Cleavable conjugates of a catechol compound and a water-soluble polymer and therapeutic methods using the same

Abstract

To provide a polymer conjugate of a compound having a catechol moiety to provide for sustained pharmacokinetics, improvement of bioavailability, ease of administration and / or reduced side effects when administered to a subject.SOLUTION: Disclosed herein is a conjugate comprising a water-soluble polymer linked to a catechol moiety-containing compound via a cleavable linkage. The cleavable linkage is formed between the water-soluble polymer and a first phenolic hydroxyl group of the catechol moiety, where a second phenolic hydroxyl group is linked to a blocking group, where the hydrolytic release rate of the catechol moiety-containing compound, at least partially, is modulated through the structure or design of the blocking group of the second phenolic hydroxyl group of the catechol moiety. Accordingly, the rate of hydrolytic release of the catechol moiety-containing compound can be tuned through structural design of the group on the second phenolic hydroxyl group of the catechol moiety.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure generally relates to a conjugate comprising a water-soluble polymer and a compound, the compound being linked to the water-soluble polymer via a cleavable bond.The present disclosure more specifically relates to a conjugate comprising a water-soluble polymer and a compound comprising a catechol moiety, the compound being linked to the water-soluble polymer via a cleavable bond involving one of the two phenolic hydroxyl groups of the catechol moiety of the compound, and the release of the compound from the conjugate is controlled at least in part by the structure of the other of the two phenolic hydroxyl groups of the catechol moiety of the compound.The present disclosure also relates to intermediates useful for the synthesis of such conjugates, compounds having a catechol moiety comprising at least one blocking group, and methods of treating diseases and conditions, including but not limited to dopamine-responsive disorders, using such conjugates and compounds. [Background technology]

[0002] Compounds containing a catechol moiety have been reported to have many beneficial properties and are useful in the treatment of human diseases. A particular group of compounds containing a catechol moiety are dopamine receptor agonists. A representative compound is apomorphine. Apomorphine and other dopamine agonists are useful in the treatment of dopamine-responsive disorders, including but not limited to Parkinson's disease.

[0003] A common early treatment for Parkinson's disease is levodopa. However, treatment with levodopa often results in motor complications and "on-off" periods due to the short-acting nature of levodopa (and other orally administered drugs for the treatment of Parkinson's disease). Subcutaneous apomorphine has proven highly effective in rapidly reversing these "off" periods, but apomorphine delivered in this manner is only effective for a limited time because apomorphine has a very short in vivo half-life.

[0004] Oral administration of apomorphine is ineffective due to only a 1.7% oral bioavailability, mainly due to first-pass metabolism in the liver. Buccal delivery formulations of apomorphine have also been developed, but these require heavy use and may cause stomatitis and dental caries. Lipid-based prodrugs have also been shown to extend the in vivo half-life of the drug, but have not significantly improved the hydrolysis profile (e.g., due to hepatic metabolism).

[0005] The delivery time of apomorphine can be extended by using a microneedle pump patch (available in Europe under the brand name Apo-Go).The use of a microneedle pump patch requires daily relocation of the patch and the involvement of medical personnel.This approach is obviously inconvenient and prone to discomfort due to the use of the microneedle patch.In addition, this approach can cause burning sensations on the skin of the user, skin nodules and skin infections.

[0006] There is clearly a need for improved delivery of compounds comprising a catechol moiety (such as apomorphine) for the treatment of diseases and conditions, including but not limited to dopamine-responsive disorders. The present disclosure provides a solution to the problem in the art by providing compounds comprising a catechol moiety that include at least one blocking group at the phenolic hydroxyl group of the catechol moiety, polymer conjugates of compounds comprising a catechol moiety that upon administration to a subject result in sustained pharmacokinetics, improved bioavailability, ease of administration, and / or reduced side effects. [Brief description of the drawings]

[0007] [Figure 1]Figure 1 shows the percent hydrolysis of the POZ-apomorphine conjugates of Example 6 (Apo-A, inverted triangles), Example 7 (Apo-B, diamonds), Example 8 (Apo-C, open squares), Example 9 (Apo-F, filled circles), Example 12 (Apo-D, filled squares), Example 13 (Apo-E, triangles), and Example 15 (Apo-G, open circles). Calculated t values ​​are also shown for each POZ-apomorphine conjugate. [Diagram 2] 1 shows the PK profiles of free apomorphine in female monkeys following subcutaneous injection of apomorphine HCl and POZ-apomorphine A and POZ-apomorphine B. [Diagram 3] 1 shows the PK profiles of total apomorphine in female monkeys following subcutaneous injection of apomorphine HCl and POZ-apomorphine A and POZ-apomorphine B. [Figure 4A] Shown is a depiction of the skin response 5 days after a single subcutaneous dose (by slow infusion) of free apomorphine (Group 1, Animal 1502). [Figure 4B] Shown is a depiction of the skin response 5 days after administration of a single subcutaneous dose (by injection) of POZ-apomorphine A (group 2, animal 2502). [Figure 4C] Shown is a depiction of the skin response 5 days after administration of a single subcutaneous dose (by injection) of POZ-apomorphine B (Group 3, Animal 3502). [Figure 5A] Shown is a depiction of the skin reaction 12 hours after administration of the third dose of POZ-apomorphine A (Group 1) via subcutaneous administration (by injection) on day 14. [Figure 5B] Shown is a depiction of the skin reaction 12 hours after administration of the third dose of POZ-apomorphine B (Group 2) via subcutaneous administration (by injection) on day 14. [Figure 5C] Shown is a depiction of the skin reaction 12 hours after administration of the third dose of POZ-apomorphine G (Group 3) via subcutaneous administration (by injection) on day 14. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] definition As used herein, the terms "active" or "activated" when used in conjunction with a particular functional group refers to a reactive functional group that readily reacts with an electrophile or nucleophile on another molecule, as opposed to a group that requires a catalyst or difficult reaction conditions in order to react (i.e., a "non-reactive" or "inactive" group).

[0009] As used herein, the terms "bond," "link," "linked," or "linkage," when used in reference to a polymer or compound described herein, or a component thereof, refer to a bond, usually a covalent bond, that is typically formed as a result of a chemical reaction.

[0010] As used herein, the terms "cleavable bond," "cleavable linker," "hydrolyzable linker," "hydrolyzable functional group," "releasable linker," or "releasable functional group" refer to a chemical bond that includes a cleavable moiety. The terms hydrolyzable and releasable do not imply any particular mechanism by which the linker is cleaved.

[0011] As used herein, the term "cleavable moiety" refers to a group (such as a cleavable bond) that is cleavable in vivo in a subject under physiological conditions of the subject after the conjugate of the present disclosure is administered to the subject. In one embodiment, the cleavable moiety is cleaved by a chemical reaction. In one aspect of this embodiment, the cleavage is by hydrolysis or reduction of an ester group, such as, but not limited to, reduction of a disulfide. In one embodiment, the cleavable moiety is cleaved by a substance that is naturally present or induced to be present in the subject. In one aspect of this embodiment, such a substance is an enzyme or a polypeptide. Thus, in one embodiment, the cleavable moiety is cleaved by an enzymatic reaction. In one embodiment, the cleavable moiety is cleaved by the combination of the above.

[0012] As used herein, the terms "inert" or "non-reactive" when used in conjunction with a particular functional group refers to a functional group that does not readily react with an electrophile or nucleophile on another molecule, and requires a catalyst or difficult reaction conditions in order to react.

[0013] As used herein, the term "first phenolic hydroxyl group" or "first hydroxyl group" refers to a hydroxyl group of a catechol moiety that is attached to a water-soluble polymer, such as a polyoxazoline polymer, either directly or through a linking group. It is understood that the term "first phenolic hydroxyl group" or "first hydroxyl group" does not refer to a particular hydroxyl group of the catechol moiety, nor does it refer to a particular position of the hydroxyl group of the compound.

