant plasma concentration of oxycodone, e.g., by providing a lower C max and / or a later T maxand is used to delay and thus reduce any euphoric effects otherwise produced by the opioid. Accordingly, in some embodiments, the dosage forms of the present invention will have a lower potential for abuse and misuse.

[0251] In certain embodiments, a pharmaceutical composition containing a compound of the present disclosure can achieve a delayed release profile of the pharmaceutically active ingredient (e.g., an opioid analgesic). For example, the compounds of the present invention can be slowly converted to the parent opioid compound in the GI tract of a patient upon oral administration. In such cases, such pharmaceutical compositions are considered delayed release formulations.

[0252] Delayed release formulations prevent the rapid onset of the pharmacological effect and are formulated in such a way that the pharmaceutically active ingredient is available over an extended period of time. In some embodiments, the compounds of the present disclosure can achieve a delayed release profile simply based on the fact that they need to be converted to the parent opioid. Thus, in one embodiment, the compounds of the present disclosure can be formulated without using controlled release excipients but still produce a delayed release of the opioid upon oral administration.

[0253] Delayed release formulations can also include formulation features, e.g., by incorporating a sustained release matrix or a sustained release coating or some variation thereof, to achieve a delayed release profile of one or more parent opioid compounds. Controlled release formulation techniques are well known in the art and can be combined with the present invention to obtain a particular desired release profile. In some embodiments, the parent opioid and one or more compounds of the present disclosure can be combined into a single oral dosage form, wherein the opioid provides an immediate release profile and the one or more compounds of the present invention effectively provide a delayed release profile of oxycodone. Such combination formulations may or may not also contain a sustained release matrix or a sustained release coating or some variation thereof.

[0254] The present disclosure also provides a method of treating pain in a mammal (e.g., a human patient) determined to be in need thereof, the method comprising administering to the mammal an effective amount of a compound of the present disclosure. In certain embodiments, the compound of the present disclosure is administered orally to the mammal.

[0255] In one embodiment, the present disclosure provides a method of reducing the potential for abuse of an opioid in a mammal in need of opioid therapy, the method comprising orally administering to the mammal an effective amount of a compound of the present disclosure that exhibits reduced parenteral (i.e., non-oral) bioavailability compared to the parent opioid.

[0256] In another embodiment, the present disclosure provides a method of reducing the abuse potential of oxycodone in a mammal in need of oxycodone therapy, the method comprising orally administering to the mammal an effective amount of a compound of any one of Formulas II-V or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is CH3, R 3 / R 31 is OH, R 4 is CH3, and R 2 is -C(=O)R 5 and R 5 is as defined above for Formula II. In another embodiment, the method comprises administering a compound selected from the group consisting of:

[0257] or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, 6-acetyl oxycodone or a pharmaceutically acceptable salt or solvate thereof is administered.

[0258] In another embodiment, the present disclosure provides a method of treating pain and reducing the abuse potential of oxycodone in a mammal in need of oxycodone therapy, the method comprising orally administering to the mammal an effective amount of a compound of Formula VI or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is CH3, R 4 is CH3, and R 3 is -OC(=O)R 6 and R 6 is as defined above for Formula I. In another embodiment, the method comprises administering the compound

[0259]

[0260] In another embodiment, the present disclosure provides a method of treating pain and reducing the abuse potential of oxymorphone in a mammal in need of oxymorphone therapy, the method comprising orally administering to the mammal an effective amount of a compound of Formula II or Formula III or a pharmaceutically acceptable salt or solvate thereof, wherein in the compound of Formula II or Formula III, R 1 is hydrogen, R 3 is OH, R 4 is CH3, and R 2 is -C(=O)R 5 and R 5As defined above for Formula II. Alternatively, administering an effective amount of a compound of Formula IV or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, R 31 is OH, R 4 is methyl, and R 5 is as defined above for Formula II.

[0261] In one embodiment, the present disclosure provides a method of treating pain and reducing the abuse potential of hydrocodone in a mammal in need of hydrocodone therapy, the method comprising orally administering to the mammal an effective amount of a compound of any one of Formulas II-IV or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is CH3, R 3 / R 31 is H, R 4 is CH3, and R 2 is -C(=O)R 5 and R 5 is as defined above for Formula II, provided that the compound is not

[0262]

[0263] In one embodiment, the present disclosure provides a method of treating pain and reducing the abuse potential of hydromorphone in a mammal in need of hydromorphone therapy, the method comprising orally administering to the mammal an effective amount of a compound of any one of Formulas II-IV or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H, R 3 or R 31 is H, R 4 is CH3, and R 2 is -C(=O)R 5 and R 5 is as defined above for Formula II, provided that the compound is not

[0264]

[0265] In one embodiment, the present disclosure provides a method of reducing the abuse potential of a parent opioid compound, the method comprising orally administering to the mammal an effective amount of a compound of any one of Formulas I-VI or a pharmaceutically acceptable salt or solvate thereof, provided that 1) the compound is not

[0266]

[0267] 2) when R 1 is an unsubstituted alkyl, R 3 is hydrogen and R 4 is unsubstituted C1-6 When R is an alkyl group, then R 5 is not an optionally substituted phenyl group or an optionally substituted pyridyl group; or

[0268] 3) When R 1 is an unsubstituted alkyl group, R 4 is an unsubstituted C 1-6 alkyl group and R 3 is -OC(=O)R 6 then R 5 and R 6 are both not an optionally substituted pyridyl group. In one embodiment, the present disclosure provides a method for reducing the abuse potential of a parent opioid compound, the method comprising orally administering to the mammal an effective amount of a compound of any one of Formulas I to VI or a pharmaceutically acceptable salt or solvate thereof, provided that the compound is not

[0269]

[0270] In one embodiment, the present invention is a method for effecting such therapy in a mammal in need of opioid therapy (e.g., for treating pain), the method comprising orally administering to the mammal a therapeutically effective amount of a compound of any one of Formulas I to VI or a pharmaceutically acceptable salt or solvate thereof, wherein at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% of the compound of any one of Formulas I to VI or a pharmaceutically acceptable salt or solvate thereof is hydrolyzed into the parent opioid in intestinal fluid at pH 6.8 in the presence of pancreatin at 37°C within about 2 hours.

[0271] In one embodiment, the present invention is a method for effecting such therapy in a mammal in need of oxycodone therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound of any one of Formulas II to IV or a pharmaceutically acceptable salt or solvate thereof, wherein in the compounds of Formulas II to IV, R 1 is CH3, R 3 / R 31 is OH, R 4 is CH3, and R 2 is -C(=O)R 5 , and R 5 is as defined above for Formula II, wherein at least about 10%, at least about 20%, at least about 30%, at least about 40% or at least about 50% of the compound of any one of Formulas II to IV or a salt or solvate thereof is hydrolyzed into oxycodone in intestinal fluid at pH 6.8 in the presence of pancreatin at 37°C within about 2 hours.

[0272] In a particular embodiment, the method comprises orally administering to the mammal a therapeutically effective amount of a compound of any one of Formulas II-IV or a pharmaceutically acceptable salt or solvate thereof, wherein in the compounds of Formulas II-IV, R 1 is CH3, R 3 / R 31 is OH, R 4 is CH3, and R 2 is -C(=O)R 5 and R 5 is as defined above for Formula II, wherein at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 90% or about 100% of the compound of any one of Formulas II-IV or its salt or solvate is hydrolyzed to oxycodone in intestinal fluid at pH 6.8 in the presence of pancreatin at 37°C within about 2 hours.

[0273] In one embodiment, the method comprises orally administering 6-acetyl oxycodone or a pharmaceutically acceptable salt thereof, wherein about 80%, about 90%, about 95% or about 100% of 6-acetyl oxycodone or its salt is hydrolyzed to oxycodone in intestinal fluid at pH 6.8 in the presence of pancreatin at 37°C within about 2 hours.

[0274] In another embodiment, the present disclosure provides a method of reducing the abuse potential of oxycodone in a mammal in need of oxycodone therapy, the method comprising orally administering to the mammal an effective amount of a compound of Formula VI or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is CH3, R 4 is CH3, and R 3 is -OC(=O)R 6 and R 6 is as defined above for Formula I, wherein at least about 10%, at least about 20%, at least about 30%, at least about 40% or at least about 50% of the compound of Formula VI or its salt or solvate is hydrolyzed to oxycodone in intestinal fluid at pH 6.8 in the presence of pancreatin at 37°C within about 2 hours.

[0275] In some embodiments, the bioavailability of a compound of any one of Formulas I-VI or a pharmaceutically acceptable salt or solvate thereof as a parent opioid provided by any parenteral route (e.g., intravenous, intranasal, or inhalation) is less than about 70%, less than about 50%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the bioavailability of the parent opioid administered by the same route.

[0276] In other embodiments, the present disclosure provides an extended-release formulation of oxycodone, the formulation comprising an effective amount of

[0277]

[0278] or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients or carriers. The extended-release formulation of oxycodone may further comprise oxycodone or a pharmaceutically acceptable salt or solvate thereof in immediate-release form or extended-release form or both. The present disclosure also provides methods of using such extended-release oxycodone formulations, such as methods of treating pain in a mammal in need of opioid therapy or methods of reducing the potential for abuse of an opioid in a mammal in need of opioid therapy.

[0279] The compounds of the present disclosure exhibit a relatively high degree of stability, i.e., resistance to hydrolysis, when subjected to "kitchen chemistry" that might be used by potential abusers.

[0280] 6-Substituted enol esters and their use as prodrugs

[0281] The inventors have found that certain 6-substituted enol esters of Formula IV as defined above are μ-opioid receptor agonists and can also be used as prodrugs, i.e., they can be used for the same purposes as their parent opioid compounds. Thus, when these compounds are made bioavailable from a dosage form such as, for example, a transdermal, subcutaneous, intramuscular, intravenous, or parenteral dosage form, they are analgesic compounds. When these 6-substituted enol esters are administered orally to a patient, they are converted to the parent opioid, such as oxycodone, in certain parts of the patient's gastrointestinal tract. Thus, a formulation containing certain 6-substituted enol esters can provide μ-opioid agonist function from both the prodrug of Formula IV and the parent opioid for a period of time after oral administration.

[0282] In this aspect of the invention, the present disclosure provides the following specific embodiments.

[0283] {Ia}. A compound of Formula IV:

[0284]

[0285] or a pharmaceutically acceptable salt or solvate thereof, wherein

[0286] R 1 、R 4 and R 5 are as defined above for formula I or II, and R 31 is hydrogen or OH.

[0287] {IIa}. The compound according to {Ia} or a pharmaceutically acceptable salt or solvate thereof, wherein

[0288] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[0289] R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of said groups optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[0290] R 5 is selected from the group consisting of unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p -R 7 ;

[0291] R7 selected from the group consisting of hydrogen and C 1-6 alkyl;

[0292] m is an integer between 1 and 9;

[0293] n and p are each independently an integer between 1 and 20; and

[0294] PEG is an ethylene oxide unit or an oligomer having 2 to about 10 ethylene oxide subunits, provided that the compound is not

[0295]

[0296] {IIIa}. The compound according to claim {IIa} or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl, and R 4 is unsubstituted C 1-6 alkyl.

[0297] {IVa}. The compound according to claim {IIa} or {IIIa} or a pharmaceutically acceptable salt thereof, wherein R 3 is OH.

[0298] {Va}. The compound according to any one of {IIa}-{IVa} or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 4 are methyl.

[0299] {VIa}. The compound according to any one of {IIa}-{Va} or a pharmaceutically acceptable salt thereof, wherein R 5 is unsubstituted C 1-6 alkyl.

[0300] {VIIa}. The compound according to any one of {IIa}-{VIa} or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.

[0301] {VIIIa}. The compound according to any one of {IIa}-{Va} or a pharmaceutically acceptable salt thereof, wherein R 5 is unsubstituted C 7-12 alkyl.

[0302] {IXa}. The compound according to any one of {IIa}-{Va} and {VIIIa} or a pharmaceutically acceptable salt thereof, wherein R 5 is unsubstituted heptyl, octyl or nonyl.

[0303] {Xa}. A compound as described in any one of {IIa}-{Va} and {VIIIa} or a pharmaceutically acceptable salt thereof, wherein R 5 is an unsubstituted decyl, undecyl or dodecyl.

[0304] {XIa}. A compound as described in {Xa} or a pharmaceutically acceptable solvate thereof, wherein R 5 is undecyl.

[0305] {XIIa}. A compound as described in any one of {IIa}-{Va} or a pharmaceutically acceptable salt thereof, wherein

[0306] R 5 is selected from the group consisting of: -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p -R 7 ;

[0307] R 7 is hydrogen or C 1-4 alkyl;

[0308] m is 1, 2, 3, 4 or 5;

[0309] n and p are each independently selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0310] {XIIIa}. A compound as described in any one of {IIa}-{Va} and {XIIa} or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen or methyl.

[0311] {XIVa}. A compound as described in any one of {IIa}-{Va} and {XIIa} or a pharmaceutically acceptable salt thereof, wherein R 5 is -CH2-O-(CH2CH2O) m -R 7 .

[0312] {XVa}. A compound as described in any one of {IIa}-{Va} and {XIIa}-{XIVa} or a pharmaceutically acceptable salt thereof, wherein m is 1, 2 or 3.

[0313] {XVIa}. A compound as described in {XVa} or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0314] {XVIIa}. The compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of {XIVa}-{XVIa}, wherein R 7 is methyl.

[0315] {XVIIIa}. The compound as described in {Ia} and any one of {IIa}-{VIIa}, the compound being

[0316]

[0317] or a pharmaceutically acceptable salt or solvate thereof.

[0318] {XIXa}. The compound as described in {XVIIIa}, the compound being

[0319]

[0320] or a pharmaceutically acceptable salt or solvate thereof.

[0321] {XXa}. The compound as described in {IIa}, the compound being

[0322]

[0323] or a pharmaceutically acceptable salt or solvate thereof.

[0324] {XXIa}. A pharmaceutical composition, the pharmaceutical composition comprising the compound as described in any one of {Ia}-{XXa} or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0325] {XXIIa}. A composition, the composition comprising one or more compounds as described in {Ia}-{XXa} or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

[0326] {XXIIIa}. The composition as described in {XXIIa}, the composition comprising from about 0.1 wt% to about 30 wt% of the at least one parent opioid.

[0327] {XXIVa}. The composition as described in {XXIIa} or {XXIIIa}, the composition comprising from about 1 wt% to about 20 wt% of the at least one parent opioid.

[0328] {XXVa}. The composition as described in any one of {XXIIa}-{XXIVa}, wherein the at least one parent opioid is oxycodone.

[0329] {XXVIa}. An oral formulation, said oral formulation comprising a therapeutically effective amount of a composition as described in any one of {XXIIa}-{XXVa}.

[0330] {XXVIIa}. A method of treating or preventing a disorder in a patient responsive to modulation of one or more opioid receptors, said method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound as described in any one of {Ia}-{XXa} or a pharmaceutically acceptable salt or solvate thereof.

[0331] {XXVIIIa}. The method as described in {XXVIIa}, wherein said disorder is pain.

[0332] {XXIXa}. A method of treating, ameliorating or preventing pain in a patient, said method comprising administering to a patient in need of such treatment, amelioration or prevention an effective amount of a compound as described in any one of {Ia}-{XXa} or a pharmaceutically acceptable salt or solvate thereof.

[0333] {XXXa}. The method as described in {XXIXa}, wherein said method is for treating pain.

[0334] {XXXIa}. The method as described in {XXXa}, wherein said pain is acute pain, chronic pain or surgical pain.

[0335] {XXXIIa}. The method as described in {XXXIa}, wherein said pain is chronic pain.

[0336] {XXXIIIa}. The method as described in {XXXIIa}, wherein said chronic pain is neuropathic pain, postoperative pain or inflammatory pain.

[0337] {XXXIVa}. A method of slowing the onset of opioid activity in a mammal in need of opioid therapy, said method comprising orally administering to said mammal a therapeutically effective amount of a compound or mixture of compounds as described in any one of {Ia}-{XXa}, or a pharmaceutically acceptable salt or solvate thereof.

[0338] {XXXVa}. A method of treating a disorder in a mammal in need of opioid therapy responsive to modulation of one or more opioid receptors and delaying the onset of opioid activity, said method comprising orally administering to said mammal a therapeutically effective amount of a compound or mixture of compounds as described in any one of {Ia}-{XXa}, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, said method further comprises one or more parent opioid compounds, wherein the total amount of the compounds of the present disclosure and the parent opioid compounds constitutes said therapeutically effective amount.

[0339] {XXXVIa}. A method as described in {XXXIVa} or {XXXVa}, the method further comprising co-administering one or more other therapeutic agents.

[0340] {XXXVIIa}. A method as described in {XXXVIa}, wherein the one or more other therapeutic agents are one or more non-steroidal anti-inflammatory agents.

[0341] {XXXVIIIa}. A method as described in {XXXVIa}, wherein the one or more other therapeutic agents are one or more opioid agonists.

[0342] {XXXIXa}. A method as described in {XXXVIa}, wherein the one or more other therapeutic agents are one or more opioid antagonists.

[0343] Short-chain 14-substituted enol esters and their use as prodrugs

[0344] The inventors have discovered that certain 14-substituted enol esters of formula VI having a short-chain substituent at the 14-position act as μ-opioid receptor agonists and can be used as prodrugs. Thus, when these compounds are made bioavailable from dosage forms such as, for example, transdermal, subcutaneous, intramuscular, intravenous or parenteral dosage forms, they are analgesic compounds. When the prodrugs are orally delivered to a patient and made bioavailable only in the lower gastrointestinal tract of the patient, they are converted over time to parent opioids such as oxycodone, thereby providing μ-opioid agonist function from both the prodrug of formula VI and the parent opioid.

[0345] In this aspect of the invention, the present disclosure provides the following specific embodiments.

[0346] {Ib}. A compound of formula VI:

[0347]

[0348] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0349] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[0350] R4 selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any one of said groups being optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[0351] R 3 is -OC(=O)R 6 wherein R 6 is selected from the group consisting of: unsubstituted C 1-4 alkyl, unsubstituted C 2-4 alkenyl, unsubstituted C 2-4 alkynyl or -CH2-O-(CH2CH2O) m -R 7 ;

[0352] m is 1;

[0353] R 7 is selected from the group consisting of: hydrogen and C 1-6 alkyl; and

[0354] PEG is an ethylene oxide unit or an oligomer having from 2 to about 10 ethylene oxide subunits,

[0355] provided that the compound is not

[0356]

[0357] {IIb}. The compound according to {Ib} or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is unsubstituted methyl, ethyl, propyl or butyl.

[0358] {IIIb}. The compound according to {Ib} or a pharmaceutically acceptable salt thereof, wherein R 6 is unsubstituted C 2-4 alkenyl, unsubstituted C 2-4 alkynyl or -CH2-O-CH2CH2O-R 7 ; and R 7 is selected from the group consisting of: hydrogen or methyl.