[0014] As used herein, the term "second phenolic hydroxyl group" or "second hydroxyl group" refers to the hydroxyl group on the catechol moiety adjacent (i.e., ortho) to the first phenolic hydroxyl group. It is understood that the term "second phenolic hydroxyl group" or "second hydroxyl group" does not refer to a particular hydroxyl group on the catechol moiety, nor does it refer to a particular position of the hydroxyl group on the compound.

[0015] As used herein, the term "alkyl," whether used alone or as part of a substituent, is a term of art and refers to saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C5 for straight chain). 30 , C3-C for branched chains 30 ), alternatively about 20 or less, or 10 or less. In certain embodiments, the term "alkyl" refers to any of C1-C 10 In certain embodiments, the term "alkyl" refers to a C1-C6 straight chain alkyl group. In certain embodiments, the term "alkyl" refers to a C3-C6 straight chain alkyl group. 12It refers to a branched alkyl group. In certain embodiments, the term "alkyl" refers to a C3-C8 branched alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0016] As used herein, the term "heteroalkyl" refers to a straight- or branched-chain alkyl group, preferably having 2 to 14 carbons in the chain, one or more of which are substituted with a heteroatom selected from S, O, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like, where the heteroatoms may be optionally substituted.

[0017] As used herein, the term "alkenyl" is a term of art, whether used alone or as part of a substituent, and refers to an unsaturated aliphatic group containing a straight or branched chain hydrocarbon radical containing 2 to 30 carbons and containing at least one carbon-carbon double bond resulting from the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond(s) of the alkenyl group can be located anywhere in the moiety and can have either a (Z) or (E) configuration about the double bond(s). The alkenyl group can be optionally substituted.

[0018] As used herein, the term "alkynyl" is a term of art, whether used alone or as part of a substituent, and refers to an unsaturated aliphatic group containing a straight or branched chain hydrocarbon radical containing 2 to 30 carbon atoms and at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. Alkynyl groups can be optionally substituted.

[0019] The phrases "substituted alkyl," "substituted heteroalkyl," "substituted alkenyl," and "substituted alkynyl" refer to any group in which one or more of the bonds to the carbon(s) or hydrogen(s) has been replaced with a non-hydrogen or non-carbon atom, such as, but not limited to, halogen atoms of halides, e.g., F, Cl, Br, and I, oxygen atoms of groups such as carbonyl, carboxyl, hydroxyl, alkoxy, aryloxy, heterocyclyloxy, and ester groups, sulfur atoms of groups such as thiol groups, alkyl and aryl sulfides, sulfone, sulfonyl, and sulfoxide groups, amines, amides, alkylamines, dialkylamines, alkyl ... The term "substituted alkyl" or "substituted heteroalkyl" refers to a C1-C2 alkyl group, a C1-C2 alkyl group, a C2-C3 alkyl group, a C1-C4 alkyl group, a C1-C5 alkyl group, a C1-C6 alkyl group, a C1-C7 alkyl group, a C1-C8 alkyl group, a C1-C9 alkyl group, a C1-C10 alkyl group, a C1-C12 alkyl group, a C1-C14 alkyl group, a C1-C26 alkyl group, a C1-C36 alkyl group, a C1-C4 alkyl group, a C1-C16 alkyl group, a C1-C26 alkyl group, a C1-C36 alkyl group, a C1-C12 ... 14 It refers to a straight or branched chain alkyl or heteroalkyl group.

[0020] The terms "halo" or "halogen," whether used alone or as part of a substituent, are terms of art and refer to -F, -Cl, -Br, or -I.

[0021] The term "alkoxy" whether used alone or as part of a substituent group, is a term of art and refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0022] The term "aralkyl" or "arylalkyl", whether used alone or as part of a substituent, is a term of art and refers to an alkyl group substituted with an aryl group, which is attached to the parent molecule via the alkyl group. The arylalkyl group can be optionally substituted. "Substituted aralkyl" has the same meaning for unsubstituted aralkyl groups as substituted aryl groups have for unsubstituted aryl groups. However, substituted aralkyl groups also include groups in which a carbon or hydrogen bond in the alkyl portion of the group is replaced with a bond to a non-carbon or non-hydrogen atom.

[0023] The term "heteroaralkyl" or "heteroarylalkyl", whether used alone or as part of a substituent, is a term of art and refers to an alkyl group substituted with a heteroaryl group, which is attached to the parent molecular moiety via the alkyl group. The heteroarylalkyl can be optionally substituted. The term "substituted heteroarylalkyl" has the same meaning with unsubstituted heteroarylalkyl groups that substituted aryl groups have with unsubstituted aryl groups.

[0024] The term "heterocyclylalkyl", whether used alone or as part of a substituent, is a term of art and refers to an unsubstituted or substituted alkyl, alkenyl or alkynyl group in which a hydrogen or carbon bond of the unsubstituted or substituted alkyl, alkenyl or alkynyl group is replaced with a bond to a heterocyclyl group. Heterocyclylalkyl can be optionally substituted. "Substituted heterocyclylalkyl" has the same meaning for unsubstituted heterocyclylalkyl groups that substituted aryl groups have for unsubstituted aryl groups. However, substituted heterocyclylalkyl groups also include groups in which a non-hydrogen atom is bonded to a heteroatom of the heterocyclyl group of the heterocyclylalkyl group, such as, but not limited to, the nitrogen atom of the piperidine ring of a piperidinylalkyl group.

[0025] The term "aryl", whether used alone or as part of a substituent, is a term of art and refers to monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene and pyrene. The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (these rings are "fused rings"), where at least one of the rings is aromatic hydrocarbon, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In certain embodiments, the term "aryl" refers to a phenyl group. The aryl group can be optionally substituted. "Substituted aryl" includes aryl groups in which one of the aromatic carbons is bonded to a non-carbon or non-hydrogen atom, such as, but not limited to, those atoms mentioned above for substituted alkyl, as well as aryl groups in which one or more aromatic carbons of the aryl group are bonded to a substituted and / or unsubstituted alkyl, alkenyl, or alkynyl group as defined herein. This includes bonding arrangements in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyl group to define a fused ring system (e.g., dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase "substituted aryl" includes, but is not limited to, tolyl, and hydroxyphenyl, among others.

[0026] The term "cycloalkyl," whether used alone or as part of a substituent, is a term of art that refers to a saturated carbocyclic group containing from 3 to 6 ring carbon atoms, which ring may be optionally substituted with a substituted or unsubstituted alkyl group or the substituents described for substituted alkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclobutyl, and 4-ethylcyclohexyl.

[0027] The term "heteroaryl," whether used alone or as part of a substituent group, is a term of art that refers to monocyclic, bicyclic, and polycyclic aromatic groups having a total of 3 to 30 atoms, including one or more heteroatoms, e.g., nitrogen, oxygen, or sulfur, in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, and the like. The "heteroaryl" may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings"), where at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl.

[0028] The term "heterocyclyl," whether used alone or as part of a substituent, is a term of art and refers to radicals of non-aromatic ring systems, including, but not limited to, monocyclic, bicyclic, and tricyclic rings having 3 to 15 atoms, including at least one heteroatom, e.g., nitrogen, oxygen, or sulfur, which may be fully saturated or may contain one or more units of unsaturation (for the avoidance of doubt, this degree of unsaturation does not result in an aromatic ring system). For illustrative purposes, which should not be construed as limiting the scope of the invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, dioxalanyl, oxazolyl. , thiazolyl, triazinyl, isothiazolyl, isoxazolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.Heterocyclyl groups can be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like.

[0029] The terms "treatment," "treat," and "treating" refer to a course of action (e.g., administering a conjugate described herein or a pharmaceutical composition comprising a conjugate described herein) to prevent, eliminate, or reduce a symptom, feature, or characteristic of a disease or condition. Such treatment need not be absolutely efficacious. In one embodiment, treatment includes a course of action that is initiated simultaneously with or after the onset of a symptom, feature, or characteristic of a disease or condition. In another embodiment, treatment includes a course of action that is initiated prior to the onset of a symptom, feature, or characteristic of a disease or condition.

[0030] The term "in need of treatment" refers to a judgment by a caregiver that a patient requires or would benefit from treatment, which is within the caregiver's area of ​​expertise, but is made based on a variety of factors, including knowledge that the patient is ill or will become ill as a result of a disease or condition treatable by the methods or compounds of the present disclosure.

[0031] The terms "individual," "subject," or "patient" refer to any animal, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans. The terms may specify or exclude males or females, or both. In preferred embodiments, the terms "individual," "subject," or "patient" refer to humans.

[0032] The term "therapeutically effective amount" refers to an amount of a conjugate or compound, alone or as part of a pharmaceutical composition, capable of having any detectable positive effect on any symptom, characteristic, or property of a disease or condition. Such effect need not be absolutely beneficial.

[0033] Certain compounds contained in the conjugates and / or compositions of the present disclosure may exist in specific geometric or stereoisomeric forms. In addition, compounds contained in the conjugates and / or compositions of the present disclosure may also be optically active. The present disclosure contemplates all such compounds within the scope of the present invention, including cis and trans isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are intended to be included in the present invention.

[0034] For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, in which case the resulting diastereomeric mixture is separated and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, a diastereomeric salt may be formed with a suitable optically active acid or base, and the resulting diastereomers subsequently separated by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomer.

[0035] It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the permitted valences of the substituted atom and substituent, as well as that the substitution results in a stable compound that is not spontaneously subject to transformation, such as, for example, by rearrangement, cleavage, decomposition, cyclization, elimination, or other reaction.

[0036] It will be understood that when a group is specified as part of a compound, the substitution of the group can be adjusted to correspond to the particular bond. For example, if an alkyl group is bonded to two other groups, the alkyl group is considered to be an alkylene group.

[0037] The term "substituted" is also intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, for example, those described herein above. For purposes of this disclosure, the heteroatoms, e.g., oxygen or nitrogen, may have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatoms. Exemplary substituents include, but are not limited to, hydroxy, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0038] Other chemical terms herein are used in accordance with conventional usage in the art, such as The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco (incorporated by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0039] As used herein, the term "pharmaceutical acceptable salt" includes salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms may include forms in which the ratio of the molecules comprising the salt is not 1:1. For example, the salt may include more than one inorganic or organic acid molecule per base molecule, for example, two molecules of hydrochloric acid per molecule of conjugate. As another example, the salt may include less than one inorganic or organic acid molecule per base molecule, for example, two molecules of conjugate per molecule of inorganic or organic acid.

[0040] As used herein, the terms "carrier" and "pharmaceutical acceptable carrier" refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or is formulated for administration. Non-limiting examples of such pharmaceutical acceptable carriers include liquids such as water, saline, and oils, and solids such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by EW Martin, which is incorporated herein in its entirety by reference.

[0041] Introduction Previous patents by the applicant have addressed problems related to the administration of dopamine agonists (such as rotigotine and ropinirole) to a subject by providing conjugates comprising polyoxazoline polymers linked to the dopamine agonist via a linking group comprising a cleavable moiety (e.g., an ester group), where the structure of the linking group provides a controlled release of the dopamine agonist from the polyoxazoline polymer in vivo. In animal studies and human clinical trials, the pharmacokinetics of rotigotine hydrolysis demonstrated a steady-state delivery suitable for weekly subcutaneous injections.

[0042] Further investigation showed that when this approach was carried out with the dopamine agonist apomorphine, which was linked to the polymer via a linking group containing an ester moiety as a cleavable moiety on one of the two phenolic hydroxyl groups of the catechol moiety, apomorphine was released into human plasma at a rate much faster than expected or desired. Moreover, the structure of the linking group was not shown to provide the desired control over the release rate seen for the rotigotine polymer conjugates.

[0043] Apomorphine is a compound that contains a catechol moiety. The structure of apomorphine is shown below, with the two adjacent phenolic hydroxyl groups characteristic of a catechol moiety being present at positions 10 and 11 of apomorphine. Thus, apomorphine (and compounds containing a catechol moiety in general) have a first and a second phenolic hydroxyl group. [ka]

[0044] Without being bound to any particular theory, it is believed that neighboring group participation by a free adjacent phenolic hydroxyl group (a hydroxyl group that is not attached to the polymer via a linking group) causes rapid cleavage of a cleavable moiety in the linking group (in this case an ester group) and explains, at least in part, the fact that the structure of the linking group did not provide the desired control over the release rate of apomorphine from the polyoxazoline polymer.

[0045] The present disclosure provides a novel approach for the administration of compounds comprising a catechol moiety, including dopamine agonists. Specifically, the present disclosure provides a conjugate comprising a water-soluble polymer and a compound comprising a catechol moiety, the compound being attached to the polymer via a bond (e.g., a direct bond or a linking group between the polymer and the first hydroxyl group) comprising a first cleavable moiety to a first phenolic hydroxyl group of the catechol moiety, and the cleavage of the first cleavable moiety of the bond is controlled, at least in part, through the structure of a blocking group of a second phenolic hydroxyl group of the catechol moiety. In certain embodiments, the bond is a linking group. In certain embodiments, the first phenolic hydroxyl group is generated when the first cleavable moiety is cleaved. In certain embodiments, the blocking group comprises a second cleavable moiety, and the second phenolic hydroxyl group is generated when the second cleavable moiety is cleaved. The blocking group is not directly attached to the water-soluble polymer.

[0046] In one embodiment, a free hydroxyl group is generated at the second phenolic hydroxyl group of the catechol moiety upon cleavage of the second cleavable moiety. In one embodiment, a free hydroxyl group is generated at the first phenolic hydroxyl group of the catechol moiety upon cleavage of the first cleavable moiety. In one embodiment, a free hydroxyl group is generated at both the first and second phenolic hydroxyl groups of the catechol moiety upon cleavage of the first and second cleavable moieties. In one embodiment, at least one of the first and second cleavable moieties is positioned and / or constructed such that a free hydroxyl group is generated at the first and / or second phenolic hydroxyl group of the catechol moiety upon cleavage of the first and / or second cleavable moieties. In one embodiment, each of the first and second cleavable moieties is positioned and / or constructed such that, upon cleavage of the first and second cleavable moieties, free hydroxyl groups are generated at the first and second phenolic hydroxyl groups of the catechol moiety.

[0047] Without being bound to any particular theory, it is believed that the blocking group blocks or inhibits the participation of an adjacent group by the second phenolic hydroxyl group, slowing the cleavage of the first cleavable moiety at the bond. The structure of the blocking group can be altered to control the cleavage of the first cleavable moiety and the rate of release of the compound from the polymer.

[0048] The described conjugates provide sustained pharmacokinetics, improved bioavailability and / or ease of administration of compounds that include a catechol moiety. In certain embodiments, the described conjugates reduce side effects when administered to a subject (compared to unconjugated compounds administered in suitable formulations). In one aspect of this embodiment, the side effects are skin reactions at the site of administration.

[0049] Water-soluble polymer conjugates The present disclosure provides a polymer conjugate consisting of, consisting essentially of, or comprising a water-soluble polymer and a compound comprising a catechol moiety. In one embodiment, the bond is a direct bond, and the compound is bonded to the polymer backbone by a direct bond via a reactive group of the compound (preferably the first phenolic hydroxyl group) and a reactive group of the polymer. In one embodiment, the direct bond comprises at least a first cleavable moiety, and the compound is released from the polymer after administration of the polymer conjugate to a subject, such as, but not limited to, in vivo under physiological conditions in the body of a human. The direct bond can form the first cleavable moiety in the reaction that bonds the polymer to the compound. Such cleavable moieties are discussed herein.