[0359] {IVb}. A compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of {Ib}-{IIIb}, wherein R 1 is H or unsubstituted C 1-6 alkyl, and R 4 is unsubstituted C 1-6 alkyl.

[0360] {Vb}. A compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of {Ib}-{IVb}, wherein R1 and R 4 are methyl.

[0361] {VIb}. A compound as described in {Vb}, wherein R 6 is unsubstituted ethyl, propyl or butyl.

[0362] {VIIb}. A pharmaceutical composition comprising a compound having the formula VI:

[0363]

[0364] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0365] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of hydroxyl, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxyl, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[0366] R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of the groups optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of hydroxyl, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxyl, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[0367] R 3 is - OC(=O)R 6 wherein R 6 is selected from the group consisting of: unsubstituted C 1-4 alkyl, unsubstituted C 2-4 alkenyl, unsubstituted C 2-4 alkynyl or - CH2 - O - (CH2CH2O) m -R 7 ;

[0368] m is 1;

[0369] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl; and

[0370] PEG is an ethylene oxide unit or an oligomer having from 2 to about 10 ethylene oxide subunits,

[0371] and one or more pharmaceutically acceptable carriers.

[0372] {VIIIb}. The pharmaceutical composition according to {VIIb}, the pharmaceutical composition comprising a compound according to any one of {Ib}-{VIb} or a pharmaceutically acceptable salt thereof.

[0373] {IXb}. The pharmaceutical composition according to {VIIb}, the pharmaceutical composition comprising

[0374] or a pharmaceutically acceptable salt or solvate thereof.

[0375] {Xb}. The pharmaceutical composition according to any one of {VIIb}-{IXb}, the pharmaceutical composition further comprising at least one parent opioid.

[0376] {XIb}. The pharmaceutical composition according to {Xb}, the pharmaceutical composition comprising from about 0.1% to about 30% of the at least one parent opioid.

[0377] {XIIb}. The pharmaceutical composition according to {Xb} or {XIb}, the composition comprising from about 1 wt% to about 20 wt% of the at least one parent opioid.

[0378] {XIIIb}. The pharmaceutical composition according to any one of {Xb}-{XIIb}, wherein the at least one parent opioid is oxycodone.

[0379] {XIVb}. The pharmaceutical composition according to any one of {VIIb}-{XIIIb}, wherein the composition is formulated for an oral dosage form.

[0380] {XVb}. A composition comprising one or more compounds as described in {Ib}-{VIb} or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

[0381] {XVIb}. The composition as described in {XVb}, the composition comprising from about 0.1 wt% to about 30 wt% of the at least one parent opioid.

[0382] {XVIIb}. The composition as described in {XVb} or {XVIb}, the composition comprising from about 1 wt% to about 20 wt% of the at least one parent opioid.

[0383] {XVIIIb}. The composition as described in any one of {XVb}-{XVIIb}, wherein the at least one parent opioid is oxycodone.

[0384] {XIXb}. An oral formulation comprising a therapeutically effective amount of the composition as described in any one of {XVb}-{XVIIIb}.

[0385] {XXb}. A method of treating or preventing a condition in a patient responsive to modulation of one or more opioid receptors, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound having formula VI:

[0386]

[0387] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0388] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[0389] R 4 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4)alkyl, any one of said groups being optionally substituted by 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[0390] R 3 is -OC(=O)R 6 , wherein R 6 is selected from the group consisting of: unsubstituted C 1-4 alkyl, unsubstituted C 2-4 alkenyl, unsubstituted C 2-4 alkynyl or -CH2-O-(CH2CH2O) m -R 7 ;

[0391] m is 1;

[0392] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl; and

[0393] PEG is an ethylene oxide unit or an oligomer having from 2 to about 10 ethylene oxide subunits.

[0394] {XXIb}. The method according to {XXb}, wherein a compound as described in any one of {Ib}-{VIb} or a pharmaceutically acceptable salt or solvate thereof is administered.

[0395] {XXIIb}. The method according to {XXb}, wherein the compound is

[0396] or a pharmaceutically acceptable salt or solvate thereof.

[0397] {XXIIIb}. The method according to any one of {XXb}-{XXIIb}, wherein the disorder is pain.

[0398] {XXIVb}. A method of treating, ameliorating or preventing pain in a patient, the method comprising administering to a patient in need of such treatment, amelioration or prevention an effective amount of a compound having the formula VI:

[0399]

[0400] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0401] R 1is H; C optionally substituted with 1, 2 or 3 substituents 1-6 alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[0402] R 4 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[0403] R 3 is -OC(=O)R 6 , wherein R 6 is selected from the group consisting of: unsubstituted C 1-4 alkyl, unsubstituted C 2-4 alkenyl, unsubstituted C 2-4 alkynyl or -CH2-O-(CH2CH2O) m -R 7 ;

[0404] m is 1;

[0405] R 7 is selected from the group consisting of: hydrogen and C 1-6 alkyl; and

[0406] PEG is an ethylene oxide unit or an oligomer having from 2 to about 10 ethylene oxide subunits.

[0407] {XXVb}. The method according to {XXIVb}, wherein a compound as described in any one of {Ib}-{VIb} or a pharmaceutically acceptable salt or solvate thereof is administered to a patient in need of such treatment, amelioration or prevention.

[0408] {XXVIb}. The method as described in {XXIVb}, wherein the compound is

[0409] or a pharmaceutically acceptable salt or solvate thereof.

[0410] {XXVIIb}. The method as described in any one of {XXIVb}-{XXVIb}, wherein the method is for treating pain.

[0411] {XXVIIIb}. The method as described in {XXVIIb}, wherein the pain is acute pain, chronic pain or surgical pain.

[0412] {XXIXb}. The method as described in {XXVIIIb}, wherein the pain is chronic pain.

[0413] {XXXb}. The method as described in {XXIXb}, wherein the chronic pain is neuropathic pain, postoperative pain or inflammatory pain.

[0414] {XXXIb}. A method for delaying the onset of opioid activity in a mammal in need of opioid therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds as described in any one of {Ib}-{VIIIc}, or a pharmaceutically acceptable salt or solvate thereof.

[0415] {XXXIIb}. A method for treating a condition in a mammal in need of opioid therapy that is responsive to the modulation of one or more opioid receptors and delaying the onset of opioid activity, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds as described in any one of {Ib}-{VIIIb}, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the method further comprises one or more parent opioid compounds, wherein the total amount of the compounds of the present disclosure and the parent opioid compounds constitutes the therapeutically effective amount.

[0416] {XXXIIIb}. The method as described in {XXXIb} or {XXXIIb}, the method further comprising co-administering one or more other therapeutic agents.

[0417] {XXXIVb}. The method as described in {XXXIIIb}, wherein the one or more other therapeutic agents are one or more non-steroidal anti-inflammatory agents.

[0418] {XXXVb}. The method as described in {XXXIIIb}, wherein the one or more other therapeutic agents are one or more opioid agonists.

[0419] {XXXVIb}. The method according to {XXXIIIb}, wherein said one or more other therapeutic agents are one or more opioid antagonists.

[0420] Medium-chain 6,14-disubstituted enol esters and their use as prodrugs

[0421] The inventors have discovered that certain 6,14-disubstituted enol esters of formula II having medium-length chains as substituents at both the 6- and 14-positions act as μ-opioid receptor agonists and can also be used as prodrugs. Thus, when these compounds are made bioavailable from dosage forms such as, for example, transdermal, subcutaneous, intramuscular, intravenous, or parenteral dosage forms, they are analgesic compounds. When the prodrugs are made bioavailable only in the lower gastrointestinal tract of the patient, they are converted to a parent opioid such as oxycodone over a period of time, thereby providing a μ-opioid agonist function from both the prodrug of formula II and the parent opioid.

[0422] In this aspect of the invention, the present disclosure provides the following specific embodiments.

[0423] {Ic}. A compound of formula II:

[0424]

[0425] Its pharmaceutically acceptable salt or solvate, wherein:

[0426] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[0427] R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of said groups optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4)Alkylamino, carboxyl, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[0428] R 2 is -C(=O)R 5 and R 3 is -OC(=O)R 6 wherein

[0429] R 5 and R 6 are the same or different and are selected from the group consisting of: straight-chain unsubstituted C 7-9 alkyl, straight-chain unsubstituted C 7-9 alkenyl, straight-chain unsubstituted C 7-9 alkynyl, -CH2-O-(CH2CH2O) m -R 7 -O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p -R 7 ;

[0430] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0431] m is 2 or 3;

[0432] n and p are each independently 2, 3 or 4; and

[0433] PEG is an ethylene oxide unit or an oligomer having 2 to about 10 ethylene oxide subunits.

[0434] {IIc}. The compound according to {Ic} or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 are each independently selected from the group consisting of heptyl, octyl, nonyl, -CH2-O-(CH2CH2O) m -R 7 -O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p -R 7 ; wherein R 7 is hydrogen or C 1-4 alkyl.

[0435] {IIIc}. The compound according to {Ic} or {IIc}, wherein R 5 and R 6 are the same and have the formula V:

[0436]

[0437] or a pharmaceutically acceptable salt or solvate thereof.

[0438] {IVc}. A compound as described in {IIIc} or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -CH2-O-(CH2CH2O) m -R 7 wherein R 7 is hydrogen or methyl.

[0439] {Vc}. A compound as described in {Ic} or {IIc} or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 are different.

[0440] {VIc}. A compound as described in any one of {Ic}-{Vc} or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl, and R 4 is unsubstituted C 1-6 alkyl.

[0441] {VIIc}. A compound as described in any one of {Ic}-{VIc} or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R 4 are methyl.

[0442] {VIIIc}. A compound as described in {Ic} or {IIIc}, the compound being

[0443]

[0444] or a pharmaceutically acceptable salt or solvate thereof.

[0445] {IXc}. A pharmaceutical composition comprising a compound as described in any one of {Ic}-{VIIIc} or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0446] {Xc}. A composition comprising one or more compounds as described in {Ic}-{VIIIc} or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

[0447] {XIc}. The composition as described in {Xc}, the composition comprising from about 0.1 wt% to about 30 wt% of the at least one parent opioid.

[0448] {XIIc}. A composition as described in {Xc} or {XIc}, said composition comprising from about 1 wt% to about 20 wt% of said at least one parent opioid.

[0449] {XIIIc}. A composition as described in any one of {Xc}-{XIIc}, wherein said at least one parent opioid is oxycodone.

[0450] {XIVc}. An oral formulation comprising a therapeutically effective amount of a composition as described in any one of {Xc}-{XIVc}.

[0451] {XVc}. A method of treating or preventing a disorder in a patient responsive to modulation of one or more opioid receptors, said method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound as described in any one of {Ic}-{VIIIc} or a pharmaceutically acceptable salt or solvate thereof.

[0452] {XVIc}. The method as described in {XVc}, wherein said disorder is pain.

[0453] {XVIIc}. A method of treating, ameliorating or preventing pain in a patient, said method comprising administering to a patient in need of such treatment, amelioration or prevention an effective amount of a compound as described in any one of {Ic}-{VIIIc} or a pharmaceutically acceptable salt or solvate thereof.

[0454] {XVIIIc}. The method as described in {XVIIc}, wherein said method is for treating pain.

[0455] {XIXc}. The method as described in {XVIIIc}, wherein said pain is acute pain, chronic pain or surgical pain.

[0456] {XXc}. The method as described in {XIXc}, wherein said pain is chronic pain.

[0457] {XXIc}. The method as described in {XXc}, wherein said chronic pain is neuropathic pain, postoperative pain or inflammatory pain.

[0458] {XXIIc}. A method of slowing the onset of opioid activity in a mammal in need of opioid therapy, said method comprising orally administering to said mammal a therapeutically effective amount of a compound or mixture of compounds as described in any one of {Ic}-{VIIIc}, or a pharmaceutically acceptable salt or solvate thereof.

[0459] {XXIIIc}. A method for treating a disorder in a mammal in need of opioid therapy that is responsive to modulation of one or more opioid receptors and delaying the onset of opioid activity, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of {Ic}-{VIIIc}, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the method further comprises one or more parent opioid compounds, wherein the total amount of the compounds of the present disclosure and the parent opioid compounds constitutes the therapeutically effective amount.

[0460] {XXIVc}. The method according to {XXIIc} or {XXIIIc}, the method further comprising co-administering one or more other therapeutic agents.

[0461] {XXVc}. The method according to {XXIVc}, wherein the one or more other therapeutic agents are one or more non-steroidal anti-inflammatory agents.

[0462] {XXVIc}. The method according to {XXIVc}, wherein the one or more other therapeutic agents are one or more opioid agonists.

[0463] {XXVIIc}. The method according to {XXIVc}, wherein the one or more other therapeutic agents are one or more opioid antagonists.

[0464] Long-chain 6,14-disubstituted enol esters and their use as abuse-deterrent prodrugs

[0465] The inventors have found that certain 6,14-disubstituted enol esters of formula II having long chains as substituents at both the 6- and 14-positions provide μ-opioid receptor agonist function only when converted to the corresponding 6-substituted compounds and parent opioid in the lower intestine. Specifically, the inventors have found that 6,14-dilauroyl oxycodone provides μ-opioid agonist function when converted to 6-lauroyl oxycodone and oxycodone in the lower intestine of a patient. Thus, a compound of formula II as defined above (wherein R 5 and R 6 are both long) can be used as an abuse-deterrent opioid prodrug. When these prodrugs are made bioavailable only in the lower gastrointestinal tract of a patient, the enol ester at the 14-position will hydrolyze to the 6-substituted enol ester compound over time and further hydrolyze to the parent opioid such as oxycodone, thereby providing μ-opioid agonist function from both the 6-substituted enol ester prodrug and the parent opioid of formula IV discussed above.

[0466] In this aspect of the invention, the present disclosure provides the following specific embodiments.

[0467] {Id}. A compound of formula II:

[0468]

[0469] Its pharmaceutically acceptable salt or solvate, wherein:

[0470] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[0471] R 4 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of said groups optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[0472] R 2 is -C(=O)R 5 and R 3 is -OC(=O)R 6 wherein

[0473] R 5 and R 6 are the same or different and are selected from the group consisting of: straight-chain unsubstituted C 10-12 alkyl, straight-chain unsubstituted C 10-12 alkenyl, straight-chain unsubstituted C 10-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p-R 7 ;

[0474] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0475] m is an integer between 4 and 9;

[0476] n and p are each independently an integer between 4 and 20; and

[0477] PEG is an ethylene oxide unit or an oligomer having 2 to about 10 ethylene oxide subunits.

[0478] {IId}. The compound as described in {Id} or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 are each independently selected from the group consisting of decyl, undecyl, and dodecyl.

[0479] {IIId}. The compound as described in {Id} or {IId}, wherein R 5 and R 6 are the same and have the formula V:

[0480]

[0481] or a pharmaceutically acceptable salt or solvate thereof.

[0482] {IVd}. The compound as described in {IIId} or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is undecyl.

[0483] {Vd}. The compound as described in {Id} or {IId} or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 are different.

[0484] {VId}. The compound as described in any one of {Id}-{Vd} or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl, and R 4 is unsubstituted C 1-6 alkyl.

[0485] {VIId}. The compound as described in any one of {Id}-{VId} or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R 4 are methyl.

[0486] {VIIId}. The compound as described in {Id} or {IIId}, the compound being

[0487]

[0488] or a pharmaceutically acceptable salt or solvate thereof.

[0489] {IXd}. A pharmaceutical composition comprising a compound as described in any one of {Id}-{VIIId} or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0490] {Xd}. A composition comprising one or more compounds as described in {Id}-{VIIId} or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

[0491] {XId}. The composition as described in {Xd}, comprising from about 0.1 wt% to about 30 wt% of the at least one parent opioid.

[0492] {XIId}. The composition as described in {Xd} or {XId}, comprising from about 1 wt% to about 20 wt% of the at least one parent opioid.

[0493] {XIIId}. The composition as described in any one of {Xd}-{XIId}, wherein the at least one parent opioid is oxycodone.

[0494] {XIVd}. An oral formulation comprising a therapeutically effective amount of the composition as described in any one of {Xd}-{XIVd}.

[0495] {XVd}. A method of treating or preventing a disorder in a patient responsive to modulation of one or more opioid receptors, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound as described in any one of {Id}-{VIIId} or a pharmaceutically acceptable salt or solvate thereof.

[0496] {XVId}. The method as described in {XVd}, wherein the disorder is pain.

[0497] {XVIId}. A method of treating, ameliorating or preventing pain in a patient, the method comprising administering to a patient in need of such treatment, amelioration or prevention an effective amount of a compound as described in any one of {Id}-{VIId} or a pharmaceutically acceptable salt thereof.

[0498] {XVIIId}. The method as described in {XVIId}, wherein the method is for treating pain.

[0499] {XIXd}. The method as described in {XVIIId}, wherein the pain is acute pain, chronic pain or surgical pain.

[0500] {XXd}. The method as described in {XIXd}, wherein the pain is chronic pain.

[0501] {XXId}. The method as described in {XXd}, wherein the chronic pain is neuropathic pain, postoperative pain or inflammatory pain.

[0502] {XXIId}. A method for treating or preventing pain in a mammal determined to require opioid therapy and delaying the onset of activity, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of {Id}-{VIIId}, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the method further comprises one or more parent opioid compounds, wherein the total amount of the compounds of the present disclosure and the parent opioid compounds constitutes the therapeutically effective amount.

[0503] {XXIIId}. A method for treating a condition in a mammal requiring opioid therapy that responds to the modulation of one or more opioid receptors and delaying the onset of opioid activity, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of {Id}-{VIIId}, or a pharmaceutically acceptable salt or solvate thereof.

[0504] {XXIVd}. The method as described in {XXIId} or {XXIIId}, the method comprising orally administering a compound or mixture of compounds having formula V:

[0505]

[0506] or a pharmaceutically acceptable salt or solvate thereof, wherein

[0507] R 1 is H or unsubstituted C 1-6 alkyl;

[0508] R 4 is unsubstituted C 1-6 alkyl; and

[0509] R 5 is decyl, undecyl or dodecyl.

[0510] {XXVd}. The method as described in {XXIVd}, wherein R 1 is H or methyl, and R 4 is methyl.

[0511] {XXVId}. The method as described in {XXIVd} or {XXVd}, wherein R 5 is undecyl.

[0512] {XXVIId}. The method as described in any one of {XXIId}-{XXVId}, the method further comprising co-administering one or more other therapeutic agents.

[0513] {XXVIIId}. The method as described in {XXVIId}, wherein the one or more other therapeutic agents are one or more non-steroidal anti-inflammatory agents.

[0514] {XXIXd}. The method as described in {XXVIId}, wherein the one or more other therapeutic agents are one or more opioid agonists.

[0515] {XXXd}. The method as described in {XXVIId}, wherein the one or more other therapeutic agents are one or more opioid antagonists.

[0516] {XXXId}. The method as described in any one of {XXIVd}-{XXVId}, wherein the compound or mixture of compounds is administered in a single dosage form further comprising an effective amount of a parent opioid.