[0050] In another embodiment, the bond is via a linking group, and the compound is bonded to the polymer via a linking group to the reactive group of the compound (preferably the first phenolic hydroxyl group).In one embodiment, the linking group comprises at least a first cleavable moiety, and the compound is released from the polymer after administration of the polymer conjugate to a subject, for example, but not limited to, in vivo, under physiological conditions in the human body. Such cleavable moieties are discussed herein.In one embodiment, the linking group comprises, in addition to the first cleavable moiety, a group capable of forming a bond with the reactive group of the polymer and a group capable of forming a bond with the reactive group of the compound.

[0051] As discussed herein, cleavage of the first cleavable portion of the bond is controlled, at least in part, through the structure of a blocking group on the second phenolic hydroxyl group of the catechol moiety.

[0052] For convenience and clarity, this specification describes a direct bond or linking group that reacts with the first phenolic hydroxyl group and a blocking group that reacts with the second phenolic hydroxyl group. Those skilled in the art will understand that the situation can be reversed.

[0053] In a general embodiment, the polymer conjugates of the present disclosure can be represented by the general formula I, or a pharma- ceutically acceptable salt thereof: POL n -(LA) b I During the ceremony, POL is a water-soluble polymer, n is 1 to 1000 and represents the number of monomer units constituting the water-soluble polymer; n is always greater than or equal to b, where b is between 1 and 50; A is a compound comprising a catechol moiety, the catechol moiety comprising at least a first and a second phenolic hydroxyl group, wherein the compound is attached to the polymer via the first phenolic hydroxyl group and the second phenolic hydroxyl group is optionally attached to a blocking group; L is a bond containing a first cleavable moiety that connects the compound (A) and the polymer (POL).

[0054] In certain embodiments, L is a linking group that comprises a first cleavable moiety. In certain embodiments, L is a direct bond, which comprises the first cleavable moiety (in certain aspects, the direct bond forms the first cleavable moiety in the reaction that attaches the polymer to the compound).

[0055] Exemplary compounds suitable for A are described herein. In one embodiment, A is a compound of formula III. In one embodiment, A is a compound of formula IV. In one embodiment, A is a compound of formula IV, and R 19 is CH3.

[0056] In one embodiment, the first phenolic hydroxyl group is modified by forming a bond with the polymer moiety. In one embodiment, the oxygen atom of the first phenolic hydroxyl group participates in the formation of a bond with the polymer moiety. The formation of the bond can include the formation of a chemical bond between the first phenolic hydroxyl group (e.g., an oxygen atom) and an atom or group of the polymer or the linking group. In one embodiment, the second phenolic hydroxyl group is modified via reaction with the blocking group. In one embodiment, the oxygen atom of the second phenolic hydroxyl group participates in the formation of a bond with the blocking group. The formation of the chemical bond can be between the first phenolic hydroxyl group (e.g., an oxygen atom) and an atom or group of the blocking group. In each of the foregoing embodiments, the modification of the first and / or second phenolic hydroxyl group can result in the formation of an ester bond, the ester bond including an oxygen atom of the first and / or second phenolic hydroxyl group. In each of the foregoing embodiments, the modification of the first and / or second phenolic hydroxyl groups may form an ester bond, the ester bond comprising the oxygen atom of the first and / or second phenolic hydroxyl groups, and the ester bond forming the first and / or second cleavable moiety. Thus, in certain embodiments, the first and second cleavable moieties are the same. Thus, in certain embodiments, the first cleavable moiety is an ester bond, the second cleavable moiety is an ester bond, or both the first cleavable moiety and the second cleavable moiety are ester bonds.

[0057] The polymer portion of the polymer conjugate of the present disclosure may take a variety of forms. In certain embodiments, the polymer is poly(oxazoline) (POZ), poly(5,6-dihydro-4h-1,3-oxazine), dextran, oxidatively modified dextran, polyethylene glycol (PEG), poly(hydroxypropyl methacrylate), polyglutamic acid, polylactic acid-polyglutamic acid mixtures, polysialic acid, polycaprolactone, polyvinylpyrrolidone, glycosaminoglycan, polyglycerol, poly(acryloyloxyethyl phosphorylcholine), or methacrylate-based synthetic phosphorylcholine copolymers, including combinations of the above.

[0058] In one embodiment, the polymer is a POZ polymer. In yet another embodiment, the polymer is a PEG polymer. In yet another embodiment, the polymer is a dextran polymer. In yet another embodiment, the polymer is an oxidatively modified dextran polymer.

[0059] In one embodiment where the water-soluble polymer is a copolymer, the copolymer can be prepared by reacting one or more monomer units of a first water-soluble polymer with one or more monomer units of at least a second polymer, which may optionally be a water-soluble polymer. Such copolymers include both block and random copolymers. In certain aspects, the copolymer comprises a POZ polymer and at least a second polymer. In certain aspects, the copolymer comprises a POZ polymer and at least a second polymer, and the POZ polymer portion comprises more than 25%, 50%, 75%, 85%, 95%, 98%, 99%, or 99.5% of the polymer (weight-to-weight basis for all polymer components). In certain embodiments, the copolymer comprises a POZ polymer and at least a second polymer, the POZ polymer comprising more than 25%, 50%, 75%, 85%, 95%, 98%, 99%, or 99.5% of the polymer (weight-to-weight basis for all polymeric components), and at least one of the additional polymers is a water-soluble polymer. In any of the foregoing, the additional water-soluble polymer(s) can be any water-soluble polymer described above. In any of the foregoing, the additional water-soluble polymer(s) can be PEG, dextran, and / or oxidatively modified dextran. In certain embodiments, the copolymer comprises a POZ polymer and at least a second polymer, the POZ polymer comprising more than 25%, 50%, 75%, 85%, 95%, 98%, 99%, or 99.5% of the polymer (weight-to-weight basis), and the additional polymer(s) is not a water-soluble polymer.

[0060] L may form a bond with any reactive group of the polymer and the reactive group of the compound, suitably the first phenolic hydroxyl group of the catechol moiety of the compound. In one embodiment, L is a bond between the compound and the terminus of the polymer. In one embodiment, L is a bond between the compound and a side group of the polymer (referred to herein as a "pendant" position or "pendant"). Additionally, L may include a component(s) of a group originally present on the polymer and / or the compound.

[0061] Suitable parameters for L are described herein. In certain embodiments, L is a linking group that includes a first cleavable moiety.

[0062] In certain embodiments, the polymer conjugates of the present disclosure may be represented by the general formula II, or a pharma- ceutically acceptable salt thereof. R-POZ n -(LA) b II During the ceremony, R is an initiating group, POZ is a polyoxazoline polymer; n is 1 to 1000 and represents the number of monomer units constituting the polyoxazoline polymer; n is always greater than or equal to b, where b is between 1 and 50; A is a compound comprising a catechol moiety, the catechol moiety comprising at least a first and a second phenolic hydroxyl group, wherein the compound is attached to the polymer via the first phenolic hydroxyl group and the second phenolic hydroxyl group is optionally attached to a blocking group; L is a bond containing a first cleavable moiety that connects the compound (A) and the polymer (POL).

[0063] In certain embodiments, the POZ conjugate of the present disclosure is represented by the general formula IIA, or a pharma- ceutically acceptable salt thereof, and the bond between the compound and the polymer is formed at the "pendant" position. [ka] During the ceremony, R is an initiating group, POZ is a polyoxazoline polymer; n is 1 to 1000 and represents the number of monomer units constituting the polyoxazoline polymer; n is always greater than or equal to b, where b is between 1 and 50; A is a compound comprising a catechol moiety, the catechol moiety comprising at least a first and a second phenolic hydroxyl group, wherein the compound is attached to the polymer via the first phenolic hydroxyl group and the second phenolic hydroxyl group is optionally attached to a blocking group; L is a bond containing a first cleavable moiety that connects the compound (A) to the polymer (POL); T is a terminal group.

[0064] In another specific embodiment, the POZ conjugate of the present disclosure may be represented by the general formula IIB, or a pharma- ceutically acceptable salt thereof, wherein the bond between the compound and the polymer is formed at the "pendant" position. [ka] During the ceremony, R is an initiating group, A is a compound comprising a catechol moiety, the catechol moiety comprising at least a first and a second phenolic hydroxyl group, wherein the compound is attached to the polymer via the first phenolic hydroxyl group and the second phenolic hydroxyl group is optionally attached to a blocking group; L is a bond containing a first cleavable moiety that connects the compound (A) to the polymer (POL); R1 is a non-reactive pendant moiety, independently selected for each repeat unit; X is independently selected for each repeat unit from -LA; Y is independently selected for each repeat unit from -LA, a non-reactive pendant moiety, or a pendant moiety that includes an active functional group; a is ran indicating a random copolymer or block indicating a block copolymer; o1 is an integer from 1 to 50, The sum of o1 and o2 must be less than or equal to 50, and o2 must be between 0 and 49. n is an integer from 1 to 1000, T is a terminal group.

[0065] Unless otherwise specified, the following descriptions apply to each of the conjugates of formulas II, IIA, and IIB.

[0066] In certain embodiments, L is a linking group that comprises a first cleavable moiety. In certain embodiments, L is a direct bond, which comprises the first cleavable moiety (in certain aspects, the direct bond forms the first cleavable moiety in the reaction that attaches the polymer to the compound).

[0067] Exemplary compounds suitable for A are described herein. In one embodiment, A is a compound of formula III. In one embodiment, A is a compound of formula IV. In one embodiment, A is a compound of formula IV, and R 19 is CH3.

[0068] In one embodiment, the first phenolic hydroxyl group is modified by forming a bond with L. In one embodiment, the first phenolic hydroxyl group is modified by formation of a bond between L and the oxygen atom of the first phenolic hydroxyl group. In one embodiment, the second phenolic hydroxyl group is modified by forming a bond with the blocking group. In one embodiment, the second phenolic hydroxyl group is modified through formation of a bond between the oxygen atom of the second phenolic hydroxyl group and the blocking group. In each of the foregoing embodiments, modification of the first and / or second phenolic hydroxyl group may form an ester bond, the ester bond comprising an oxygen atom of the first and / or second phenolic hydroxyl group. In each of the foregoing embodiments, modification of the first and / or second phenolic hydroxyl group may form an ester bond, the ester bond comprising an oxygen atom of the first and / or second phenolic hydroxyl group, the ester bond forming the first and / or second cleavable moiety. Thus, in certain embodiments, the first cleavable moiety is an ester bond, the second cleavable moiety is an ester bond, or both the first cleavable moiety and the second cleavable moiety are each an ester bond.

[0069] Exemplary R groups include, but are not limited to, hydrogen, alkyl, and substituted alkyl. In one embodiment, R is an alkyl group, such as a C1-C4 alkyl group. In the particular embodiment above, the initiator group is a methyl group. In another embodiment, the initiator group is H. In yet another embodiment, the initiator group is selected to lack a functional group. Further exemplary initiator groups are disclosed in U.S. Patent Nos. 7,943,141, 8,088,884, 8,110,651, and 8,101,706, each of which is incorporated herein by reference for such disclosure.

[0070] L may form a bond with any reactive group of the polymer and the reactive group of the compound, suitably the first phenolic hydroxyl group of the catechol moiety of the compound. In one embodiment, L is a bond between the compound and the terminus of the polymer. In one embodiment, L is a bond between the compound and a side group of the polymer (referred to herein as a "pendant" position or "pendant"). Additionally, L may include a component(s) of a group originally present on the polymer and / or the compound.

[0071] Suitable parameters for L are described herein. In certain embodiments, L is a linking group that includes a first cleavable moiety.

[0072] In certain embodiments, the polymer conjugates of the present disclosure may be represented by the general formula IIB, or a pharma- ceutically acceptable salt thereof.

[0073] In one embodiment of the conjugates of formula IIA and IIB, T is a thioalkyl carboxylic acid, a thiocarboxylic ester, or a hydroxyl group. In one embodiment of the conjugates of formula IIA and IIB, T is ZBQ, Z is S, O, or N, B is an optional linking group, and Q is a terminal nucleophile or part of a terminal nucleophile. In certain embodiments of the conjugates of formula IIA and IIB, Q is non-reactive (i.e., does not contain a functional group). In other embodiments, Q contains a functional group.

[0074] Exemplary B groups include, but are not limited to, alkylene groups. In certain embodiments, B is -(CH) 1-16 In certain embodiments, B is -(CH2). 1-10 -, -(CH2) 1-8 -, -(CH2) 1-6 -, -(CH2) 1-4 -, or -(CH2)2-. In certain embodiments of the conjugates of formula IIA and IIB, Z is S. The polyoxazoline conjugates containing sulfur groups described herein can be prepared by terminating the cations at the ends of the polyoxazoline polymers with mercaptide reagents, such as, but not limited to, mercaptoesters (e.g., -S-CH2CH2-CO2CH3 or -S-CH2CH2-CO2H), amines (e.g., -S-CH2CH2-NH2) or mercapto-protected amines (e.g., -S-CH2CH2-NH-tBoc). Such POZ conjugates provide for effective large-scale purification by ion exchange chromatography (to remove secondary amines), as well as allowing for control of polydispersity (polydispersity of 1.10 or less) and the creation of high molecular weight POZ polymer conjugates. In another embodiment of the conjugates of formula IIA and IIB, Z is N. In further embodiments of the conjugates of formulae IIA and IIB, Z is O.

[0075] As mentioned above, Q may be non-reactive or may contain a functional group. When Q contains a functional group, exemplary functional groups include, but are not limited to, alkyne, alkene, amine, oxyamine, aldehyde, ketone, acetal, thiol, ketal, maleimide, ester, carboxylic acid, activated carboxylic acid (such as, but not limited to, N-hydroxysuccinimidyl (NHS) and 1-benzotriazine activated ester), activated carbonate, chloroformate, alcohol, azide, vinyl sulfone, or orthopyridyl disulfide (OPSS). When Q contains a functional group, the functional group may be chemically orthogonal to one or more or all other functional groups present in the conjugate. When Q is a non-reactive group, any non-reactive group may be used, including, but not limited to, unsubstituted alkyl and -C6H5.

[0076] In one embodiment of the conjugates of formulas IIA-IIB, L is a linking group and comprises a first cleavable moiety, Z is S, and B is -(CH) y In another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is O, and B is -(CH2). y In yet another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is N, and B is -(CH2). y - and Q is -COOH. In any of the above embodiments, the first cleavable moiety can be an ester group. In any of the foregoing, y is 2.

[0077] In one embodiment of the conjugates of formulas IIA-IIB, L is a linking group and comprises a first cleavable moiety, Z is S, and B is -(CH) y In another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is O, and B is -(CH). y- and Q is -COOCH3. In yet another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is N, and B is -(CH2). y - and Q is -COOCH3. In any of the above embodiments, the first cleavable moiety can be an ester group. In any of the foregoing, y is 2.

[0078] In one embodiment of the conjugates of formulas IIA-IIB, L is a linking group and comprises a first cleavable moiety, Z is S, and B is -(CH) y In another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is O, and B is -(CH). y In yet another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is N, and B is -(CH). y - and Q is -NH2. In any of the above embodiments, the first cleavable moiety can be an ester group. In any of the foregoing, y is 2.