[0517] Long-chain 14-substituted enol esters and their use as partial agonists and partial antagonists

[0518] The inventors have found that certain 14-substituted enol esters of formula VI having a long-chain substituent at the 14-position act as partial μ-opioid receptor agonists and partial μ-opioid receptor antagonists, such as 16-lauroyl oxycodone. Accordingly, these long-chain substituted enol esters can be used in methods for treating or preventing opioid-induced adverse pharmacodynamic responses induced by administration of another opioid. Opioid-induced adverse pharmacodynamic responses include, for example, bowel dysfunction, nausea, vomiting, drowsiness, dizziness, respiratory depression, headache, dry mouth, sedation, sweating, fatigue, hypotension, restlessness, delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence, and tolerance. In one embodiment, the opioid-induced adverse pharmacodynamic responses are selected from the group consisting of constipation, diarrhea, alcohol withdrawal, and drug withdrawal.

[0519] In this aspect of the invention, the present disclosure provides the following specific embodiments.

[0520] {Ie}. A compound of formula VI:

[0521]

[0522] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0523] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[0524] R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of said groups optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[0525] R 3 is -OC(=O)R 6 wherein R 6 is selected from the group consisting of straight-chain unsubstituted C 10-12 alkyl, straight-chain unsubstituted C 10-12 alkenyl, straight-chain unsubstituted C 10-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p -R 7 ;

[0526] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0527] m is an integer between 4 and 9;

[0528] n and p are each independently an integer between 4 and 20; and

[0529] PEG is an ethylene oxide unit or an oligomer having 2 to about 10 ethylene oxide subunits.

[0530] {IIe}. The compound as described in {Ie} or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is decyl, undecyl or dodecyl.

[0531] {IIIe}. The compound as described in {Ie} or {IIe} or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or an unsubstituted C 1-6 alkyl, and R 4 is an unsubstituted C 1-6 alkyl.

[0532] {IVe}. The compound as described in any one of {Ie}-{IIIe} or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is undecyl.

[0533] {Ve}. The compound as described in any one of {Ie}-{IVe} or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R 4 are methyl.

[0534] {VIe}. The compound as described in {Ie}, the compound being

[0535]

[0536] or a pharmaceutically acceptable salt or solvate thereof.

[0537] {VIIe}. A pharmaceutical composition, the pharmaceutical composition comprising the compound as described in any one of {Ie}-{VIe} or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0538] {VIIIe}. A composition, the composition comprising one or more compounds as described in {Ie}-{VIe} or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

[0539] {IXe}. The composition as described in {VIIIe}, the composition comprising about 0.1 wt% to about 30 wt% of the at least one parent opioid.

[0540] {Xe}. The composition as described in {VIIIe} or {IXe}, the composition comprising about 1 wt% to about 20 wt% of the at least one parent opioid.

[0541] {XIe}. The composition according to any one of {VIIIe}-{Xe}, wherein the at least one parent opioid is oxycodone.

[0542] {XIIe}. An oral formulation comprising a therapeutically effective amount of the composition according to any one of {VIIIe}-{XIe}.

[0543] {XIIIe}. A method of treating or preventing a disorder in a patient responsive to modulation of one or more opioid receptors, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound according to any one of {Ie}-{VIe} or a pharmaceutically acceptable salt or solvate thereof.

[0544] {XIVe}. The method according to {XIIIe}, wherein the disorder is constipation, diarrhea, alcohol withdrawal or drug withdrawal.

[0545] {XVe}. A method of treating or preventing opioid-induced adverse pharmacodynamic responses, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of {Ie}-{VIe} or a pharmaceutically acceptable salt or solvate thereof to treat or prevent adverse pharmacodynamic effects induced by administration of another opioid.

[0546] {XVIe}. A method of treating, ameliorating or preventing constipation, diarrhea, alcohol withdrawal or drug withdrawal in a patient, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound according to any one of {Ie}-{VIe} or a pharmaceutically acceptable salt or solvate thereof.

[0547] Pharmaceutical composition

[0548] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the present disclosure and a pharmaceutically acceptable carrier. If desired, the pharmaceutical composition of the present invention may further contain one or more other compatible pharmaceutically active agents.

[0549] Pharmaceutical compositions within the scope of the present invention include all compositions in which the compounds disclosed herein are present in an amount effective (via conversion to the parent opioid) to achieve their intended purpose. Although individual requirements will vary, given the present disclosure, determining the optimal range of the effective amount of each component is within the skill in the art. In some embodiments, the compounds disclosed herein can be administered to a mammal. In some embodiments, the mammal is a human, and preferably a patient being treated for a disorder treatable with an opioid, such as pain. As will be apparent from the present disclosure, the compounds and their mixtures disclosed herein are preferably administered orally. In some embodiments, the compounds disclosed herein are administered at a dose of 0.1 to 5 mg / kg of the body weight of the mammal being treated or a molar equivalent of their pharmaceutically acceptable salts.

[0550] In some embodiments, the unit oral dose comprises between 5 mg and 640 mg, between 5 mg and 320 mg, between 5 mg and 200 mg, between 5 mg and 160 mg, between 5 mg and 100 mg, between 5 mg and 50 mg, between 5 mg and 25 mg, between 5 mg and 20 mg, and between 5 mg and 10 mg of the compounds or mixtures thereof disclosed herein. In some embodiments, the unit oral dose is 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 160 mg, 320 mg, or 640 mg of the free compounds disclosed herein or a molar equivalent of their pharmaceutically acceptable salts.

[0551] In some embodiments, the oral dosage form is a unit oral dosage form administered every 4 hours, every 6 hours, every 8 hours, every 12 hours, or every 24 hours.

[0552] In some embodiments, the compounds or mixtures thereof disclosed herein can be administered as part of a pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present disclosure contain one or more suitable pharmaceutically acceptable carriers selected from known excipients and adjuvants to facilitate the processing of the compounds into pharmaceutical dosage forms and / or to facilitate or otherwise control the dissolution of the dosage form. In a particular embodiment, the pharmaceutical compositions of the present disclosure are in an orally administrable dosage form. In some embodiments, the pharmaceutical composition is in the form of a solid oral dosage form, such as a powder, granule, tablet, pellet, multiparticulate, dragee, or capsule. In other embodiments, the pharmaceutical composition is in the form of a liquid oral dosage form, such as an oral solution, oral suspension, or oral emulsion.

[0553] In some embodiments, the oral dosage form contains from 0.01% to 99% by weight, from 0.01% to 90% by weight, from 0.01% to 85% by weight, from 0.01% to 80% by weight, or from 0.01% to 75% by weight of a compound or mixture thereof of the present disclosure, together with one or more excipients.

[0554] The pharmaceutical compositions of the present disclosure for oral administration may contain one or more excipients. Suitable excipients include fillers such as sugars (e.g., lactose or sucrose, mannitol, sodium saccharin, or sorbitol), magnesium carbonate, cellulose preparations, and / or calcium phosphate (e.g., tricalcium phosphate or calcium hydrogen phosphate), and binders such as starch paste using, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrating agents such as the starches mentioned above, as well as carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts such as sodium alginate, may be added. Auxiliaries are primarily flow regulators and lubricants such as silica, talc, stearic acid or its salts such as magnesium stearate or calcium stearate, and / or polyethylene glycol; sweeteners such as fructose, aspartame, or saccharin; flavoring agents such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives to provide a pharmaceutically palatable preparation. Additionally, dyes or pigments may be added to the tablet or dragee coating, for example, for identification or to facilitate characterization of combinations of the active compound dosage. Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences, pages 1447 - 1676 (Alfonso R. Gennaro, ed., 19th ed. 1995), which is incorporated herein by reference. In one embodiment, the excipient is of pharmaceutical grade.

[0555] In some embodiments, the pharmaceutical compositions of the present disclosure are manufactured in a manner known in view of the present disclosure, such as, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilization methods.

[0556] The pharmaceutical compositions of the present disclosure can be administered by any means to achieve their intended purpose. Preferably, the administration is by the oral route. The dosage administered and the frequency of administration will depend on the age, health status, gender, medical condition, and weight of the recipient, any concurrent treatment (if any), the frequency of treatment, and the nature of the desired effect, as well as other factors.

[0557] The compounds or mixtures thereof of the present disclosure can be delivered in immediate release systems, controlled release systems, or sustained release systems. For a more detailed description of controlled release or sustained release systems, see, for example, U.S. Patent Nos. 5,672,360, 5,968,551, 6,294,195, 7,270,831, and 7,514,100. Controlled release or sustained release systems can also be prepared by methods known in the art (see, for example, Goodson, Medical Applications of Controlled Release, Volume 2, pages 115 - 138 (1984)). Other controlled release or sustained release systems discussed by Langer, Science 249:1527 - 1533 (1990) can also be used.

[0558] The compounds or mixtures thereof of the present disclosure can be formulated into a gastric retention drug delivery system that remains in the stomach or the upper part of the gastrointestinal tract for controlled delivery. For a more detailed description of gastric retention drug delivery systems, see, for example, U.S. Patent Nos. 5,232,704; 7,157,100; 7,838,028; and U.S. Patent Application Publication No. 2006 / 0013876. Gastric retention drug delivery systems can also be prepared by methods known in the art (see, for example, Sharma, N. et al., International Journal of Research in Pharmaceutical and Biomedical Sciences 2:428 - 441 (2011)).

[0559] The production of tablets and granules as disclosed in U.S. Patent Nos. 4,167,558 and 6,090,411 can also be used. The preparation of bilayer tablets as disclosed in U.S. Patent No. 4,140,755 can also be used.

[0560] The powder containing an active agent, a hydrocolloid, a pH - dependent polymer, and a binder in U.S. Patent No. 5,169,638, all of which are placed in a capsule. The forms disclosed in this document are suitable for delivering the compounds of the present invention.

[0561] U.S. Patent No. 6,635,279 discloses a mixture of polyvinyl acetate and polyvinylpyrrolidone and excipients. These forms can be prepared by simple methods and exhibit extraordinary mechanical strength. The forms disclosed in this document are suitable for delivering one or more compounds of the present disclosure.

[0562] In some embodiments, the compounds of the present disclosure are co - administered with one or more other therapeutic agents.

[0563] In some embodiments, the compounds of the present disclosure can be co-administered with one or more non-opioid analgesics. Suitable non-opioid analgesics include, but are not limited to, non-steroidal anti-inflammatory agents selected from aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, alaprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, mefenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, their pharmaceutically acceptable salts, and mixtures thereof. Other suitable non-opioid analgesics include, but are not limited to, salicylate derivatives including, but not limited to, sodium salicylate, choline magnesium trisalicylate, salsalate, diflurisal, salicylsalicylic acid, sulfasalazine, and olsalazine; p-aminophenol derivatives including, but not limited to, acetaminophen; indole and indene acetic acids including, but not limited to, indomethacin, sulindac, and etodolac; heteroaryl acetic acids including, but not limited to, tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates) including meclofenamic acid and mefenamic acid; enolic acids including, but not limited to, the oxicams (piroxicam and tenoxicam), and pyrazolidinediones (phenylbutazone and oxyphenthartazone); and alkanones including, but not limited to, nabumetone. For a more detailed description of non-opioid analgesics that can be co-administered with the compounds according to the present disclosure, see Paul A. Insel, Analgesic-Antipyretic and Anti-Inflammatory Agents and Drugs Employed in The Treatment of Gout in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 617-657 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed. 1996), and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy, Volume II, 1196-1221 (A. R. Gelmaro ed., 19th ed. 1995).

[0564] In some embodiments, the compounds of the present disclosure may be co-administered with one or more opioid agonists. Suitable opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzydamine, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, deprenylamine, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, maphentermine, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, their pharmaceutically acceptable salts, and mixtures thereof.

[0565] In some embodiments, the compounds of the present disclosure can be co-administered with one or more anti-migraine agents. Suitable anti-migraine agents include, but are not limited to, apripiprazole, dihydroergotamine, dolasetron, ergocornine, ergocryptine, ergocariine, ergot, ergotamine, flumethienone acetate, dimethixene, lisuride, lomerizine, methysergide, octotridecacontanol, pizotifen, and mixtures thereof.

[0566] In some embodiments, the compounds of the present disclosure can be co-administered with one or more antiemetic agents. Suitable antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine acethylleucine monoethanolamine, alizapride, azasetron, benquinamide, aminophylline ethanolamine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, mesarol, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioridazine, tropisetron, and mixtures thereof.

[0567] In some embodiments, the compounds of the present disclosure can be co-administered with one or more β-adrenergic blockers. Suitable β-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulalol, arotinolol, atenolol, benfurole, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, butofilolol, bunolol, bupranolol, butidrine hydrochloride, butolol, carteolol, carteolol hydrochloride, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, naphthoxylol, nebivolol, nifedolol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, propanolol, sotalol, tiroxolol, talinolol, tertatolol, tilisolol, timolol, tolindolol, xibenolol, and mixtures thereof.

[0568] In some embodiments, the compounds of the present disclosure can be co-administered with one or more anticonvulsants. Suitable anticonvulsants include, but are not limited to, acetophenone, albuterol, allodione, aminoglutethimide, 4-amino-3-hydroxybutyric acid, phenyllactamine, beclamide, brabamate, calcium bromide, carbamazepine, cinnamon bromide, clomethiazole, clonazepam, decimid, disadione, dimethadione, dioxenitroin, etibitor, ethiprole, ethosuximide, ethotoin, felbamate, fluphenazine, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, methylphenobarbital, metharbital, methitoin, Methsuximide, 5-methyl-5-(3-phenanthrenyl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nitrazepam, nitrazepam, oxcarbazepine, methylethyldione, phenylacetylurea, phenethylbarbital, phenbutyrylurea, phenobarbital, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, phenthiotoin sodium, potassium bromide, pregabalin, primidone, progab, sodium bromide, nightshade, strontium bromide, succinil, thiothiazide, titratoin, tiagabine, topiramate, trimethadione, valproic acid, valproamide, vigabatrin, zonisamide and mixtures thereof.

[0569] In some embodiments, the compounds of the present disclosure can be co-administered with one or more antidepressants. Suitable antidepressants include, but are not limited to, benzedrine, caroxazone, citalopram, dimethoxanate, fencamfamine, indalpine, indeloxazine hydrochloride, nefopam, nomifensine, hydroxytryptophan, oxypipam, paroxetine, sertraline, thioxanthene, trazodone, benmoxine, iproclozide, isoniazid, isocarboxazid, nialamide, octamoxine, phenelzine, cotinine, rolipram, rolipram, maprotiline, meptazinol, mianserin, mirtazapine, alprazolam, amitriptyline, oxyamitriptyline, amoxapine, butriptyline, clomipramine, desipramine, desipramine, diphenylpyramine, dimetacrine, dosulepin, doxepin, fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptilin, opipramol, pizotifen, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, butacitin, diosazul, duloxetine, etoperidone, felbamate, fesoterodine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, pirazolamine, prolintane, pyrisuccideanol, ritanserin, rokitansky, rubidium chloride, sulpiride, tandospirone, tozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, zimeldine, and mixtures thereof.

[0570] In some embodiments, the compounds of the present disclosure can be co-administered with one or more Ca 2+ -channel blockers. Suitable Ca 2+ -channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, simodiline, terodiline, verapamil, amlodipine, arecoline, barnidipine, benidipine, cilnidipine, efonidipine, eguidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, benzocyclane, etafenone, pantofarone, perhexiline, and mixtures thereof.

[0571] In some embodiments, the compounds of the present disclosure can be co-formulated or co-administered with opioid antagonists according to International Patent Application Publication No. WO 03 / 084520, such as naltrexone, naloxone, nalmefene, nalorphine, nalbuphine, naloxoneazinen, methylnaltrexone, ketylcyclazocine, norbinaltorphimine, naltrexindole, 6-β-nalol, 6-β-naltrexol, alvimopan, cyprodime, diprenorphine, gemazocine, 5'-guanidinonaltrexindole, JDTic ((3R)-7-hydroxy-N-[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide), levallorphan, naldemedine, nalmethone, nalorphine dinicotinate, naloxazone, naloxegol, nalol, naoloxonazine, naltiben, oxilorphan, quadazocine, samidorphan, and mixtures thereof.

[0572] Since certain compounds of the present disclosure can act as prodrugs, they can be used for the same purposes as their parent compounds. In some embodiments, the compounds of the present disclosure can be used to treat, ameliorate, or prevent pain, including acute pain, chronic pain, neuropathic pain, inflammatory pain, and surgical pain. In another embodiment, the compounds of the present disclosure can be used to treat, ameliorate, or prevent opioid-induced adverse pharmacodynamic reactions.

[0573] The compounds of the present disclosure can be used to treat or prevent acute pain, chronic pain (including but not limited to neuropathic pain, post-surgical pain, and inflammatory pain), or surgical pain. Examples of pain that can be treated or prevented using the compounds of the present invention include but are not limited to cancer pain, neuropathic pain, labor pain, myocardial infarction pain, pancreatic pain, colic, post-surgical pain, headache, muscle pain, joint pain, and pain associated with periodontal disease (including gingivitis and periodontitis).

[0574] Acute pain includes but is not limited to perioperative pain, post-surgical pain, post-traumatic pain, pain associated with acute diseases, and pain associated with diagnostic procedures, orthopedic procedures, and myocardial infarction. Acute pain in the perioperative setting includes pain caused by pre-existing diseases, surgical procedures (e.g., associated drains, chest tubes, or nasogastric tubes), or a combination of complication- and disease-related and procedure-related sources.

[0575] Chronic pain includes, but is not limited to, inflammatory pain, postoperative pain, cancer pain, osteoarthritis pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain, and other forms of neuralgia, neuropathic, and idiopathic pain syndromes.

[0576] The compounds of the present disclosure can be used to treat or prevent pain associated with inflammation or inflammatory diseases in a patient. Such pain can occur at sites where body tissues are inflamed (which can be a local inflammatory response or a systemic inflammation). For example, the compounds of the present disclosure can be used to treat or prevent pain associated with inflammatory diseases, including but not limited to organ transplant rejection; reperfusion injury caused by organ transplantation (including but not limited to heart, lung, liver, or kidney transplantation) (see Grupp et al., J. Mol, Cell Cardiol. 31:297 - 303 (1999)); chronic inflammatory diseases of joints, including arthritis, rheumatoid arthritis, osteoarthritis, and bone diseases associated with increased bone resorption; inflammatory bowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway diseases; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmia, and endophthalmitis; chronic inflammatory diseases of the gums, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis, and nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis, and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS - related neurodegeneration, and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis; autoimmune diseases, including type I and type II diabetes; diabetes complications, including but not limited to diabetic cataract, glaucoma, retinopathy, nephropathy (such as microalbuminuria and progressive diabetic nephropathy), foot gangrene, atherosclerotic coronary artery disease, peripheral artery disease, non - ketotic hyperglycemic - hyperosmolar coma, foot ulcers, joint problems, and skin or mucosal complications (such as infections, shin spots, candidal infections, or necrobiosis lipoidica diabeticorum), immune complex vasculitis, and systemic lupus erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and atherosclerosis; and various other diseases that can have a significant inflammatory component, including pre - eclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The compounds of the present disclosure can also be used to treat or prevent pain associated with inflammatory diseases (which can be, for example, a systemic inflammation of the body), such as Gram - positive or Gram - negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro - inflammatory cytokines, such as shock associated with pro - inflammatory cytokines. Such shock can be induced, for example, by chemotherapeutic agents administered as cancer treatment.

[0577] The compounds of the present disclosure can be used to treat or prevent pain associated with nerve injury (i.e., neuropathic pain). Chronic neuropathic pain is a heterogeneous disease state of unknown etiology. In chronic pain, pain can be mediated by multiple mechanisms. This type of pain is generally caused by damage to peripheral or central nerve tissue. Syndromes include pain associated with spinal cord injury, multiple sclerosis, postherpetic neuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflex sympathetic dystrophy and back pain. Chronic pain differs from acute pain in that patients with chronic neuropathic pain have abnormal pain sensation, which can be described as spontaneous pain, persistent superficial burning, and / or deep soreness. Pain can be induced by heat, cold, and mechanical hyperalgesia or cold or mechanical allodynia.

[0578] Chronic neuropathic pain can be caused by damage or infection of the peripheral sensory nerves. It includes, but is not limited to, pain caused by peripheral nerve trauma, herpes virus infection, diabetes, causalgia, nerve plexus avulsion, neuroma, amputation, and vasculitis. Neuropathic pain can also be caused by nerve damage due to chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiency. Stroke (spinal cord or brain) and spinal cord injury can also induce neuropathic pain. Cancer-related neuropathic pain is due to tumor growth compressing adjacent nerves, brain, or spinal cord. In addition, cancer treatments (including chemotherapy and radiotherapy) can cause nerve damage. Neuropathic pain includes, but is not limited to, pain caused by nerve damage (such as the pain suffered by diabetic patients).

[0579] The compounds of the present disclosure can be used to treat or prevent pain associated with migraine, including but not limited to migraine without aura ("common migraine"), migraine with aura ("classical migraine"), acephalgic migraine, basilar migraine, familial hemiplegic migraine, migrainous infarction, and prolonged aura migraine.

[0580] In some embodiments, the compounds of the present disclosure can be used as antitussives and for the treatment or improvement of dyspnea, diarrhea, and dysentery.

[0581] In each of the above-mentioned cases, the methods of the present invention require administering to a mammal in need of such treatment an effective amount of a compound of any one of Formulas I to VI or a pharmaceutically acceptable salt or solvate thereof, or a mixture thereof.

[0582] In some embodiments, the μ, κ, δ, or ORL-1 opioid receptor binding activity of the compounds of the present disclosure and their functional profiles at the μ, κ, δ, or ORL-1 opioid receptors are tested by the following in vitro binding assays.

[0583] In Vitro Assay Protocol

[0584] μ-Opioid Receptor Binding Assay Procedure: A radioligand dose-displacement binding assay for the μ-opioid receptor can be performed using 0.3 nM 3 [H]-diprenorphine (Perkin Elmer, Shelton, CT) with 5 mg membrane protein / well in binding buffer (10 mM MgCl2, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4) in a final volume of 500 μl. Reactions are carried out in the presence or absence of increasing concentrations of unlabeled naloxone. All reactions are conducted for 2 hours at room temperature in 96-deep well polypropylene plates. The binding reaction is terminated by rapid filtration on a 96-well Unifilter GF / C filter plate (Perkin Elmer, Shelton, CT) pre-soaked in 0.5% polyethyleneimine using a 96-well tissue harvester (Perkin Elmer, Shelton, CT), followed by three filtration washes with 500 μl of ice-cold binding buffer. Subsequently, the filter plate is dried at 50 °C for 2 - 3 hours. BetaScint scintillation cocktail (Perkin Elmer, Shelton, CT) (50 μl / well) is added, and the plate is counted using a Packard Top-Count at 1 minute / well. Data are analyzed using the one-site competition curve fitting function in GraphPad PRISM TM Version 3.0 or higher (San Diego, Calif.) or an in-house one-site competition curve fitting function. Data are expressed as mean ± S.E.M. Results are expressed as the inhibition constant K i value (the concentration of the compound that produces half-maximal inhibition).

[0585] μ-Opioid Receptor Functional Assay Procedure: The 35 [35S]GTPγS functional assay is performed using freshly thawed μ-receptor membranes, which are either prepared in-house from cell lines expressing recombinant μ-opioid receptors in a HEK-293, CHO, or U-2OS cell background or purchased from commercial sources (Perkin Elmer, Shelton, CT; or DiscovRx, Fremont, CA). The assay reaction (indicating final concentrations) is prepared by sequentially adding the following reagents to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice: membrane protein (0.026 mg / mL), saponin (10 mg / mL), GDP (3 mM), and 35S]GTPγS (0.20 nM; Perkin Elmer, Shelton, CT). Transfer the prepared membrane solution (190 μl / well) to a 96-well shallow polypropylene plate containing 10 μl of agonist [D-Ala 2 , N-methyl-Phe 4 Gly-ol 5 -enkephalin (DAMGO) in 20x concentrated stock solution prepared in dimethyl sulfoxide (DMSO). Incubate the plate with shaking at approximately 25 °C for 30 minutes. Terminate the reaction by rapid filtration on a 96-well Unifilter GF / B filter plate (Perkin Elmer, Shelton, CT) using a 96-well tissue harvester (Perkin Elmer, Shelton, CT), followed by three filtration washes with 200 μl of ice-cold wash buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Subsequently, dry the filter plate at 50 °C for 2 - 3 hours. Add BetaScint scintillation cocktail (Perkin Elmer, Shelton, CT) (50 μl / well) and count the plate using a Packard Top-Count at 1 minute / well. Analyze the data using the sigmoidal dose-response curve fitting function in GraphPad PRISM version 3.0 or an in-house non-linear sigmoidal dose-response curve fitting function. Data are expressed as mean ± S.E.M. The results of the functional assay are expressed as EC 50 value (the effective concentration of the compound that causes 50% of the maximum response).

[0586] Freshly thawed μ-receptor membranes prepared from a cell line expressing recombinant μ-opioid receptor in a CHO-K1 cell background can also be used for 35 S]GTPγS functional assay.

[0587] κ-opioid receptor binding assay procedure: Prepare membranes from HEK-293, CHO, or U-2OS cells expressing recombinant human κ-opioid receptor (κ) by lysing the cells in ice-cold hypotonic buffer (2.5 mM MgCl2, 50 mM HEPES, pH 7.4) (10 mL / 10 cm dish), followed by homogenization with a tissue grinder / Teflon pestle. Membranes from cell lines that naturally express κ-opioid receptor can also be used. Collect the membranes by centrifugation at 30,000 x g for 15 minutes at 4 °C and resuspend the pellet in hypotonic buffer to a final concentration of 1 - 3 mg / mL. Determine the protein concentration using BioRad protein assay reagent with bovine serum albumin as the standard. Aliquots of the κ-receptor membranes are stored at -80 °C.

[0588] Radioligand dose displacement assays were performed using 0.4 nM 3 [3H]-U69,593 (GE Healthcare, Piscataway, NJ; 40 Ci / mmole) and 15 μg of membrane protein (recombinant κ-opioid receptor expressed in HEK 293 cells; in-house preparation) in binding buffer (5% DMSO, 50 mM Trizma base, pH 7.4) at a final volume of 200 μl. Nonspecific binding was determined in the presence of 10 μM unlabeled naloxone or U69,593. All reactions were carried out for 1 h at a temperature of approximately 25 °C in 96-well polypropylene plates. The binding reaction was terminated by rapid filtration over 96-well Unifilter GF / C filter plates (Perkin Elmer, Shelton, CT) presoaked in 0.5% polyethylenimine (Sigma). Collection was performed using a 96-well tissue harvester (Perkin Elmer, Shelton, CT), followed by five filtration washes with 200 μl of ice-cold binding buffer. The filter plates were then dried at 50 °C for 1–2 h. 50 μl / well of scintillation mixture (Perkin Elmer, Shelton, CT) was added, and the plates were counted in a Packard Top-Count at 1 min / well. Data were analyzed using the one-site competition curve fitting function in GraphPad PRISM TM version 3.0 or later (San Diego, Calif.) or an in-house one-site competition curve fitting function. Data are represented as mean ± S.E.M. Results are expressed as inhibition constant K i values (compound concentration producing half-maximal inhibition).

[0589] κ-Opioid receptor function assay procedure: Functional 35 [35S]GTPγS binding assays were performed as follows. By combining κ membrane protein (in-house) at a final concentration of 0.026 μg / μl, 10 μg / mL saponin, 3 μM GDP, and 0.20 nM 35κ-opioid receptor membrane solution was prepared by adding GTPγS sequentially to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 μl / well) was transferred to a 96-well shallow-well polypropylene plate containing 10 μl of a 20x concentrated stock solution of agonist prepared in DMSO. The plate was incubated with shaking at a temperature of about 25 °C for 30 minutes. The reaction was terminated by rapid filtration on a 96-well Unifilter GF / B filter plate (Perkin Elmer, Shelton, CT) using a 96-well tissue harvester (Packard), followed by three filtration washes with 200 μl of ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Subsequently, the filter plate was dried at 50 °C for 2 - 3 hours. 50 μl / well of scintillation cocktail (Perkin Elmer, Shelton, CT) was added, and the plate was counted in a Packard Top-Count at 1 minute / well. The data was analyzed using the one-site competition curve fitting function in GraphPad PRISM TM version 3.0 or later (San Diego, Calif.) or an in-house one-site competition curve fitting function. The data is represented as mean ± S.E.M. The results of the functional assay are represented as EC 50 value (the effective concentration of the compound that causes 50% of the maximum response).

[0590] δ-opioid receptor binding assay procedure: The δ-opioid receptor binding assay procedure was carried out as follows. The radioligand dose displacement experiment can be performed using 0.3 nM [3 H- Naltroxindole (Perkin Elmer, Shelton, CT; 33.0 Ci / mmole) and 5 μg membrane protein (Perkin Elmer, Shelton, CT). Nonspecific binding was determined in the presence of 25 μM unlabeled naloxone. All reactions were carried out in 96-well deep-well polypropylene plates at a temperature of approximately 25 °C for 1 hour. The binding reaction was terminated by rapid filtration through a 96-well Unifilter GF / C filter plate (Perkin Elmer, Shelton, CT) pre-impregnated with 0.5% polyethyleneimine (Sigma). Collection was performed using a 96-well tissue harvester (Perkin Elmer, Shelton, CT), followed by five filtration washes with 500 μl of ice-cold binding buffer. Subsequently, the filter plates were dried at 50 °C for 1 - 2 hours. 50 μl / well of scintillation cocktail (Perkin Elmer, Shelton, CT) was added, and the plates were counted in a Packard Top-Count at 1 minute / well. The data were analyzed using the single-site competition curve fitting function in GraphPad PRISM TM version 3.0 or higher (San Diego, Calif.) or the in-house single-site competition curve fitting function. The data are represented as mean ± S.E.M. The results are expressed as the inhibition constant K i value (the concentration of the compound that produces half-maximal inhibition).

[0591] δ-opioid receptor function assay procedure: The function 35 can be carried out as follows for the [S]GTPγS binding assay. By adding δ membrane protein (Perkin Elmer, Shelton, CT) at a final concentration of 0.026 μg / μl, 10 μg / mL saponin, 3 μM GDP, and 0.20 nM 35δ-opioid receptor membrane solution was prepared by sequentially adding GTPγS to the binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 μl / well) was transferred to a 96-well shallow polypropylene plate containing 10 μl of a 20x concentrated stock solution of the agonist prepared in DMSO. The plate was incubated with shaking at a temperature of about 25 °C for 30 minutes. The reaction was terminated by rapid filtration on a 96-well Unifilter GF / B filter plate (Perkin Elmer, Shelton, CT) using a 96-well tissue harvester (Packard), followed by three filtration washes with 200 μl of ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Subsequently, the filter plate was dried at 50 °C for 1 - 2 hours. 50 μl / well of scintillation mixture (Perkin Elmer, Shelton, CT) was added, and the plate was counted in a Packard Top-count at 1 minute / well. The data was analyzed using the single-site competition curve fitting function in GraphPad PRISM TM version 3.0 or higher (San Diego, Calif.) or an in-house single-site competition curve fitting function. The data is represented as mean ± S.E.M. The results of the functional assay are expressed as EC 50 value (the effective concentration of the compound that causes 50% of the maximum response).

[0592] ORL-1 receptor binding assay procedure: Membranes from recombinant HEK-293 cells expressing the human opioid receptor-like receptor (ORL-1) (Perkin Elmer, Shelton, CT) can be prepared by lysing the cells in ice-cold hypotonic buffer (2.5 mM MgCl2, 50 mM HEPES, pH 7.4) (10 ml / 10 cm dish), followed by homogenization with a tissue grinder / Teflon pestle. The membranes were collected by centrifugation at 30,000 x g for 15 minutes at 4 °C, and the pellet was resuspended in hypotonic buffer to a final concentration of 1 - 3 mg / ml. Protein concentration was determined using BioRad protein assay reagent with bovine serum albumin as the standard. Aliquots of the ORL-1 receptor membranes were stored at -80 °C.

[0593] Radioactive ligand binding assays (screening and dose displacement) were performed using 0.1 nM in a final volume of 500 μl binding buffer (10 mM MgCl2, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4) 3H]-nociceptin (PerkinElmer, Shelton, CT; 87.7 Ci / mmole) and 12 μg of membrane protein. Nonspecific binding was determined in the presence of 10 nM unlabeled nociceptin (American Peptide Company). All reactions were carried out for 1 h at room temperature in 96-well deep-well polypropylene plates. The binding reaction was terminated by rapid filtration through 96-well Unifilter GF / C filter plates (PerkinElmer, Shelton, CT) presoaked in 0.5% polyethylenimine (Sigma). Collection was performed using a 96-well tissue harvester (Perkin Elmer, Shelton, CT), followed by three filtration washes with 500 μl of ice-cold binding buffer. The filter plates were then dried at 50 °C for 2 - 3 h. 50 μl / well of scintillation mixture (Perkin Elmer, Shelton, CT) was added, and the plates were counted in a Packard Top-Count at 1 min / well. Data from screening and dose-displacement experiments were analyzed using the curve-fitting functions in Microsoft Excel and GraphPad PRISM TM version 3.0 or higher or the one-site competition curve-fitting function built-in. Data are represented as mean ± S.E.M. Results are presented as inhibition constant K i value (compound concentration that produces half-maximal inhibition).

[0594] ORL-1 receptor functional assay procedure: Membranes (Perkin Elmer, Shelton, CT) from recombinant HEK-293 cells expressing the human opioid receptor-like (ORL-1) can be prepared by lysing the cells in ice-cold hypotonic buffer (2.5 mM MgCl2, 50 mM HEPES, pH 7.4) (10 ml / 10 cm dish), followed by homogenization using a tissue grinder / Teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4 °C, and the pellet was resuspended in hypotonic buffer to a final concentration of 1 - 3 mg / ml. Protein concentration was determined using BioRad protein assay reagent with bovine serum albumin as the standard. Aliquots of the ORL-1 receptor membranes were stored at -80 °C.

[0595] The following functional 35 S] GTPγS binding assay was performed. By combining ORL-1 membrane protein at a final concentration of 0.026 μg / μl, 10 μg / ml saponin, 3 μM GDP, and 0.20 nM 35The ORL-1 membrane solution was prepared by adding GTPγS sequentially to the binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 μl / well) was transferred to a 96-well shallow polypropylene plate containing 10 μl of a 20x concentrated stock solution of the agonist / dynorphin A prepared in DMSO. The plate was incubated with shaking at room temperature for 30 minutes. The reaction was terminated by rapid filtration on a 96-well Unifilter GF / B filter plate (Perkin Elmer, Shelton, CT) using a 96-well tissue harvester (Packard), followed by three filtration washes with 200 μl of ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Subsequently, the filter plate was dried at 50 °C for 2 - 3 hours. 50 μl / well of scintillation mixture (Perkin Elmer, Shelton, CT) was added and the plate was counted in a Packard Top-Count at 1 minute / well. The data was analyzed using the sigmoidal dose-response curve fitting function in GraphPad PRISM version 3.0 or higher or an in-house non-linear sigmoidal dose-response curve fitting function. The results of the functional assay were expressed as EC 50 values (the effective concentration of the compound that causes 50% of the maximum response).

[0596] In Vivo Pharmacology

[0597] Brain Distribution: The in vivo distribution of the compounds of the present disclosure in the brain after oral administration can be tested using, for example, the following assay. Sprague Dawley rats were orally administered 10 mg / kg of the test compound. The dosing solution was in 25% 2-hydroxypropyl-β-cyclodextrin (HPBCD) and the dosing volume was 5 mL / kg. One hour after administration, the highest possible volume of blood was withdrawn by cardiac puncture. Plasma was separated from whole blood by centrifugation and submitted for analysis. After bleeding, the whole brain was collected, briefly rinsed in cold saline, and then rapidly frozen in liquid nitrogen. Both plasma and brain samples were stored at -70 °C prior to analysis.

[0598] For the analysis of plasma samples, a calibration curve was prepared by spiking known amounts of the analyte into commercially available control rat plasma. 800 μl of an aqueous solution of the internal standard (oxycodone) was added to 200 μl aliquots of the standards and study samples and according to the following procedure on C 18Solid-phase cartridge (96-well format, 3M) extraction. The cartridge was activated by sequentially applying 500 μl of methanol and 500 μl of water. The sample was then applied, and the cartridge was washed with 500 μl of water and then eluted successively with 2 x 500 μl of methanol containing 1% formic acid and 2 x 500 μl of methanol containing 2% ammonia. After evaporation and reconstitution, the sample was analyzed by LC / MS / MS. For the analysis of brain samples, the study samples and control brains were homogenized with water at a weight ratio of 1:10 per volume. Calibration curves were prepared by spiking known amounts of the analyte into the control brain homogenate. 500 μl of an aqueous solution of the internal standard (oxycodone) was added to 500 μL aliquots of the standards and study samples and the procedure described earlier for plasma samples was followed on C 18 Solid-phase cartridge (96-well format, 3M) extraction. After evaporation and reconstitution, the sample was analyzed by LC / MS / MS.

[0599] Chromatography of the analyte and internal standard was performed on a Zorbax Extended C 18 column (4.6 x 150 mm, 3.5 μm particle size) under water-acetonitrile gradient conditions (specific gradients for each analyte). The effluent was analyzed by MS / MS. The analyte was registered as a "daughter" ion of the "analyte" molecular ion on the second quadrupole of the instrument. The MS / MS conditions were optimized for each analyte to achieve maximum selectivity and sensitivity.