[0079] In one embodiment of the conjugates of formulas IIA-IIB, L is a linking group and comprises a first cleavable moiety, Z is S, and B is -(CH) y - and Q is NH-tBoc. In another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is O, and B is -(CH2) y - and Q is NH-tBoc. In yet another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is N, and B is -(CH2). y - and Q is -NH-tBoc. In any of the above embodiments, the first cleavable moiety can be an ester group. In any of the foregoing, y is 2.

[0080] In one embodiment of the conjugate of formula IIA-IIB, R1 is independently selected for each repeat unit from unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl. In one embodiment, R1 is unsubstituted or substituted alkyl, e.g., C1-C4 unsubstituted or substituted alkyl. In certain embodiments, R1 is methyl, ethyl, propyl, or butyl. Exemplary R1 groups are described in U.S. Patent Nos. 7,943,141, 8,088,884, 8,110,651, and 8,101,706, each of which is incorporated herein by reference for such disclosure.

[0081] In one embodiment of the conjugate of formula IIB, Y is -LA. When Y is -LA, the -LA group of Y can be the same as the -LA group of X. When Y is -LA, the -LA group of Y can be different from the -LA group of X.

[0082] In one embodiment of the conjugate of formula IIB, Y is a pendant moiety. When Y is a pendant moiety, Y can be a non-reactive pendant moiety or a pendant moiety that contains an active functional group. In one embodiment when Y is a pendant moiety, Y is selected independently for each repeat unit from unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl. In one embodiment, Y is an alkyl or substituted alkyl. In certain embodiments, Y is methyl, ethyl, propyl, or butyl. In certain embodiments, Y is a pendant moiety that contains an active functional group. Suitable reactive functional groups include, but are not limited to, alkynes, amines, oxyamines, aldehydes, ketones, acetals, ketals, maleimides, esters, carboxylic acids, activated carboxylic acids (such as, but not limited to, N-hydroxysuccinimidyl (NHS) and 1-benzotriazinyl activated esters), activated carbonates, chloroformates, alcohols, azides, vinyl sulfones, and orthopyridyl disulfides (OPSS). In certain embodiments, the active functional group of Y is chemically orthogonal to one or more or all of the other functional groups of the conjugate. In certain embodiments, the active functional group of Y is not chemically orthogonal to one or more or all of the other functional groups of the conjugate. In one embodiment, Y is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl group.

[0083] In one embodiment of the conjugate of formula II-IIB, L is a linking group and includes a first cleavable moiety. In one embodiment, the first cleavable moiety is an ester group. In one embodiment, the ester group incorporates the O atom of the first phenolic hydroxyl group.

[0084] In one embodiment of the conjugate of formula IIB, o1 is 1-20 or less and o2 is 0. In one embodiment, o1 is 1-20 or less and o2 is 1-30. In one embodiment, o1 is 1-20 or less and o2 is 1-30, and at least a portion of Y is a pendant moiety comprising a functional group. In one embodiment, o1 is 1-10 or less and o2 is 1-30, and at least a portion of Y is -LA, and the -LA of X and Y are the same as each other. In one embodiment, o1 is 1-10 or less and o2 is 1-30, and at least a portion of Y is -LA, and the -LA of X and Y are different from each other.

[0085] In certain embodiments of the conjugates of Formulae IIA-IIB, T is ZBQ.

[0086] In one embodiment of the conjugates of formula IIA-IIB, L is a linking group and comprises a first cleavable moiety, Z is S, B is -CH2CH2-, and Q is -COOH. In another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is O, B is -CH2CH2-, and Q is -COOH. In yet another particular embodiment, L is a linking group and comprises a first cleavable moiety, Z is N, B is -CH2CH2-, and Q is -COOH. In any of the above embodiments, the first cleavable moiety can be an ester group.

[0087] In the above embodiment where the polymer is a polyoxazoline polymer, various polyoxazoline polymers can be used in the conjugates of the present disclosure. The polyoxazoline polymer may contain a single type or class of functional group, or may contain multiple types or classes of functional groups. The polyoxazoline polymer may be a linear polyoxazoline polymer, a branched polyoxazoline polymer, or a multi-arm polyoxazoline polymer, any of the foregoing may contain pendant groups. Various representative polyoxazoline polymers are described herein. The POZ polymer may be prepared by living cationic polymerization or other methods known in the art. Representative POZ polymers are described in U.S. Patent Nos. 7,943,141, 8,088,884, 8,110,651, and 8,101,706, each of which is incorporated herein by reference for such disclosure. In one embodiment, the POZ polymer is prepared by living cationic polymerization.

[0088] In the foregoing embodiments where the polymer is a polyoxazoline polymer, n is from 1 to 500. In one embodiment, n is from 1 to 250. In one embodiment, n is from 1 to 100. In one embodiment, n is from 1 to 50. In one embodiment, n is from greater than 25 to less than 250. In one embodiment, n is from greater than 25 to less than 150.

[0089] In the foregoing embodiments where the polymer is a polyoxazoline polymer, the portion of the polyoxazoline polymer (excluding A and L) has a molecular weight between 2 kDa and 100 kDa. In one embodiment, the portion of the polyoxazoline polymer (excluding A and L) has a molecular weight between 10 kDa and 30 kDa. In one embodiment, the portion of the polyoxazoline polymer (excluding A and L) has a molecular weight between 15 kDa and 25 kDa. In one embodiment, the portion of the polyoxazoline polymer (excluding A and L) has a molecular weight of 20 kDa. When molecular weights are provided herein for polymers, particularly polyoxazoline polymers, unless otherwise specified, the molecular weight is the number average molecular weight.

[0090] In the foregoing embodiments of the conjugates of Formula I, II and IIA, b is 1 to 40. In one embodiment, b is 1 to 30. In one embodiment, b is 1 to 20. In one embodiment, b is 1 to 15. In one embodiment, b is 1 to 10. In one embodiment, b is 5 or more and 15 or less. In one embodiment, b is 10.

[0091] In any of the foregoing embodiments of the conjugates of formula I and II-IIB, L may form a bond with any reactive group of the polymer and any reactive group of the compound (preferably the first phenolic hydroxyl group). In any of the foregoing embodiments, L is a bond between the compound and a terminus of the polymer. In any of the foregoing embodiments, L is a bond between the compound and a side group of the polymer (referred to herein as a "pendant" position or "pendant"). In any of the foregoing embodiments, L may include a component of a group originally present on the polymer and / or the compound. Suitable parameters for L are described herein. In any of the foregoing embodiments, L is a linking group that includes a first cleavable moiety.

[0092] In any of the above-mentioned embodiments of the conjugates of formula I and II-IIB, regardless of the form of the bond (whether direct or through a linking group), the bond is a cleavable bond that allows the release of the compound from the polymer via cleavage of the first cleavable moiety after administration of the conjugate to a subject. Cleavage of the first cleavable moiety (release rate) of the compound from the conjugate (which is controlled, at least in part, by the structure of the blocking group of the second phenolic hydroxyl group) provides for controllable delivery of the compound. In any of the above-mentioned embodiments, cleavage of the first cleavable moiety generates a free phenolic hydroxyl group at the first phenolic hydroxyl group.

[0093] In any of the foregoing embodiments of the conjugates of formula I and II-IIB, the cleavage (release rate) of the first cleavable moiety of the compound from the polymer is controlled, at least in part, by the structure of the blocking group of the second phenolic hydroxyl group. In any of the foregoing embodiments, the cleavage (release rate) of the first cleavable moiety of the compound from the polymer is controlled, at least in part, by the structure of the linking group and the structure of the blocking group of the second phenolic hydroxyl group. In any of the foregoing embodiments, the blocking group comprises a second cleavable moiety, which may be the same as or different from the first cleavable moiety. In any of the foregoing embodiments, the first and second cleavable moieties are the same. In any of the foregoing embodiments, the first and second cleavable moieties are different. In any of the foregoing embodiments, at least one of the first and second cleavable moieties is an ester bond. In any of the foregoing embodiments, both the first and second cleavable moieties are ester bonds.