[0600] The concentration of the unknown sample was calculated based on the parameters of the corresponding calibration curve. Brain concentrations expressed as "ng / g tissue" were obtained by multiplying the corresponding homogenate concentration by a factor of 10 (the dilution factor during the homogenization step). The brain-blood ratio was calculated as the ratio of the corresponding brain (ng / g) concentration to the plasma (ng / mL) concentration for each animal and the mean and standard deviation were calculated for triplicates.

[0601] Study of antinociceptive activity in mice: The antinociceptive activity of the compounds of the present invention can be tested in the formalin model as described in Hunskaar, S., O. B. Fasmer and K. Hole, J. Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice (20-30 g; Harlan, San Diego, CA) are used in all experiments. Food is withdrawn on the day of the experiment. The mice are placed in plexiglass jars for at least 1 hour to acclimatize to the environment. After the acclimatization period, the mice are weighed and administered the test compound orally in a vehicle or an appropriate volume of vehicle (10% Tween-80). Thirty minutes after oral administration, formalin (20 μl of saline containing 5% formaldehyde solution) is injected into the dorsal side of the right hind paw of the mice. The mice are transferred to plexiglass jars and the amount of time spent licking or biting the injected paw is monitored. Licking and biting episodes are recorded at 5-minute intervals for 1 hour after formalin injection. All experiments are conducted in a blinded manner during the light cycle. The early measurement of the formalin response is licking / biting between 0 and 5 minutes, and the late measurement is from 15 to 50 minutes. The differences between the vehicle and drug-treated groups are analyzed by one-way analysis of variance (ANOVA). A p-value ≤ 0.05 is considered significant. Compounds that have activity blocking the acute and second phases of formalin-induced paw licking activity are considered effective against acute and chronic pain.

[0602] In vivo pain assay using rats as test animals

[0603] Test animals: Rats weighing between 200-260 g are used in each experiment at the start of the experiment. The rats are housed in groups and have free access to food and water at all times until the compounds of the present disclosure are administered orally, at which time food is removed approximately 16 hours before dosing. A control group is used for comparison with the rats treated with the compounds of the present disclosure. The vehicle for the compounds of the present disclosure is administered to the control group. The volume of the vehicle administered to the control group is the same as the volume of the vehicle and the compounds of the present disclosure administered to the test group.

[0604] Acute pain: To evaluate the effect of the compounds of the present disclosure in treating or preventing acute pain, the rat tail-flick test can be used. Gently restrain the rat by hand and expose the point 5 cm from the tip of the tail to a focused beam of radiant heat using a tail-flick device (Model 7360, commercially available from Ugo Basile, Italy). The tail-flick latency is defined as the interval between the onset of the thermal stimulus and the tail-flick. Animals that do not respond within 20 seconds are removed from the tail-flick device and assigned a withdrawal latency of 20 seconds. The tail-flick latency is measured immediately before administering the compounds of the present disclosure (pre-treatment) and at 1, 3, and 5 hours after administering the compounds of the present disclosure. The data are expressed as tail-flick latency and the percentage of the maximum possible effect (%MPE) is calculated as follows, where 20 seconds is:

[0605]

[0606] The rat tail-flick test is described in F.E. D'Amour et al., "A Method for Determining Loss of Pain Sensation," J. Pharmacol. Exp. Ther. 72:74-79 (1941).

[0607] To evaluate the effect of the compounds of the present disclosure in treating or preventing acute pain, the rat hot plate test can also be used. Rats are tested using a hot plate apparatus (Model 7280, commercially available from Ugo Basile, Italy) consisting of a transparent Plexiglas cylinder and a heated metal floor maintained at a temperature of 48°C - 52°C. The rat is placed in the cylinder on the hot plate apparatus for a maximum duration of 30 seconds or until it exhibits pain response behavior (behavioral endpoint), at which time the rat is removed from the hot plate and the response latency is recorded. The hot plate latency is measured immediately before administering the compounds of the present invention (pre-treatment) and at 1, 3, and 5 hours after administering the compounds of the present invention. The pain response behavioral endpoint is defined as any one of the following: 1) paw withdrawal, persistent lifting or shaking or licking; 2) alternating foot lifting; 3) escape from or attempt to escape from the test device; or 4) vocalization. The data are expressed as response latency and the percentage of the maximum possible effect is calculated as described above for the tail-flick test. The hot plate test is described in G. Woolfe and A.D. MacDonald, J. Pharmacol. Exp. Ther. 80:300-307 (1944).

[0608] Inflammatory pain: To evaluate the effect of the compounds of the present disclosure in treating or preventing inflammatory pain, the Freund's incomplete adjuvant ("FCA") model of inflammatory pain can be used. FCA-induced hind paw inflammation in rats is associated with the appearance of persistent inflammatory mechanical hyperalgesia and provides a reliable prediction of the anti-hyperalgesic effect of clinically available analgesic drugs (L. Bartho et al., "Involvement of Capsaicin-sensitive Neurones in Hyperalgesia and Enhanced Opioid Antinociception in Inflammation," Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)). A plantar injection of 50 μL of 50% FCA was administered to the left hind paw of each animal. As described below, the response of the animals to noxious mechanical stimuli was evaluated by determining the PWT before (baseline) and 24 hours after the injection of FCA. Subsequently, a single injection of 1, 3, or 10 mg / kg of the compound of the present invention; a control drug selected from celecoxib, indomethacin, or naproxen at 30 mg / kg; or a vehicle was administered to the rats. The response to noxious mechanical stimuli was determined at 1, 3, 5, and 24 hours after administration. The percentage of recovery of hyperalgesia in each animal was defined as:

[0609] [(PWT after administration) - (PWT before administration)]

[0610] % Recovery = x 100

[0611] [(Baseline PWT) - (PWT before administration)]

[0612] Neuropathic pain: To evaluate the effect of the compounds of the present disclosure in treating or preventing neuropathic pain, the Seltzer model or the Chung model can be used.

[0613] In the Seltzer model, a partial sciatic nerve ligation model of neuropathic pain was used to produce neuropathic hyperalgesia in rats (Z. Seltzer et al., "A Novel Behavioral Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury," Pain 43:205-218 (1990)). The partial ligation of the left sciatic nerve was performed under isoflurane / O2 inhalation anesthesia. After induction of anesthesia, the left thigh of the rat was shaved and the sciatic nerve was exposed through a small incision at the level of the greater trochanter, and the surrounding connective tissue in the area near the trochanteric membrane was carefully cleared, the trochanteric membrane being distal to the point where the common sciatic nerve bifurcates into the biceps femoris semitendinosus nerves. A 7-0 suture silk was inserted into the nerve with a 3 / 8 curved reverse cutting mini-needle and tightly ligated such that the dorsal 1 / 3 to 1 / 2 remained within the ligature. The wound was closed with a single muscle suture (4-0 nylon (Vicryl)) and Vetbond tissue adhesive. After surgery, the wound area was sprayed with antibiotic powder. Sham-operated rats underwent the same surgical procedure except that the sciatic nerve was not manipulated. After surgery, the animals were weighed and placed on a warm pad until they recovered from anesthesia. The animals were then returned to their home cages until the start of behavioral testing. As described below, the response of the animals to noxious mechanical stimuli was evaluated by measuring PWT before surgery (baseline), then immediately prior to drug administration and at 1, 3, and 5 hours after drug administration. The percentage recovery of neuropathic hyperalgesia was defined as:

[0614]

[0615] In the Chung model, a spinal nerve ligation model of neuropathic pain is used to produce mechanical allodynia, thermal hyperalgesia, and tactile allodynia in rats. The surgery is performed under isoflurane / O2 inhalation anesthesia. After induction of anesthesia, a 3-cm incision is made and the left paravertebral muscle is dissected from the spinous processes at the L4-S2 level. A small rongeur is used to carefully remove the L6 transverse process to visually identify the L4-L6 spinal nerves. The left L5 (or L5 and L6) spinal nerve is dissected and tightly ligated with silk thread. Complete hemostasis is confirmed and the wound is sutured using non-absorbable sutures (such as nylon sutures or stainless steel staples). Sham-operated rats undergo the same surgical procedure except that the spinal nerves are not manipulated. After surgery, the animals are weighed, saline or lactated Ringer's is administered subcutaneously (s.c.), the wound area is sprayed with antibiotic powder and they are maintained on a warm pad until they recover from anesthesia. The animals are then returned to their home cages until the start of behavioral testing. As described below, the response of the animals to noxious mechanical stimuli is evaluated by measuring the PWT before surgery (baseline), then immediately prior to administration of the compound of the invention and at 1, 3, and 5 hours after administration of the compound of the invention. As described below, the response of the animals to noxious thermal stimuli or tactile allodynia can also be evaluated. The Chung model of neuropathic pain is described in S.H. Kim, "An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat," Pain 50(3):355-363 (1992).

[0616] Response to mechanical stimuli as an assessment of mechanical allodynia: Mechanical allodynia can be evaluated using paw pressure measurement. For this measurement, the paw withdrawal threshold (PWT) to noxious mechanical stimuli is determined using a dolorimeter (model 7200, commercially available from Ugo Basile, Italy) as described in the following reference: C. Stein, "Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds," Pharmacol. Biochem. and Behavior 31:451-455 (1988). The rat is gently restrained, its hind paw is placed on a small circular platform, and a punctate pressure is applied in a graded manner to the dorsal surface of the hind paw. The maximum weight applied to the hind paw is set at 250 g and the endpoint is considered as complete paw withdrawal. At each time point, the PWT of each rat is measured once, and only the affected (ipsilateral; on the same side as the injury) hind paw is tested, or both the ipsilateral and contralateral (uninjured; opposite to the injury) hind paws are tested.

[0617] Response to thermal stimuli as an assessment of thermal allodynia: Thermal allodynia can be evaluated using the plantar test. For this test, a plantar test device (commercially available from Ugo Basile, Italy) is used to determine the paw withdrawal latency to noxious thermal stimuli applied to the plantar surface of the hind paw according to the technique described by K. Hargreaves et al., "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia," Pain 32(1):77-88 (1988). The maximum exposure time is set at 32 seconds to avoid tissue damage, and paw withdrawal from any direction of the heat source is considered as the endpoint. Three latencies are measured and averaged at each time point. Only the affected (ipsilateral) paw is tested, or both the ipsilateral and contralateral (uninjured) paws are tested.

[0618] Assessment of allodynia: To assess allodynia, rats were placed in a transparent plexiglass compartment with a wire mesh floor and habituated for a period of at least 15 minutes. After habituation, a series of von Frey filaments were presented to the plantar surface of the affected (ipsilateral) paw of each rat. The series of von Frey filaments consisted of six filaments of increasing diameter, with the smallest diameter fiber presented first. Five trials were conducted with each filament, with each trial separated by approximately 2 minutes. Each presentation lasted for a period of 4 - 8 seconds, or until a nociceptive withdrawal behavior was observed. A withdrawn paw, paw withdrawal, or paw lick was considered a nociceptive behavioral response.

[0619] Assessment of respiratory depression: To assess respiratory depression, rats were prepared by implanting a femoral artery cannula for blood sampling. Blood samples were taken before drug administration, and then at 1, 3, 5, and 24 hours post-treatment. Blood samples were processed using an arterial blood gas analyzer (e.g., IDEXX VetStat with a respiratory / blood gas test cartridge). Equivalent devices are standard tools for blood gas analysis (e.g., D. Torbati et al., Intensive Care Med. (26):585 - 591 (2000).

[0620] Assessment of gastric motility: Animals were treated by oral gavage at a volume of 10 mL / kg with vehicle, reference compound, or test article. One hour after dosing, all animals were treated with a solution of charcoal powder (5% activated charcoal in 1% aqueous carboxymethylcellulose) at a volume of 10 mL / kg. Two hours after dosing (one hour after charcoal), the animals were sacrificed by carbon dioxide inhalation or isoflurane overdose, and the passage of charcoal powder was identified. The stomach and small intestine were carefully removed and placed on saline-soaked absorbent surfaces. The distance between the pylorus and the most distal progression of the charcoal powder was measured and compared to the distance between the pylorus and the ileocecal junction. Passage of charcoal powder was expressed as a percentage of the length of the small intestine traversed.

[0621] The compositions of the present disclosure are prepared by a method comprising mixing a compound of the present disclosure with a pharmaceutically acceptable carrier or excipient. Mixing can be accomplished using known methods for mixing a compound (or derivative) with a pharmaceutically acceptable carrier or excipient. In one embodiment, the compound of the present disclosure is present in the composition in an effective amount.

[0622] The present disclosure also relates to a kit comprising a sterile container containing an effective amount of a compound of the present disclosure and instructions for therapeutic use.

[0623] The following examples illustrate the compounds, compositions, and methods of the present invention, but are not limiting. Appropriate modifications and adaptations of the various conditions and parameters commonly encountered in clinical therapy and that are obvious to those skilled in the art in light of the present disclosure are within the spirit and scope of the present invention.

[0624] Example

[0625] "HPLC" means high performance liquid chromatography.

[0626] "CDCl3" means deuterochloroform.

[0627] "DCM" means dichloromethane.

[0628] "THF" means tetrahydrofuran.

[0629] "RT" means room temperature.

[0630] 1 1H NMR spectra were recorded in CDCl3 on a Varian Mercury Plus 400 MHz NMR instrument.

[0631] HPLC spectra were recorded in a MeOH / H2O mixture on an Agilent 1100 Series LC / MS instrument.

[0632] "COSY NMR" means correlated spectroscopy NMR, which is a type of two-dimensional nuclear magnetic resonance spectroscopy (2D NMR). COSY NMR spectra were recorded in CDCl3 on a Varian Mercury Plus 400 MHz NMR instrument.

[0633] "FTIR" means Fourier transform infrared spectroscopy. FTIR was recorded in solid form on a Thermo Scientific Nicolet 6700 FTIR instrument.

[0634] "HATR" means horizontal attenuated total reflection.

[0635] "HRMS" means high resolution mass spectrometry. HRMS was recorded in a MeOH / H2O mixture on a Thermo Scientific Q exactive LC / MS instrument.

[0636] LCMS analysis of the compounds was carried out by the following method

[0637] Column type: Phenomenex Luna C18 column, 5 microns, 2 x 50 mm;

[0638] Instrument: Agilent 1100 Series LC / MS instrument;

[0639] Detector wavelength: 250 nm; and

[0640] Mobile phase: 90% aqueous solution of 2.8 nM ammonium formate, 10% MeOH, pH 10, with NH4OH and MeOH.

[0641] Example 1

[0642] Preparation of 6-acetyl-oxycodone

[0643]

[0644] Oxycodone free base (0.316 g, 1 mmol) was mixed with LiN(TMS)2 (3 mmol) in anhydrous THF (10 mL) at -78 °C for 30 minutes and stirring was continued at room temperature for 1 hour. The reaction mixture was cooled again to -78 °C and acetic anhydride (0.47 mL, 5 mmol) was added to the reaction mixture. The reaction was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was neutralized with saturated NaHCO3 and extracted with DCM (3 x 15 mL), then dried over MgSO4, filtered and concentrated to give a crude product as a amber oil.

[0645] Part of the crude product was purified by preparative HPLC under the following conditions and parameters:

[0646] Column type: Gemini 5μm NX-C18 (Supplier: Phenomenex part #00F-4454-N0); Dimensions: 150 x 10 mm

[0647] HPLC method:

[0648] Instrument: Agilent 1100 Series LC / MS instrument

[0649] Column temperature: 25 °C

[0650] Detector wavelength: 250 nm

[0651] Concentration: 10 mg / mL, 1:1 MeOH:H2O solution

[0652] Flow rate: 2.5 mL / min

[0653] Mobile phase:

[0654] Solvent B: 90% aqueous solution of 2.8 mM ammonium formate, 10% methanol, pH 10, with NH4OH

[0655] Solvent C: Methanol

[0656] Gradient conditions:

[0657]

[0658] The peak was collected at 11.0 minutes, identified by mass spectrometry and concentrated under reduced pressure. The HPLC chromatogram is provided in Figure 1D 40 mg of 90%-95% pure title product as a white powder was collected.

[0659] A sample of the title product was dissolved in CDCl3, filtered and analyzed by 1 1H NMR and COSY NMR. 1 The 1H NMR spectrum is provided in Figure 1C COSY NMR and partial 1 1H NMR spectra clearly show that the 7-proton at 5.59 ppm is a doublet of doublets (broadened from weak coupling to proton 5), as shown in Figure 1A and Figure 1B respectively.

[0660] FTIR (HATR, cm -1 ) : 2933, 2838, 1754, 1601, 1503, 1446, 1368, 1210, 1144, 1111, 1044, 910 and 796.

[0661] C 20 H 24 NO5 + (M + H + ) HRMS calculated value: 358.1654; found: 358.1644.

[0662] Example 2

[0663] Preparation of 6-PEG Oxycodone

[0664]

[0665] Oxycodone free base (0.316 g, 1 mmol) was mixed with LiN(TMS)2 (3 mmol) in anhydrous THF (20 ml) at -78 °C for 30 minutes, and then stirred at room temperature for 30 minutes. The solution was recooled to -78 °C, and a solution of the acetyl chloride derivative prepared by reacting 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (30 mg, 3 mmol) with 3 equivalents of oxalyl chloride was added to the reaction mixture. The reaction was stirred overnight and slowly warmed to room temperature. Based on LCMS, the conversion of the title compound was approximately 44%. The reaction mixture was rotary evaporated and redissolved in 20 ml of DCM. Saturated sodium bicarbonate solution was added until the aqueous layer was neutralized. After extracting the mixture with DCM (20 mL x 3 times), the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give 0.85 g of a amber oil. Purification of a portion of the residue by preparative HPLC gave 85% pure title product and 15% oxycodone (as an impurity).

[0666] Figure 2A and Figure 2B respectively show the 1 1H NMR spectrum and HPLC chromatogram of the title compound.

[0667] Example 3

[0668] Preparation of 6,14-bis-lauroyl oxycodone

[0669]

[0670] Oxycodone (0.3415 g), 4-(dimethylamino)pyridine (0.3475 g) and lauroyl chloride (7 mL) were stirred under nitrogen and heated to 80 °C for three days. The reaction mixture was then cooled and poured into water (100 mL). After stirring for two hours, the mixture was neutralized with concentrated ammonium hydroxide (2 mL) and gently extracted with chloroform (50 mL, with slight stirring). The aqueous layer was diluted with saturated NaHCO3 solution (25 mL) and extracted with chloroform (25 mL, forming an emulsion). The organic layer was allowed to separate overnight, then dried over MgSO4, filtered and concentrated under reduced pressure to give 0.39 g of an amber oil as the title product. Yield: 53%.

[0671] Figure 3A and Figure 3B respectively show the 1 1H NMR spectrum and HPLC chromatogram of the title compound.

[0672] Example 4

[0673] Preparation of 6-lauroyl oxycodone

[0674]

[0675] Oxycodone (312 mg, 1 mmol) was mixed with LiN(TMS)2 (i.e., LiHDMS) (3 mmol) in anhydrous THF (10 mL) at -78 °C for 30 minutes, followed by 30 minutes at room temperature. The solution was recooled to -78 °C, and dodecanoyl chloride (0.65 mL, 5 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for three days. Worked up with water, extracted with chloroform, then dried over MgSO4, filtered and concentrated to give an amber oil. Purification by silica gel chromatography gave 0.289 g of an amber solid product. Yield: 59%.

[0676] Figure 4A and Figure 4B respectively show the 1 1H NMR spectrum and HPLC chromatogram of the title compound.

[0677] Example 5

[0678] Preparation of 6,14-bis-valeryl oxycodone

[0679]

[0680] Oxycodone (0.3257 g) and valeric anhydride (4 mL) were stirred under nitrogen and heated at 170 °C for 21 hours. The mixture was then cooled and poured into water (100 mL). After stirring for two hours, the mixture was made basic with 30% ammonium hydroxide and extracted with DCM (2 x 30 mL). The extract was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure.

[0681] The sample was dried on a kugelrohr distiller (50 °C, 0.05 Torr) to give 0.56 g of a dark material. Purification by silica gel chromatography (10 g), chloroform solution of 0.75% methanol, 0.075% concentrated ammonium hydroxide. 4 mL (ten) and 8 mL fractions were collected successively. Fractions 10 to 21 were analyzed by LCMS, combined and concentrated under reduced pressure to give a dark oil (0.3698 g). Yield 74%.

[0682] Figure 5A and Figure 5B respectively show the 1 1H NMR spectrum and HPLC chromatogram of the title compound.

[0683] Example 6

[0684] Hydrolysis study of 6-acetyl oxycodone

[0685]

[0686] Testing was performed using serum instead of plasma because plasma contains platelets that must be stabilized to prevent clotting, and the stabilizing chemicals can interfere with enzyme activity. Serum was prepared by allowing fresh blood to clot (for approximately 30 minutes) and then centrifuging, which removes the platelets and obviates the need for chemical stabilization. Human serum (pH 7.7) was used on the day of delivery.

[0687] Freshly prepared simulated gastric fluid (pH ≈ 1) and simulated intestinal fluid (pH ≈ 6.8) were used. Buffer solutions of various pH values (4, 7, 9, 10, 11) were prepared according to the literature. The buffer solutions were then mixed with EtOH to make a 1:1 solution (to improve solubility).

[0688] Hydrolysis studies of 6-acetyl-oxycodone (“6-OAc-Oxy”) were conducted in the above media.

[0689] The results are presented in Figure 6 and summarized in the following table (note: “Oxy” represents oxycodone free base):

[0690] Table 1: Hydrolysis of 6-OAc-Oxy in human serum at 37 °C

[0691] Time (hours) Oxy (%) 6 - OAc - Oxy (%) 0 9.0 89.4 0.083 (5 minutes) 97.1 0.65 0.5 98.9 0.39

[0692] Table 2: Hydrolysis of 6-OAc-Oxy in simulated intestinal fluid at 37 °C

[0693] Time (hours) Oxy (%) 6 - OAc - Oxy (%) 0 9.0 89.4 0.5 57.6 39.8 2 94.9 0.7 4 95.3 0.0

[0694] Table 3: Hydrolysis of 6-OAc-Oxy in simulated gastric fluid at 37 °C

[0695] Time (hours) Oxy (%) 6 - OAc - Oxy (%) 0 9.0 89.4 2 17.1 68.4 4 18.4 66.1 8 22.4 58.1 24 36.3 46.2

[0696] Table 4: Hydrolysis of 6-OAc-Oxy in buffer solution (1:1 EtOH:H2O) at pH = 11

[0697] Time (hours) Oxy (%) 6 - OAc - Oxy (%) 0 9.0 89.4 0.5 97.1 1.6

[0698] Table 5: Hydrolysis of 6-OAc-Oxy in buffer solution (1:1 EtOH:H2O) at pH = 10

[0699] Time (hours) Oxy (%) 6 - OAc - Oxy (%) 0 9.0 89.4 0.5 65.2 32.3 2 96.8 1.6 4 98.3 1.2

[0700] Table 6: Hydrolysis of 6-OAc-Oxy in buffer solution (1:1 EtOH:H2O) at pH = 9

[0701]

[0702]

[0703] Table 7: Hydrolysis of 6-OAc-Oxy in buffer solution at pH = 8 (1:1 EtOH:H2O)

[0704] Time (hours) Oxy (%) 6 - OAc - Oxy (%) 0 9.4 89.4 0.5 10.4 87.4 2 8.8 87.0 26 20.9 75.3

[0705] Table 8: Hydrolysis of 6-OAc-Oxy in buffer solution at pH = 7 (1:1 EtOH:H2O)

[0706] Time (hours) Oxy (%) 6 - OAc - Oxy (%) 0 9.4 89.4 0.5 9.5 87.2 2 8.2 87.9 26 12.9 77.9

[0707] Table 9: Hydrolysis of 6-OAc-Oxy in 0.1N HCl solution

[0708] Time (hours) Oxy (%) 6 - OAc - Oxy (%) 0 89.4 0.5 6.43 89.0 2 7.8 86.4 8 9.5 86.1 24 30.1 67.3

[0709] Table 10: Hydrolysis of 6-OAc-Oxy in 1N HCl solution

[0710] Time (hours) Oxy (%) 6 - OAc - Oxy (%) 0 89.4 0.5 16.6 81.5 2 30.3 61.0 4 56.4 42.0 8 80.8 18.2 24 95.3 1.7

[0711] The above results show that 6-acetyl-oxycodone is rapidly hydrolyzed in human serum (37 °C). Most of 6-acetyl-oxycodone is hydrolyzed to oxycodone within 5 minutes.

[0712] Example 7

[0713] Preparation of 6,14-bis-acetyl-oxycodone

[0714]

[0715] Oxycodone free base (0.4711 g, 1.49 mmol) and Ac2ONa (0.1 g, 1.22 mmol) in Ac2O (5 mL) were refluxed at 160 °C - 170 °C for 2.5 hours. Excess Ac2O was removed under reduced pressure, and the product was precipitated with dilute ammonia solution. The filtered solid was recrystallized from EtOH to obtain 460 mg of the title product as a white solid. Yield: 78%.

[0716] Figure 7A and Figure 7B respectively show the 1 1H NMR spectrum and HPLC chromatogram of the title compound.

[0717] Example 8

[0718] A mixture of oxycodone, 6-acetyl-oxycodone ("6-acetyl"), 14-acetyl-oxycodone ("14-acetyl"), and 6,14-bis-acetyl-oxycodone ("6,14-bis-acetyl") was subjected to hydrolysis in simulated intestinal fluid (37 °C, pH 6.8, pancreatin), and the hydrolyzed oxycodone and enol esters were analyzed by LCMS. The results of the hydrolysis are shown in Table 11.

[0719] Table 11: Hydrolysis of a mixture of 6-acetyl, 14-acetyl, and 6,14-diacetyl

[0720]

[0721]

[0722] The results showed that 6-acetyl-oxycodone was readily hydrolyzed in the intestine, releasing oxycodone in less than 2 hours. Hydrolysis of 6,14-bis-acetyl-oxycodone produced additional 6-acetyl-oxycodone and 14-acetyl-oxycodone.

[0723] 14-Acetyl-oxycodone can be prepared, for example, as described in U.S. Patent No. 4,322,426 by reacting oxycodone free base with acetic anhydride.

[0724] Example 9

[0725] Hydrolysis study of 6-OAc-hydrocodone

[0726]

[0727] Human serum (pH 7.7), simulated gastric fluid (pH ≈ 1), simulated intestinal fluid (pH ≈ 6.8), and buffer solutions at various pH values (4, 7, 9, 10, 11) were prepared in the same manner as described in Example 6.

[0728] Hydrolysis studies of 6-acetyl-hydrocodone ("6-OAc-hydrocodone") were carried out in the above media. The results are presented in Figure 8 .

[0729] The results showed that 6-acetyl-hydrocodone was rapidly hydrolyzed in human serum (37 °C): 70% of 6-acetyl-hydrocodone was hydrolyzed to hydrocodone within 5 minutes and 99% within 30 minutes.

[0730] Example 10

[0731] Preparation and isolation of 6,14-bis-PEG-oxycodone (as the PEG salt)

[0732]

[0733] After the above reaction, the crude product was further purified by flash column using an 80 g silica gel cartridge and a 5% MeOH in EtOAc solution. Two batches of product were isolated.

[0734] The more pure fraction contained 82 mg of 88% pure 6,14-bis-PEG-oxycodone 2-[2-(2-methoxyethoxy)ethoxy]acetate and 12% of mono-PEG-oxycodone, with no oxycodone. The less pure fraction contained approximately 251 mg of 81% pure 6,14-bis-PEG-oxycodone 2-[2-(2-methoxyethoxy)ethoxy]acetate, 18% of mono-PEG-oxycodone, and 1% of oxycodone (as an impurity).

[0735] Example 11

[0736] Hydrolysis Study of 6,14-Bis-PEG-Oxycodone

[0737]

[0738] The hydrolysis study of 6,14-bis-PEG-oxycodone was started with a mixture of 86% pure 6,14-bis-PEG-oxycodone and 14% pure mono-bis-PEG-oxycodone. Freshly prepared simulated gastric fluid (pH = 1.2) and simulated intestinal fluid (pH = 6.8) were used. Human serum (pH 7.7) was used on the day of delivery. Buffer solutions of various pH (4, 7, 9, 10, 11) were prepared according to the literature. The buffer solutions were then mixed with EtOH to make a 1:1 solution (to improve solubility). The results are presented in Figure 9 in.

[0739] In addition, the hydrolysis results of the starting mixture in human serum at 37 °C are summarized in Table 12, the hydrolysis results of the starting mixture in simulated gastric fluid at 37 °C are summarized in Table 13, and the results of the starting mixture in simulated intestinal fluid at 37 °C are summarized in Table 14:

[0740] Table 12: Hydrolysis in Human Serum

[0741]

[0742] Table 13: Hydrolysis in Simulated Gastric Fluid

[0743]

[0744] Table 14: Hydrolysis in Simulated Intestinal Fluid

[0745]

[0746] Example 12

[0747] Hydrolysis Study of 6-Lauroyl-Oxycodone

[0748]

[0749] The hydrolysis study of 6-lauroyl-oxycodone was started with 99% pure 6-lauroyl-oxycodone. The pH 11 and pH 9 buffers used for the hydrolysis study contained 75% EtOH to increase the solubility of 6-lauroyl-oxycodone. Simulated intestinal fluid was freshly prepared for hydrolysis. 0.5% polysorbate 80 was added as an emulsifier to the intestinal fluid to help the uniform distribution of 6-lauroyl-oxycodone.

[0750] The hydrolysis results of 6-lauroyl-oxycodone in pH 11 and pH 9 buffers and in simulated intestinal fluid at 37 °C containing 0.5% polysorbate 80 are presented in Tables 15 - 17.

[0751] Table 15: In pH 11 buffer

[0752] Time (hours) 6 - Lauroyl - Oxy (%) Oxy (%) 0 99 0 0.5 24.5 75.5 4 7.2 92.8 8 6.2 93.8

[0753] Table 16: In pH 9 buffer

[0754] Time (hours) 6 - Lauroyl - Oxy (%) Oxy (%) 0 99 0 0.5 98 1 2 98 1 4 98 1 8 98 1

[0755] Table 17: In simulated intestinal fluid

[0756] Time (hours) 6 - Lauroyl - Oxy (%) Oxy (%) 0 99 0 0.17 56.9 43.1 0.5 54.8 45.2 1 52.6 47.4 2 50.8 49.2 Plus an additional 30 minutes of fresh intestinal fluid 18.6 81.4

[0757] Example 13

[0758] Hydrolysis study of 6,14-bis-lauroyl-oxycodone

[0759]

[0760] The hydrolysis study of 6,14-bis-lauroyl-oxycodone was started with 99% pure product. The pH 11, pH 9, pH 7 buffer solutions and 1.0 N HCl solution used for the hydrolysis study contained 75% EtOH to increase the solubility of 6,14-bis-lauroyl-oxycodone.

[0761] The hydrolysis results in buffer solutions and 1.0 N HCl solution are presented in Tables 18 - 21.

[0762] Table 18: In pH 11 buffer

[0763]

[0764] Table 19: In pH 9 buffer

[0765]

[0766] Table 20: In pH 7 buffer

[0767]

[0768]

[0769] Table 21: In 1.0N HCl

[0770]

[0771] The single-lauroyl-oxycodone (e.g., 6-lauroyl-oxycodone) can be further purified by the following HPLC method:

[0772] Column: Biotage C18HS12M 0667-1 (10 g)

[0773] Aqueous buffer: 0.14 g ammonium formate and two drops of concentrated aqueous ammonium hydroxide (1 L)

[0774] Condition: 1:1 buffer / methanol, four 12 mL fractions

[0775] 1:3 buffer / methanol, eight 12 mL fractions

[0776] Methanol, remaining fractions

[0777] Analyze the fractions by LCMS (isocratic methanol, run for 3 minutes).

[0778] Example 14

[0779] Isolation and purification of 14-lauroyl oxycodone

[0780] Isolation of 14-lauroyl oxycodone: Use a 200 mg sample of 6,14-bis-lauroyl oxycodone and about 10% of 14-lauroyl oxycodone to isolate the 14-lauroyl oxycodone sample by reverse-phase flash chromatography:

[0781] Column: Biotage C18HS 12M 0667-1 (10 g);

[0782] Aqueous buffer: 0.14 g ammonium formate and two drops of concentrated aqueous ammonium hydroxide (1 L);

[0783] Condition:

[0784] 1:1 buffer / methanol, eight 12 mL fractions,

[0785] 1:3 buffer / methanol, eight 12 mL fractions, and

[0786] Methanol, remaining fractions.

[0787] Fractions were analyzed by LCMS (isocratic methanol). Fractions 18 and 19 were combined and concentrated under reduced pressure (0.4 Torr) to afford pure 14-lauroyl oxycodone (9.1 mg). LCMS analysis showed no impurities, [M+H] + = 498. Figure 10 RP flash chromatogram of the method is shown, where “Mono” refers to 14-lauroyl oxycodone and “Di” refers to 6,14-bis-lauroyl oxycodone.

[0788] Purification of 14-lauroyl oxycodone:

[0789] A mixture of 200 mg of 14-lauroyl oxycodone and oxycodone was separated using the method described above. Fractions 18 and 19 were combined and concentrated under reduced pressure (0.4 Torr) to afford 14-lauroyl oxycodone (47.3 mg). Figure 11 RP flash chromatogram of the method is shown, where “Mono” refers to 14-lauroyl oxycodone, “Di” refers to 6,14-bis-lauroyl oxycodone, and “Oxy” refers to oxycodone.

[0790] Example 15

[0791] μ-opioid receptor binding assay

[0792] The μ-opioid receptor binding activities of the compounds listed in Table 22 were tested according to the radioligand binding assay procedure described in paragraph

[0414] above:

[0793] Table 22:

[0794]

[0795] The results of the binding assay showed that the binding constants (K i ) of 6-substituted enol esters such as 6-acetyl oxycodone, 6-PEG oxycodone and 6-lauroyl oxycodone were comparable to the K i of 0.030 obtained for the parent opioid oxycodone. Additionally, the K i of the medium-chain 6,14-bis-substituted enol ester, 6,14-bis-PEG oxycodone, was comparable to the K i of oxycodone. The K i of the short-chain 14-substituted enol esters of the compounds of formula VI (such as the exemplary 14-acetyl oxycodone) was lower than the K i of oxycodone. When compounds having a substitution pattern similar to those mentioned above are only bioavailable in the lower gastrointestinal tract, they are converted to oxycodone over time, thus providing μ-opioid agonist function from both the enol ester prodrug and the parent oxycodone.

[0796] 14-Lauroyl oxycodone, the K of an exemplary compound of the long-chain mono-14-substituted enol ester of the compound of formula VI i is higher than that of oxycodone i .

[0797] 6,14-Di-lauroyl oxycodone, the K of an exemplary compound of the long-chain mono-6,14-disubstituted enol ester of the compound of formula V i is significantly higher than that of oxycodone i . Thus, these types of compounds do not bind well to the μ-opioid receptor before being hydrolyzed in the intestine to their parent opioid compounds.

[0798] Example 16

[0799] μ-Opioid receptor function assay

[0800] In the 35 [35S]GTPγS function assay, the compounds listed in Table 22 of Example 15 (except 6,14-di-lauroyl oxycodone) were tested to evaluate whether the tested compounds are agonists or antagonists of the μ receptor. As described in the above paragraph

[0416] , functional tests were performed using freshly thawed μ receptor membranes prepared from a cell line expressing recombinant μ-opioid receptor in the CHO-K1 cell background. The results of the functional assay are provided in Table 23.

[0801] Table 23:

[0802]

[0803]

[0804] NA = Not applicable; ND = Not determined

[0805] As described in Example 15, 6,14-di-lauroyl oxycodone does not bind well to the μ-opioid receptor. Therefore, within the concentration range studied, the EC 50 value of this compound could not be determined in the functional assay.

[0806] From the results in Table 23, it can be concluded that 6-substituted enol esters are agonists of the μ-opioid receptor. 14-Acetyl oxycodone and 6,14-bis-PEG oxycodone are also μ receptor agonists as effective as oxycodone. 14-Lauroyl oxycodone is a partial agonist and partial antagonist of the μ-opioid receptor, but is a slightly weaker agonist than oxycodone and a much weaker antagonist than naltrexone (IC 50 = 15.2 nM). Naltrexone was used as a positive control when evaluating the antagonist activity of 14-lauroyl oxycodone.

[0807] This disclosure also relates to the following specific embodiments:

[0808] Embodiment 1. A compound of formula I:

[0809]

[0810] and its pharmaceutically acceptable salts or solvates, wherein:

[0811] R 1 is H; alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl; -PEG-R 7 ; or a hydroxyl protecting group PG selected from the group consisting of: alkyl, arylalkyl, heterocyclic, (heterocyclic)alkyl, acyl, silyl and carbonate, any of which groups is optionally substituted;

[0812] Z is C-OR 2 or C(=O);

[0813] is a single bond or a double bond, provided that when Z is C(=O), is a single bond, and when Z is C-OR 2 then, is a double bond;

[0814] R 2 is -C(=O)R 5 or -PEG-R 7 wherein

[0815] R 5 is selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 、-NH-(CH2CH2O) p -R 7, phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle and (5- or 6-membered heterocycle)alkyl, wherein said phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl; and wherein said 6-membered heterocyclic group is attached to R through a carbon atom or through a nitrogen atom 2 to the carbonyl carbon of

[0816] R 3 is hydrogen, OH, -Y-PEG-R 7 or -OC(=O)R 6 , wherein

[0817] Y is a covalent bond or a linking group;

[0818] R 6 is selected from the group consisting of unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7 , -NH(CH2CH2O) p -R 7 , phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle and (5- or 6-membered heterocycle)alkyl, wherein said phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl; and wherein said 6-membered heterocyclic group is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom;

[0819] provided that when Z is C(=O), R 3 is -OC(=O)R 6 ;

[0820] PEG is an ethylene oxide unit or an oligomer having two or more ethylene oxide subunits;

[0821] R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclic group, any of said groups being optionally substituted;

[0822] R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, any of which is optionally substituted with 1, 2, or 3 substituents, each of which is independently selected from the group consisting of hydroxyl, halogen, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy, and alkoxycarbonyl;

[0823] m is an integer between 1 and 9;

[0824] n and p are each independently an integer between 1 and 20; and

[0825] provided that R 2 and R 3 at least one of which is -C(=O)R 5 and -OC(=O)R 6 ; the provisos are as follows:

[0826] 1) The compound is not

[0827]

[0828] 2) When R 1 is unsubstituted alkyl, R 3 is hydrogen and R 4 is unsubstituted alkyl, then R 5 is not optionally substituted phenyl or optionally substituted pyridyl, or

[0829] 3) When R 1 is unsubstituted alkyl, R 4 is unsubstituted alkyl and R 3 is -OC(=O)R 6 then R 5 and R 6 are not both optionally substituted pyridyl.