[0094] In any of the foregoing embodiments of the conjugates of Formula I and II-IIB, the conjugate delivers a therapeutically effective amount of the compound to the subject for 12 hours to 24 hours, 24 hours to 48 hours, 24 hours to 72 hours, 24 hours to 96 hours, 24 hours to 120 hours, 24 hours to 144 hours, or 24 hours to 168 hours. In any of the foregoing embodiments, the delivery is controllable delivery or sustained controllable delivery. In any of the foregoing embodiments, the compound is delivered with a pharmacokinetic / release profile lacking peaks and troughs.

[0095] In any of the foregoing embodiments of the conjugates of Formula I and II-IIB, the conjugate delivers a therapeutically effective amount of the compound to the subject for a period of 1 week or more. In any of the foregoing embodiments, the conjugate delivers a therapeutically effective amount of the compound to the subject for a period of 1-2 weeks, 1-3 weeks, or 1-4 weeks. In any of the foregoing embodiments, the delivery is a controllable delivery or a sustained controllable delivery. In any of the foregoing embodiments, the compound is delivered with a pharmacokinetic / release profile lacking peaks and troughs.

[0096] Specific linking groups in the above embodiments for the conjugates of formula I and II-IIB are described below: For clarity, any linking group described herein may be used in the above general formula.

[0097] L In the above embodiments, L is a linking group that forms or includes a first cleavable moiety, or a direct bond that forms or includes a first cleavable moiety. In embodiments in which L forms a first cleavable moiety, the first cleavable moiety is formed by interaction of L with a group of the polymer or compound. In certain preferred embodiments, the first cleavable moiety is formed by reaction between L and the oxygen atom of the first phenolic hydroxyl group. Thus, L is a cleavable bond between the compound and the polymer. In other words, the first cleavable moiety can be cleaved in vivo in a subject after administration of the polymer conjugate of the present disclosure to the subject. In one embodiment, the cleavable moiety is cleaved by a chemical reaction. In one aspect of this embodiment, the cleavage is by hydrolysis or reduction of an ester group, such as, but not limited to, reduction of a disulfide. In one embodiment, the cleavable moiety is cleaved by a substance that is naturally present or induced to be present in the subject. In one aspect of this embodiment, such a substance is an enzyme or a polypeptide. Thus, in one embodiment, the cleavable moiety is cleaved by an enzymatic reaction. In one embodiment, the cleavable moiety is cleaved by the combination described above. L may comprise a portion of the polymer and / or a portion of the compound, which has reacted to form a linking group or a direct bond to the polymer and / or compound, as discussed herein.

[0098] Exemplary first cleavable moieties include, but are not limited to, an ester bond, a carboxylic ester bond (-C(O)-O-), a carbonate ester bond (-OC(O)-O-), a carbamate bond (-OC(O)-NH-), an amide bond (-C(O)-NH-), and a disulfide bond (SS). Other cleavable moieties are discussed herein. In certain embodiments, the first cleavable moiety is an ester bond. In another particular embodiment, the cleavable moiety is a carboxylic ester bond. In the following description, the polymer is referred to as a polyoxazoline polymer for illustrative purposes. However, the following reactions are applicable to other polymer types as well.

[0099] In one embodiment, the linking group is a disubstituted triazole and includes a first cleavable moiety in one of the R3 or R4 groups. In one embodiment, the first cleavable moiety is in the R4 group. In a particular embodiment, the disubstituted triazole has the following structure: [ka] . In another embodiment, the disubstituted triazole has the structure: [ka] . In each of the above structures: R3 is a linker that connects the triazole moiety to the polymer chain. R3 may be partially defined by the functional group of the polymer chain. In other words, R3 may include a portion of the functional group of the polymer chain. In one embodiment, R3 is -C(O)-R5-, where R5 is absent or an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or an unsubstituted or substituted heterocyclylalkyl group. In one embodiment, R5 is absent or a substituted or unsubstituted alkyl of 1-10 carbons in length. In one embodiment, R5 is absent or an unsubstituted straight chain alkyl of 1-10 carbons in length.

[0100] R4 is a linker that connects the triazole moiety to the compound, and the bond between R4 and the compound occurs between the first phenolic hydroxyl group of the catechol moiety of the compound. R4 may be defined in part by the functional group of the compound. In other words, R4 may include part of the group / functional group of the compound, for example, the O atom of the first phenolic hydroxyl group. In one embodiment, R4 is -R6-R7-R8-, where R6 is a substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, or oligo(ethylene oxide) (e.g., -(CH2CHO) e -, e is 1-10 or 1-4), R7 is a group that includes the first cleavable moiety or a group that includes a portion of the first cleavable moiety, and R8 is absent or O. In certain embodiments, R7 and R8 may combine to form the first cleavable moiety. In certain embodiments, R7 forms the first cleavable moiety. In one embodiment, R7 is -R a -C(O)-R b -, -R a -OC(O)-R b -, -R a -C(O)-OR b , -R a -C(O)-NH-cyclic-OC(O)-R b -(cyclic represents substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl), -R a -C(O)-NH-(CH)-OC(O)-R b -, -R a -OC(O)-NR 10 -R b -, -R a -CH(OH)-OR b -, -R a -SSR b -, -R a -OP(O)(OR 10 )-OR b -, or -R a -C(O)-NR 10 -R b - and R 10is H or substituted or unsubstituted C1-C5 alkyl, R a and R b are each independently absent or substituted or unsubstituted alkyl. a and R b are each independently absent or a C1-C16 substituted or unsubstituted alkyl.

[0101] In one embodiment of the foregoing, R6 is a linear substituted or unsubstituted C1-C10 alkyl or a branched substituted or unsubstituted C1-C10 alkyl, and R7 is -R a -C(O)-R b In one embodiment of the foregoing, R6 is a linear substituted or unsubstituted C1-C10 alkyl or a branched substituted or unsubstituted C1-C10 alkyl, and R7 is -R a -C(O)-OR b - and R8 does not exist.

[0102] In one embodiment of the foregoing, R6 is a linear substituted or unsubstituted C1-C4 alkyl or a branched substituted or unsubstituted C1-C4 alkyl, and R7 is -R a -C(O)-R b In one embodiment of the foregoing, R6 is linear substituted or unsubstituted C1-C4 alkyl or branched substituted or unsubstituted C1-C4 alkyl, and R7 is -R a -C(O)-OR b - and R8 does not exist.

[0103] In certain embodiments, R3 is -C(O)-(CH2)3 and R4 is -(CH2) d -C(O)-O-, -CH2-C(O)-O-, -CH2-CH2-C(O)-O-, -CH2-CH2-CH2-C(O)-O-, or -CH2(CH3)-C(O)-O-, where d is an integer of 1 to 10.

[0104] In certain embodiments, R3 is -C(O)-(CH2)3 and R4 is -(CH2)d -C(O)-, -CH2-C(O)-, -CH2-CH2-C(O)-, -CH2-CH2-CH2-C(O)-, or -CH2(CH3)-C(O)-, where d is an integer of 1 to 10.

[0105] In each of the above, the first cleavable portion may be cleaved in vivo under physiological conditions of the subject chemically, or may be cleaved in the subject by a substance that is naturally present or induced to be present in the subject under physiological conditions in vivo, or may be cleaved by a combination of the above. In one embodiment, such a substance is an enzyme or polypeptide, and the cleavage is enzymatic cleavage.

[0106] Compounds containing a catechol moiety In the above embodiments relating to general formulas I, II, IIA, and IIB, the specific compound (A) is as set forth below: For clarity, any compound (A) described herein may be used in the above general formula.