[0830] Embodiment 2. The compound according to Embodiment 1, the compound having the formula II:

[0831]

[0832] or a pharmaceutically acceptable salt or solvate thereof.

[0833] Embodiment 3. The compound according to Embodiment 1 or 2, the compound having the formula III:

[0834]

[0835] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 、R2 and R 3 and R 4 are as defined in Embodiment 1.

[0836] Embodiment 4. A compound as described in Embodiment 1 or 2, said compound having Formula IV:

[0837]

[0838] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 4 and R 5 are as defined in Embodiment 1, and R 31 is hydrogen or OH.

[0839] Embodiment 5. A compound as described in Embodiment 1 or 2, said compound having Formula V:

[0840]

[0841] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 4 and R 5 are as defined in Embodiment 1.

[0842] Embodiment 6. A compound as described in Embodiment 1, said compound having Formula VI:

[0843]

[0844] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 4 are as defined in Claim 1, and R 3 is -OC(=O)R 6 wherein R 6 is as defined in Embodiment 1.

[0845] Embodiment 7. A compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of Embodiments 1-6, wherein R 1 is H or an alkyl group optionally substituted with 1, 2 or 3 substituents, said substituents being independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl.

[0846] Embodiment 8. A compound or a pharmaceutically acceptable salt or solvate thereof as described in Embodiment 7, wherein R 1 is H or unsubstituted C 1-6 alkyl.

[0847] Embodiment 9. The compound according to any one of Embodiments 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -PEG-R 7 wherein R 7 is as defined in claim 1, and PEG is -(CH2CH2O) q - where q varies from 1 to 50.

[0848] Embodiment 10. The compound according to any one of Embodiments 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is PG, and the PG is selected from the group consisting of methyl, tert-butyl, optionally substituted benzyl, optionally substituted benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl.

[0849] Embodiment 11. The compound according to any one of Embodiments 1-3 and 7-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen.

[0850] Embodiment 12. The compound according to any one of Embodiments 1-3 and 7-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is OH.

[0851] Embodiment 13. The compound according to any one of Embodiments 1-3 and 7-10, or a pharmaceutically acceptable salt thereof, wherein R 3 is -Y-PEG-R 7 and R 2 is -C(=O)R 5 wherein Y, PEG, R 7 and R 5 are as defined in Embodiment 1.

[0852] Embodiment 14. The compound according to any one of Embodiments 1-3 and 7-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -OC(=O)R 6 wherein R 6 is as defined in Embodiment 1.

[0853] Embodiment 15. The compound according to any one of Embodiments 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is unsubstituted C 1-6 alkyl.

[0854] Embodiment 16. The compound according to any one of Embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is methyl.

[0855] Embodiment 17. The compound according to any one of Embodiments 6 and 14-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is unsubstituted C 1-6 alkyl, provided that the compound is not

[0856]

[0857] Embodiment 18. The compound according to Embodiment 6 or 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is methyl.

[0858] Embodiment 19. The compound according to any one of Embodiments 6 and 14-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is unsubstituted C 7-12 alkyl.

[0859] Embodiment 20. The compound according to any one of Embodiments 1-5 and 7-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is unsubstituted C 1-6 alkyl.

[0860] Embodiment 21. The compound according to any one of Embodiments 1-5 and 7-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is unsubstituted C 7-12 alkyl.

[0861] Embodiment 22. The compound according to any one of Embodiments 1-5 and 7-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -CH2-O-(CH2CH2O) m -CH3, where m is 1, 2 or 3.

[0862] Embodiment 23. The compound according to any one of Embodiments 1-3, 6-10 and 14-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is -CH2-O-(CH2CH2O) m -CH3, where m is 1, 2 or 3.

[0863] Embodiment 24. The compound according to Embodiment 4, wherein R 31 is OH.

[0864] Embodiment 25. The compound according to Embodiment 2 or a pharmaceutically acceptable salt or solvate thereof, wherein

[0865] R 1 is H or unsubstituted C 1-6 alkyl;

[0866] R 2 is -C(O)(C 1-6 )alkyl;

[0867] R 3 is H or OH; and

[0868] R 4 is unsubstituted C 1-6 alkyl,

[0869] provided that the compound is not

[0870]

[0871] Embodiment 26. The compound according to Embodiment 2, the compound being

[0872]

[0873] or a pharmaceutically acceptable salt or solvate thereof.

[0874] Embodiment 27. The compound according to Embodiment 26, the compound being

[0875]

[0876] or a pharmaceutically acceptable salt or solvate thereof.

[0877] Embodiment 28. The compound according to Embodiment 1, the compound being selected from the group consisting of:

[0878]

[0879] or a pharmaceutically acceptable salt or solvate thereof.

[0880] Embodiment 29. A pharmaceutical composition comprising the compound according to any one of Embodiments 1-28 or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers.

[0881] Embodiment 30. A method of treating or preventing a condition in a patient responsive to modulation of one or more opioid receptors, the method comprising administering to the patient in need of such treatment or prevention an effective amount of the compound according to any one of Embodiments 1-28 or a pharmaceutically acceptable salt or solvate thereof.

[0882] Embodiment 31. The method according to embodiment 30, wherein the disorder is pain.

[0883] Embodiment 32. A method of treating, ameliorating or preventing pain, constipation, diarrhea, alcohol withdrawal or drug withdrawal in a patient, the method comprising administering to the patient in need of such treatment or prevention an effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 1-28.

[0884] Embodiment 33. The method according to embodiment 32, wherein the method is for treating pain.

[0885] Embodiment 34. The method according to embodiment 33, wherein the pain is acute pain, chronic pain or surgical pain.

[0886] Embodiment 35. The method according to embodiment 34, wherein the pain is chronic pain.

[0887] Embodiment 36. The method according to embodiment 35, wherein the chronic pain is neuropathic pain, postoperative pain or inflammatory pain.

[0888] Embodiment 37. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 1-28, the compound or the pharmaceutically acceptable salt or solvate thereof being for treating a disorder responsive to modulation of one or more opioid receptors.

[0889] Embodiment 38. A compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 1-28, the compound or the pharmaceutically acceptable salt or solvate thereof being for treating a disorder responsive to modulation of one or more opioid receptors.

[0890] Embodiment 39. A method of preparing a pharmaceutical composition, the method comprising mixing a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 1-28 with a pharmaceutically acceptable carrier.

[0891] Embodiment 40. A kit comprising a container containing an effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 1-28, and instructions for therapeutic use.

[0892] Embodiment 41. A method for slowing the onset of opioid activity in a mammal in need of opioid therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of Embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof.

[0893] Embodiment 42. The method according to Embodiment 41, the method further comprising co-administering one or more other therapeutic agents.

[0894] Embodiment 43. The method according to Embodiment 42, wherein the one or more other therapeutic agents are one or more non-steroidal anti-inflammatory agents.

[0895] Embodiment 44. The method according to Embodiment 42, wherein the one or more other therapeutic agents are one or more opioid agonists.

[0896] Embodiment 45. The method according to Embodiment 42, wherein the one or more other therapeutic agents are one or more opioid antagonists.

[0897] The present invention has now been fully described, and those of ordinary skill in the art will understand that the present invention can be practiced within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the present invention or any of its embodiments.

[0898] Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. The specification and examples are to be considered as merely exemplary, and the true scope and spirit of the invention are indicated by the following claims.

[0899] All patents and publications cited herein are hereby incorporated by reference in their entirety.

[0900] This application also relates to the following embodiments:

[0901] 1. A compound of formula I:

[0902]

[0903] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0904] R 1 is H; alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl; -PEG-R 7; or a hydroxyl protecting group PG selected from the group consisting of: alkyl, arylalkyl, heterocyclic group, (heterocyclic group)alkyl, acyl, silyl and carbonate group, any of said groups being optionally substituted;

[0905] Z is C-OR 2 or C(=O);

[0906] is a single bond or a double bond, provided that when Z is C(=O), is a single bond, and when Z is C-OR 2 then is a double bond;

[0907] R 2 is -C(=O)R 5 or -PEG-R 7 , wherein

[0908] R 5 is selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7 , -NH-(CH2CH2O) p -R 7 , phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle and (5-membered or 6-membered heterocycle)alkyl, wherein said phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of: alkyl, hydroxyl, halogen, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl; and wherein said 6-membered heterocyclic group is attached to the carbonyl carbon of R 2 through a carbon atom or through a nitrogen atom;

[0909] R 3 is hydrogen, OH, -Y-PEG-R 7 or -OC(=O)R 6 , wherein

[0910] Y is a covalent bond or a linker;

[0911] R 6 is selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12Alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 、-NH(CH2CH2O) p -R 7 、phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle and (5-membered or 6-membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl; and wherein the 6-membered heterocyclic group is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom;

[0912] Provided that when Z is C(=O), R 3 is -OC(=O)R 6 ;

[0913] PEG is an ethylene oxide unit or an oligomer having two or more ethylene oxide subunits;

[0914] R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclic group, any of which is optionally substituted;

[0915] R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and (cycloalkyl)alkyl, any of which is optionally substituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl;

[0916] m is an integer between 1 and 9;

[0917] n and p are each independently an integer between 1 and 20; and

[0918] Provided that at least one of R 2 and R 3 is respectively -C(=O)R 5 and -OC(=O)R 6 ; Provided as follows:

[0919] 1) The compound is not

[0920]

[0921] 2) When R 1 is an unsubstituted alkyl group, R 3 is hydrogen and R 4 is an unsubstituted alkyl group, then R 5 is not an optionally substituted phenyl group or an optionally substituted pyridyl group,

[0922] 3) When R 1 is an unsubstituted alkyl group, R 4 is an unsubstituted alkyl group and R 3 is -OC(=O)R 6 then R 5 and R 6 are both not an optionally substituted pyridyl group, or

[0923] 4) The compound is not

[0924]

[0925] 2. The compound according to embodiment 1, the compound has formula II:

[0926]

[0927] or a pharmaceutically acceptable salt or solvate thereof.

[0928] 3. The compound according to embodiment 1 or 2, the compound has formula III:

[0929]

[0930] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 、R 2 、R 3 and R 4 are as defined in embodiment 1.

[0931] 4. The compound according to embodiment 1 or 2, the compound has formula IV:

[0932]

[0933] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 、R 4 and R 5 are as defined in embodiment 1, and R 31 is hydrogen or OH.

[0934] 5. The compound according to embodiment 1 or 2, the compound has formula V:

[0935]

[0936] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 4 and R 5 is as defined in embodiment 1.

[0937] 6. The compound according to embodiment 1, said compound having formula VI:

[0938]

[0939] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 4 are as defined in embodiment 1, and R 3 is -OC(=O)R 6 , wherein R 6 is as defined in embodiment 1.

[0940] 7. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or an alkyl group optionally substituted by 1, 2 or 3 substituents, said substituents being independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl.

[0941] 8. The compound according to embodiment 7 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl.

[0942] 9. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -PEG-R 7 , wherein R 7 is as defined in embodiment 1, and PEG is -(CH2CH2O) q -, where q varies from 1 to 50.

[0943] 10. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is PG, and said PG is selected from the group consisting of: methyl, tert-butyl, optionally substituted benzyl, optionally substituted benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and triisopropylsilyl.

[0944] 11. The compound according to any one of embodiments 1-3 and 7-10 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen.

[0945] 12. A compound as described in any one of embodiments 1-3 and 7-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is OH.

[0946] 13. A compound as described in any one of embodiments 1-3 and 7-10, or a pharmaceutically acceptable salt thereof, wherein R 3 is -Y-PEG-R 7 , and R 2 is -C(=O)R 5 , wherein Y, PEG, R 7 and R 5 are as defined in embodiment 1.

[0947] 14. A compound as described in any one of embodiments 1-3 and 7-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -OC(=O)R 6 , wherein R 6 is as defined in embodiment 1.

[0948] 15. A compound as described in any one of embodiments 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is unsubstituted C 1-6 alkyl.

[0949] 16. A compound as described in any one of embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is methyl.

[0950] 17. A compound as described in any one of embodiments 6 and 14-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is unsubstituted C 1-6 alkyl, provided that the compound is not

[0951]

[0952] 18. A compound as described in embodiment 6 or 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is methyl, provided that the compound is not

[0953] 19. A compound as described in any one of embodiments 6 and 14-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is unsubstituted C 7-12 alkyl.

[0954] 20. The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 - 5 and 7 - 19, wherein R 5 is unsubstituted C 1-6 alkyl.

[0955] 21. The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 - 5 and 7 - 19, wherein R 5 is unsubstituted C 7-12 alkyl.

[0956] 22. The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 - 5 and 7 - 19, wherein R 5 is -CH2-O-(CH2CH2O) m -CH3, where m is 1, 2, or 3.

[0957] 23. The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 - 3, 6 - 10 and 14 - 16, wherein R 6 is -CH2-O-(CH2CH2O) m -CH3, where m is 1, 2, or 3.

[0958] 24. The compound according to embodiment 4, wherein R 31 is OH.

[0959] 25. The compound or a pharmaceutically acceptable salt or solvate thereof according to embodiment 2, wherein

[0960] R 1 is H or unsubstituted C 1-6 alkyl;

[0961] R 2 is -C(O)(C 1-6 )alkyl;

[0962] R 3 is H or OH; and

[0963] R 4 is unsubstituted C 1-6 alkyl,

[0964] provided that the compound is not

[0965]

[0966] 26. The compound according to embodiment 4, the compound having formula IV:

[0967]

[0968] or a pharmaceutically acceptable salt or solvate thereof, wherein

[0969] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[0970] R 31 is hydrogen or OH;

[0971] R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of said groups optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[0972] R 5 is selected from the group consisting of unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p -R 7 ;

[0973] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0974] m is an integer between 1 and 9;

[0975] n and p are each independently an integer between 1 and 20; and

[0976] PEG is an ethylene oxide unit or an oligomer having 2 to about 10 ethylene oxide subunits, provided that the compound is not

[0977]

[0978] 27. The compound according to embodiment 26 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl, and R 4 is unsubstituted C 1-6 alkyl.

[0979] 28. The compound according to embodiment 26 or 27 or a pharmaceutically acceptable salt thereof, wherein R 31 is OH.

[0980] 29. The compound according to any one of embodiments 26-28 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 4 are methyl.

[0981] 30. The compound according to any one of embodiments 26-29 or a pharmaceutically acceptable salt thereof, wherein R 5 is unsubstituted C 1-6 alkyl.

[0982] 31. The compound according to any one of embodiments 26-30 or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.

[0983] 32. The compound according to any one of embodiments 26-29 or a pharmaceutically acceptable salt thereof, wherein R 5 is unsubstituted C 7-12 alkyl.

[0984] 33. The compound according to any one of embodiments 26-29 and 32 or a pharmaceutically acceptable salt thereof, wherein R 5 is unsubstituted heptyl, octyl or nonyl.

[0985] 34. The compound according to any one of embodiments 26-29 and 32 or a pharmaceutically acceptable salt thereof, wherein R 5 is unsubstituted decyl, undecyl or dodecyl.

[0986] 35. The compound according to embodiment 34 or a pharmaceutically acceptable solvate thereof, wherein R 5 is undecyl.

[0987] 36. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 26 - 29, wherein

[0988] R 5 is selected from the group consisting of: -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p -R 7 ;

[0989] R 7 is hydrogen or C 1-4 alkyl;

[0990] m is 1, 2, 3, 4 or 5;

[0991] n and p are each independently selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0992] 37. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 26 - 29 and 36, wherein R 7 is hydrogen or methyl.

[0993] 38. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 26 - 29 and 36, wherein R 5 is -CH2-O-(CH2CH2O) m -R 7 .

[0994] 39. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 26 - 29 and 36 - 38, wherein m is 1, 2 or 3.

[0995] 40. A compound or a pharmaceutically acceptable salt thereof as described in embodiment 39, wherein m is 2.

[0996] 41. A compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 38 - 40, wherein R 7 is methyl.

[0997] 42. A compound as described in any one of embodiments 2 and 26 - 31, the compound being

[0998]

[0999] or a pharmaceutically acceptable salt or solvate thereof.

[1000] 43. The compound according to embodiment 42, wherein the compound is

[1001]

[1002] or a pharmaceutically acceptable salt or solvate thereof.

[1003] 44. The compound according to embodiment 26, wherein the compound is

[1004]

[1005] or a pharmaceutically acceptable salt or solvate thereof.

[1006] 45. The compound according to embodiment 6, wherein the compound has the formula VI:

[1007]

[1008] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1009] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of hydroxyl, halogen, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxyl, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[1010] R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of the groups optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of hydroxyl, halogen, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxyl, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[1011] R 3 is -OC(=O)R 6 wherein R 6Selected from the group consisting of: unsubstituted C 1-4 alkyl, unsubstituted C 2-4 alkenyl, unsubstituted C 2-4 alkynyl or -CH2-O-(CH2CH2O) m -R 7 ;

[1012] m is 1;

[1013] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl; and

[1014] PEG is an ethylene oxide unit or an oligomer having 2 to about 10 ethylene oxide subunits,

[1015] provided that the compound is not

[1016]

[1017] 46. The compound according to embodiment 45 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is methyl or ethyl.

[1018] 47. The compound according to embodiment 45 or embodiment 46 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl, and R 4 is unsubstituted C 1-6 alkyl.

[1019] 48. The compound according to any one of embodiments 45 - 47 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R 4 are methyl.

[1020] 49. The compound according to embodiment 2, the compound having formula II:

[1021]

[1022] its pharmaceutically acceptable salt or solvate, wherein:

[1023] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of hydroxyl, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxyl, C 1-4 alkoxy and C1-4 an alkoxycarbonyl; or -PEG-R 7 ;

[1024] R 4 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[1025] R 2 is -C(=O)R 5 and R 3 is -OC(=O)R 6 wherein

[1026] R 5 and R 6 are the same or different and are selected from the group consisting of: straight-chain unsubstituted C 7-9 alkyl, straight-chain unsubstituted C 7-9 alkenyl, straight-chain unsubstituted C 7-9 alkynyl, -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p -R 7 ;

[1027] R 7 is selected from the group consisting of: hydrogen and C 1-6 alkyl;

[1028] m is 2 or 3;

[1029] n and p are each independently 2, 3 or 4; and

[1030] PEG is an ethylene oxide unit or an oligomer having from 2 to about 10 ethylene oxide subunits.

[1031] 50. The compound according to embodiment 49 or a pharmaceutically acceptable salt or solvate thereof, wherein R5 and R 6 each independently selected from the group consisting of heptyl, octyl, nonyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 and -NH-(CH2CH2O) p -R 7 ; wherein R 7 is hydrogen or C 1-4 alkyl.

[1032] 51. The compound according to embodiment 49 or 50, wherein R 5 and R 6 are the same and have the formula V:

[1033]

[1034] or a pharmaceutically acceptable salt or solvate thereof.

[1035] 52. The compound according to embodiment 51 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -CH2-O-(CH2CH2O) m -R 7 wherein R 7 is hydrogen or methyl.

[1036] 53. The compound according to embodiment 49 or 50 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 are different.

[1037] 54. The compound according to any one of embodiments 49 - 53 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl, and R 4 is unsubstituted C 1-6 alkyl.

[1038] 55. The compound according to any one of embodiments 49 - 54 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R 4 are methyl.

[1039] 56. The compound according to embodiment 49 or 51, the compound being

[1040]

[1041] or a pharmaceutically acceptable salt or solvate thereof.

[1042] 57. A compound as described in Embodiment 2, the compound having Formula II:

[1043]

[1044] Its pharmaceutically acceptable salt or solvate, wherein:

[1045] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[1046] R 4 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of the groups optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[1047] R 2 is -C(=O)R 5 , and R 3 is -OC(=O)R 6 , wherein

[1048] R 5 and R 6 are the same or different and are selected from the group consisting of: straight-chain unsubstituted C 10-12 alkyl, straight-chain unsubstituted C 10-12 alkenyl, straight-chain unsubstituted C 10-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7and -NH-(CH2CH2O) p -R 7 ;

[1049] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[1050] m is an integer between 4 and 9;

[1051] n and p are each independently an integer between 4 and 20; and

[1052] PEG is an ethylene oxide unit or an oligomer having 2 to about 10 ethylene oxide subunits.

[1053] 58. The compound according to embodiment 57 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 are each independently selected from the group consisting of decyl, undecyl, and dodecyl.

[1054] 59. The compound according to embodiment 57 or 58, wherein R 5 and R 6 are the same and have the formula V:

[1055]

[1056] or a pharmaceutically acceptable salt or solvate thereof.

[1057] 60. The compound according to embodiment 59 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is undecyl.

[1058] 61. The compound according to embodiment 57 or 58 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 are different.

[1059] 62. The compound according to any one of embodiments 57 - 61 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl, and R 4 is unsubstituted C 1-6 alkyl.

[1060] 63. The compound according to any one of embodiments 57 - 62 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R 4 are methyl.

[1061] 64. The compound according to embodiment 57 or 59, the compound is

[1062]

[1063] or a pharmaceutically acceptable salt or solvate thereof.

[1064] 65. The compound according to embodiment 6, said compound having formula VI:

[1065]

[1066] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1067] R 1 is H; C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, said substituents being independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

[1068] R 4 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents, said substituents being independently selected from the group consisting of: hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl;

[1069] R 3 is -OC(=O)R 6 wherein R 6 is selected from the group consisting of: straight-chain unsubstituted C 10-12 alkyl, straight-chain unsubstituted C 10-12 alkenyl, straight-chain unsubstituted C 10-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R7 and -NH-(CH2CH2O) p -R 7 ;

[1070] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[1071] m is an integer between 4 and 9;

[1072] n and p are each independently an integer between 4 and 20; and

[1073] PEG is an ethylene oxide unit or an oligomer having 2 to about 10 ethylene oxide subunits.

[1074] 66. The compound according to embodiment 65 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is decyl, undecyl or dodecyl.

[1075] 67. The compound according to embodiment 65 or embodiment 66 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl, and R 4 is unsubstituted C 1-6 alkyl.

[1076] 68. The compound according to any one of embodiments 65 - 67 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is undecyl.

[1077] 69. The compound according to any one of embodiments 65 - 68 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R 4 are methyl.

[1078] 70. The compound according to embodiment 65, the compound being

[1079]

[1080] or a pharmaceutically acceptable salt or solvate thereof.

[1081] 71. The compound according to embodiment 1, the compound being

[1082] or a pharmaceutically acceptable salt or solvate thereof.

[1083] 72. A pharmaceutical composition, the pharmaceutical composition comprising a compound of formula I:

[1084]

[1085] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1086] R 1 is H; alkyl optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl; -PEG-R 7 ; or a hydroxyl protecting group PG selected from the group consisting of: alkyl, arylalkyl, heterocyclic, (heterocyclic)alkyl, acyl, silyl and carbonate, any of said groups being optionally substituted;

[1087] Z is C-OR 2 or C(=O);

[1088] is a single bond or a double bond, provided that when Z is C(=O), is a single bond, and when Z is C-OR 2 then, is a double bond;

[1089] R 2 is -C(=O)R 5 or -PEG-R 7 , wherein

[1090] R 5 is selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 、-NH-(CH2CH2O) p -R 7 、phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle and (5- or 6-membered heterocycle)alkyl, wherein said phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl; and wherein said 6-membered heterocyclic group is attached to the carbonyl carbon of R 2 through a carbon atom or through a nitrogen atom;

[1091] R 3 is hydrogen, OH, -Y-PEG-R7 or -OC(=O)R 6 , wherein

[1092] Y is a covalent bond or a linking group;

[1093] R 6 is selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 , -O-(CH2CH2O) n -R 7 , -NH(CH2CH2O) p -R 7 , phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; and wherein the 6-membered heterocyclic group is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom;

[1094] provided that when Z is C(=O), R 3 is -OC(=O)R 6 ;

[1095] PEG is an ethylene oxide unit or an oligomer having two or more ethylene oxide subunits;

[1096] R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic group, any of which is optionally substituted;

[1097] R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, any of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl;

[1098] m is an integer between 1 and 9;

[1099] n and p are each independently an integer between 1 and 20; and

[1100] The prerequisite is R 2 and R 3 at least one of which is -C(=O)R 5 and -OC(=O)R 6 ; the prerequisites are as follows:

[1101] 1) The said compound is not

[1102]

[1103] 2) When R 1 is an unsubstituted alkyl group, R 3 is hydrogen and R 4 is an unsubstituted alkyl group, then R 5 is not an optionally substituted phenyl group or an optionally substituted pyridyl group,

[1104] 3) When R 1 is an unsubstituted alkyl group, R 4 is an unsubstituted alkyl group and R 3 is -OC(=O)R 6 , then R 5 and R 6 are both not an optionally substituted pyridyl group,

[1105] 4) The said compound is not

[1106]

[1107] and one or more pharmaceutically acceptable carriers.

[1108] 73. The pharmaceutical composition according to embodiment 72, wherein the pharmaceutical composition further comprises at least one parent opioid.

[1109] 74. The pharmaceutical composition according to embodiment 73, about 0.1 wt% to about 30 wt% of the at least one parent opioid.

[1110] 75. The pharmaceutical composition according to any one of embodiments 72 - 74, wherein the composition is formulated for an oral dosage form.

[1111] 76. The pharmaceutical composition according to embodiment 72, the pharmaceutical composition comprises the compound according to any one of embodiments 1 - 71 or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers.

[1112] 77. A composition, the composition comprises one or more compounds according to any one of embodiments 1 - 71 or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

[1113] 78. The composition according to embodiment 77, the composition comprising from about 0.1 wt% to about 30 wt% of said at least one parent opioid.

[1114] 79. The composition according to embodiment 77 or 78, the composition comprising from about 1 wt% to about 20 wt% of said at least one parent opioid.

[1115] 80. The composition according to any one of embodiments 77 - 79, wherein said at least one parent opioid is oxycodone.

[1116] 81. An oral formulation, the oral formulation comprising a therapeutically effective amount of the composition according to any one of embodiments 77 - 80.

[1117] 82. A composition, the composition comprising one or more compounds according to any one of embodiments 26 - 56 or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

[1118] 83. The composition according to embodiment 82, the composition comprising from about 0.1 wt% to about 30 wt% of said at least one parent opioid.

[1119] 84. The composition according to embodiment 82 or 83, the composition comprising from about 1 wt% to about 20 wt% of said at least one parent opioid.

[1120] 85. The composition according to any one of embodiments 82 - 84, wherein said at least one parent opioid is oxycodone.

[1121] 86. An oral formulation, the oral formulation comprising a therapeutically effective amount of the composition according to any one of embodiments 82 - 85.

[1122] 87. A method of treating or preventing a condition in a patient responsive to modulation of one or more opioid receptors, the method comprising administering to the patient in need of such treatment or prevention an effective amount of a compound of formula I:

[1123]

[1124] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1125] R 1 is H; alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl; -PEG-R 7; or a hydroxyl protecting group PG selected from the group consisting of: alkyl, arylalkyl, heterocyclic group, (heterocyclic group)alkyl, acyl, silyl and carbonate group, any of said groups being optionally substituted;

[1126] Z is C-OR 2 or C(=O);

[1127] is a single bond or a double bond, provided that when Z is C(=O), is a single bond, and when Z is C-OR 2 then is a double bond;

[1128] R 2 is -C(=O)R 5 or -PEG-R 7 wherein

[1129] R 5 is selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 、-NH-(CH2CH2O) p -R 7 、phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle and (5-membered or 6-membered heterocycle)alkyl, wherein said phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of: alkyl, hydroxyl, halogen, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl; and wherein said 6-membered heterocyclic group is attached to the carbonyl carbon of R 2 through a carbon atom or through a nitrogen atom;

[1130] R 3 is hydrogen, OH, -Y-PEG-R 7 or -OC(=O)R 6 wherein

[1131] Y is a covalent bond or a linking group;

[1132] R 6 is selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12Alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 、-NH(CH2CH2O) p -R 7 、phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6 - membered heterocycle and (5 - or 6 - membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted by 1, 2 or 3 substituents, and the substituents are each independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl; and wherein the 6 - membered heterocyclic group is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom;

[1133] Provided that when Z is C(=O), R 3 is -OC(=O)R 6 ;

[1134] PEG is an ethylene oxide unit or an oligomer having two or more ethylene oxide subunits;

[1135] R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocyclic group, any of which is optionally substituted;

[1136] R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and (cycloalkyl)alkyl, any of which is optionally substituted by 1, 2 or 3 substituents, and the substituents are each independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy and alkoxycarbonyl;

[1137] m is an integer between 1 and 9;

[1138] n and p are each independently an integer between 1 and 20; and

[1139] Provided that at least one of R 2 and R 3 is respectively -C(=O)R 5 and -OC(=O)R 6 ; Provided as follows:

[1140] 1) The compound is not

[1141]

[1142] 2) When R 1 is an unsubstituted alkyl group, R 3 is hydrogen and R 4 is an unsubstituted alkyl group, then R 5 is not an optionally substituted phenyl group or an optionally substituted pyridyl group,

[1143] 3) When R 1 is an unsubstituted alkyl group, R 4 is an unsubstituted alkyl group and R 3 is -OC(=O)R 6 then R 5 and R 6 are both not an optionally substituted pyridyl group,

[1144] 4) The compound is not

[1145]

[1146] 88. The method according to embodiment 87, the method comprising administering to the patient in need of such treatment or prophylaxis an effective amount of a compound as described in any one of embodiments 1 - 71 or a pharmaceutically acceptable salt or solvate thereof.

[1147] 89. The method according to embodiment 87 or 88, wherein the disorder is pain.

[1148] 90. The method according to embodiment 87 or 88, wherein the disorder is constipation, diarrhea, alcohol withdrawal or drug withdrawal.

[1149] 91. A method for treating, ameliorating or preventing pain, constipation, diarrhea, alcohol withdrawal or drug withdrawal in a patient, the method comprising administering to the patient in need of such treatment or prophylaxis an effective amount of a compound as described in any one of embodiments 1 - 71 or a pharmaceutically acceptable salt or solvate thereof.

[1150] 92. The method according to embodiment 91, wherein the method is for treating pain.

[1151] 93. The method according to embodiment 92, wherein the pain is acute pain, chronic pain or surgical pain.

[1152] 94. The method according to embodiment 93, wherein the pain is chronic pain.

[1153] 95. The method according to embodiment 94, wherein the chronic pain is neuropathic pain, postoperative pain or inflammatory pain.

[1154] 96. A pharmaceutical composition, the pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 1-71, the compound or the pharmaceutically acceptable salt or solvate thereof being for the treatment of a condition responsive to modulation of one or more opioid receptors.

[1155] 97. A compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 1-71, the compound or the pharmaceutically acceptable salt or solvate thereof being for the treatment of a condition responsive to modulation of one or more opioid receptors.

[1156] 98. A method of preparing a pharmaceutical composition, the method comprising mixing a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 1-71 with a pharmaceutically acceptable carrier.

[1157] 99. A kit, the kit comprising a container containing an effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of embodiments 1-71, and instructions regarding therapeutic use.

[1158] 100. A method of slowing the onset of opioid activity in a mammal in need of opioid therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or a mixture of compounds according to any one of embodiments 1-71, or a pharmaceutically acceptable salt or solvate thereof.

[1159] 101. The method according to embodiment 100, the method comprising orally administering a compound or a mixture of compounds having formula V:

[1160]

[1161] or a pharmaceutically acceptable salt or solvate thereof, wherein

[1162] R 1 is H or unsubstituted C 1-6 alkyl;

[1163] R 4 is unsubstituted C 1-6 alkyl; and

[1164] R 5 is decyl, undecyl or dodecyl.

[1165] 102. The method according to embodiment 101, wherein R 1 is H or methyl, and R 4 is methyl.

[1166] 103. The method according to embodiment 101 or embodiment 102, wherein R 5 is undecyl.

[1167] 104. The method according to any one of embodiments 101-103, the method further comprising co-administering one or more other therapeutic agents.

[1168] 105. The method according to embodiment 104, wherein the one or more other therapeutic agents are one or more non-steroidal anti-inflammatory agents.

[1169] 106. The method according to embodiment 104, wherein the one or more other therapeutic agents are one or more opioid agonists.

[1170] 107. The method according to embodiment 104, wherein the one or more other therapeutic agents are one or more opioid antagonists.

[1171] 108. The method according to any one of embodiments 101-103, wherein the compound or mixture of compounds is administered in a single dosage form further comprising an effective amount of the parent opioid.

[1172] 109. A method of treating, ameliorating or preventing constipation, diarrhea, alcohol withdrawal or drug withdrawal in a patient, the method comprising administering to the patient in need of such treatment or prevention an effective amount of a compound according to any one of embodiments 65-70 or a pharmaceutically acceptable salt or solvate thereof.

[1173] 110. A compound according to any one of embodiments 65-70 or a pharmaceutically acceptable salt or solvate thereof, said compound or pharmaceutically acceptable salt or solvate thereof for treating, ameliorating or preventing constipation, diarrhea, alcohol withdrawal or drug withdrawal.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is H; an alkyl group optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl; -PEG-R 7 ; or a hydroxy protecting group PG selected from the group consisting of: alkyl, arylalkyl, heterocyclic group, (heterocyclic group)alkyl, acyl, silyl and carbonate group, any of said groups being optionally substituted; Z is C-OR 2 or C(=O); is a single bond or a double bond, provided that when Z is C(=O), is a single bond, and when Z is C-OR 2 then is a double bond; R 2 is -C(=O)R 5 or -PEG-R 7 , wherein R 5 selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 、-NH-(CH2CH2O) p -R 7 、phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; and wherein the 6-membered heterocyclic group is attached to the carbonyl carbon of R 2 through a carbon atom or through a nitrogen atom; R 3 is hydrogen, OH, -Y-PEG-R 7 or -OC(=O)R 6 , where Y is a covalent bond or a linking group; R 6 selected from the group consisting of: unsubstituted C 1-12 alkyl, unsubstituted C 2-12 alkenyl, unsubstituted C 2-12 alkynyl, -CH2-O-(CH2CH2O) m -R 7 、-O-(CH2CH2O) n -R 7 、-NH(CH2CH2O) p -R 7 、phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, 6-membered heterocycle, and (5- or 6-membered heterocycle)alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl, and heterocyclic moieties are optionally substituted with 1, 2, or 3 substituents, each of which is independently selected from the group consisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; and wherein the 6-membered heterocyclic group is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom; The prerequisite is that when Z is C(=O), R 3 is -OC(=O)R 6 ; PEG is an ethylene oxide unit or an oligomer having two or more ethylene oxide subunits; R 7 selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, any of said groups being optionally substituted; R 4 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and (cycloalkyl)alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents, each of said substituents being independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl; m is an integer between 1 and 9; n and p are each independently an integer between 1 and 20; and The prerequisite is R 2 and R 3 at least one of which is -C(=O)R 5 and -OC(=O)R 6 ; The prerequisites are as follows: 1) the compound is not 2) When R 1 is an unsubstituted alkyl group, R 3 is hydrogen and R 4 is an unsubstituted alkyl group, then R 5 is not an optionally substituted phenyl group or an optionally substituted pyridyl group, 3) When R 1 is an unsubstituted alkyl group, R 4 is an unsubstituted alkyl group and R 3 is -OC(=O)R 6 then neither R 5 nor R 6 is an optionally substituted pyridyl group, or 4) the compound is not 2. The compound according to claim 1, wherein the compound has formula II: or a pharmaceutically acceptable salt or solvate thereof.

3. The compound according to claim 1 or 2, wherein the compound has formula III: or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 、R 2 、R 3 and R 4 are as defined in claim 1.

4. The compound according to claim 1 or 2, wherein the compound has formula IV: or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 、R4 and R 5 as defined in claim 1, and R 31 is hydrogen or OH.

5. A compound according to claim 1 or 2, said compound having formula V: or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 4 and R 5 are as defined in claim 1.

6. A compound according to claim 1, said compound having formula VI: or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 4 are as defined in claim 1, and R 3 is -OC(=O)R 6 , wherein R 6 is as defined in claim 1.

7. A compound according to any one of claims 1-6 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or an alkyl group optionally substituted with 1, 2 or 3 substituents, said substituents being independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy and alkoxycarbonyl.

8. A compound according to claim 7 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or unsubstituted C 1-6 alkyl.

9. A compound according to any one of claims 1-6 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -PEG-R 7 , wherein R 7 is as defined in claim 1, and PEG is -(CH2CH2O) q -, where q varies from 1 to 50.

10. A compound according to any one of claims 1-6 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is PG, and said PG is selected from the group consisting of methyl, tert-butyl, optionally substituted benzyl, optionally substituted benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and triisopropylsilyl.

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