[0107] The compound containing the catechol moiety can be any compound known in the art that is useful for the diagnosis or treatment of a disease or condition.Compounds containing the catechol moiety have been reported to have a wide range of activities, including but not limited to adrenergic, antiviral, anti-inflammatory, emetic, cardiac, antiasthmatic, enzyme inhibitor, antibiotic, antineoplastic, anticholinergic, antispasmodic, bronchodilator, antihypertensive, dopamine receptor agonist, antioxidant, spermicide, and insecticide activity.The compound containing the catechol moiety can be a diagnostic or therapeutic agent.

[0108] In one embodiment, the compound containing a catechol moiety is represented by Formula III, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R 11 , R 12 , R 13 and R14 are independently selected from H, OH, halogen, alkoxy, NO, unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl, substituted alkyl, heteroalkyl, alkenyl, or alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, heteroarylalkyl, substituted heteroarylalkyl, or adjacent to each other, R 11 , R 12 , R 13 and R 14 any two of may be taken together with the carbons to which they are attached to form an optionally substituted aryl, heteroaryl, or heterocyclyl ring; R 15 or R 16 One of them is L, R 15 or R 16 The other is a blocking group.

[0109] In certain embodiments, a "substituted alkyl" or "substituted heteroalkyl" refers to a C-C alkyl group substituted with up to five groups selected from the group consisting of -OH, -NH, -NH-NH, =O(OH), substituted aryl, and =O. 14 It refers to a straight or branched chain alkyl or heteroalkyl group.

[0110] As discussed herein, in one embodiment, the first phenolic hydroxyl group (R 15 or R 16 (represented by R ) is modified by forming a bond with L. In one embodiment, the oxygen atom of the first phenolic hydroxyl group participates in the formation of a bond with L. The formation of the bond can include the formation of a chemical bond between the first phenolic hydroxyl group (e.g., an oxygen atom) and an atom or group of the polymer or the linking group. In one embodiment, the second phenolic hydroxyl group (represented by R 15 or R 16(represented by the other of) is modified by forming a bond with the blocking group. In one embodiment, the oxygen atom of the second phenolic hydroxyl group participates in the formation of a bond with the blocking group. The formation of the chemical bond can be between the first phenolic hydroxyl group (e.g., an oxygen atom) and an atom or group of the blocking group. In each of the foregoing embodiments, the modification of the first and / or second phenolic hydroxyl group can form an ester bond, the ester bond comprising an oxygen atom of the first and / or second phenolic hydroxyl group. In each of the foregoing embodiments, the modification of the first and / or second phenolic hydroxyl group can form an ester bond, the ester bond comprising an oxygen atom of the first and / or second phenolic hydroxyl group, the ester bond forming the first and / or second cleavable moiety. Thus, in certain embodiments, the first and the second cleavable moieties are the same. Thus, in certain embodiments, the first cleavable moiety is an ester bond, the second cleavable moiety is an ester bond, or both the first cleavable moiety and the second cleavable moiety are each an ester bond.

[0111] In one embodiment, the blocking group comprises a second cleavable moiety or forms a second cleavable moiety upon bond formation (i.e., modification) with the second phenolic hydroxyl group. In one embodiment, the blocking group forms the second cleavable moiety upon bond formation with the second phenolic hydroxyl group. In one embodiment, the cleavable moiety is cleaved by a chemical reaction. In one aspect of this embodiment, the cleavage is by hydrolysis or reduction of an ester group, such as, but not limited to, reduction of a disulfide. In one embodiment, the cleavable moiety is cleaved by a substance that is naturally present or induced to be present in the subject. In one aspect of this embodiment, such a substance is an enzyme or a polypeptide. Thus, in one embodiment, the cleavable moiety is cleaved by an enzymatic reaction. In one embodiment, the cleavable moiety is cleaved by a combination of the above.

[0112] Exemplary second cleavable moieties include, but are not limited to, an ester bond, a carboxylate bond (-C(O)-O-), a carbonate bond (-OC(O)-O-), a carbamate bond (-OC(O)-NH-), an amide bond (-C(O)-NH-), and a disulfide bond (SS). Other cleavable moieties are discussed herein. In certain embodiments, the first cleavable moiety is an ester bond. In another particular embodiment, the cleavable moiety is a carboxylate bond.

[0113] In one embodiment, the blocking group is -R 17 -R 18 and R 17 is -C(O)-, -C(O)-O-, -C(O)-NH-cyclic-OC(O)- (cyclic represents substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl or cycloalkyl), -C(O)-NH-(CH)-OC(O)-, CH(CH) 1-4 -OC(O)-(CH2) 1-4 -C(O)- or -OP(O)(OR)(O)- (R is H or substituted or unsubstituted C-C alkyl), R 18 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

[0114] In one embodiment, R 17 forms a bond with the oxygen atom of the second phenolic hydroxyl group, and R 17 and the O to which it is attached form the second cleavable moiety. In one embodiment, the second cleavable moiety is -C(O)-O.

[0115] In one embodiment, R 18 is substituted or unsubstituted alkyl. In one embodiment, R 18 is substituted or unsubstituted C1-C6 alkyl. In one embodiment, R 18is a substituted or unsubstituted C1-C6 straight chain alkyl. In one embodiment, R 18 is a substituted or unsubstituted C1-C6 branched alkyl. In one embodiment, R 18 is a substituted or unsubstituted aralkyl. In one embodiment, R 18 is a substituted or unsubstituted aryl.

[0116] In one embodiment, the blocking group has the structure [ka] where when y is 1 then x is 2, or when y is 2 then x is 1, or when y is 3 then x is 0. In one embodiment, the blocking group has the structure [ka] where when y is 1 then x is 2, or when y is 2 then x is 1, or when y is 3 then x is 0. In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In the foregoing, the underlined portion represents the portion of the compound that contains the catechol moiety and is not considered part of the blocking group.

[0117] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In the foregoing, the underlined portion represents the portion of the compound that contains the catechol moiety and is not considered part of the blocking group.

[0118] Thus, in certain embodiments, the present disclosure provides conjugates of formula I, II, IIA, and IIB comprising a water-soluble polymer and a compound of formula III. In certain preferred aspects, the water-soluble polymer is a polyoxazoline polymer. Such conjugates are useful for treating diseases or conditions described herein, including, but not limited to, dopamine-responsive disorders such as Parkinson's disease.

[0119] In one embodiment, the compound is a compound described in Yang et al. (Molecules, 2007, 12, 878-884, especially in Figure 1 and Table S1, etc.). In one embodiment, the compound is apomorphine, dopamine, norepinephrine, levodopa, levonordefrin, isoproterenol, epinephrine, nordefrin, (r)-(+)-fenoldopam, fenoldopam, isoetharine, carbidopa, dobutamine, tolcapone, and entacapone. In one embodiment, the compound is a compound described in Yang et al. (especially in Figure 1 and Table S1, etc.), which is useful for treating dopamine-responsive conditions, such as, but not limited to, Parkinson's disease. In one embodiment, the compound is apomorphine, albutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levopoda, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam.In another embodiment, the compound is apomorphine, fenoldopam, entacapone, tolcapone, chf-1303, dopamantine, dopamine, droxipoda, etilevodopa, exifon, or levodopa.In another embodiment, the compound is apomorphine, fenoldopam, entacapone, tolcapone, or levodopa. In the preceding list of exemplary compounds, the first phenolic hydroxyl group of the catechol moiety is R 15 or R 16 and the second phenolic hydroxyl group of the catechol moiety is modified with one of R 15 and R 16 As an example, consider the compound entacapone, which has the following structure: [ka] When entacapone is compound (A) as described herein, the conjugate may be prepared by the steps of: [ka] It is understood that the term "conventional" includes both.

[0120] In certain embodiments, the compound is used to treat dopamine-responsive disorders. Representative dopamine-responsive disorders are described herein, including, but not limited to, Parkinson's disease. Parkinson's disease is a central nervous system disorder caused by the loss of dopamine neurons in the substantia nigra pars compacta. The loss of these neurons in the brain leads to a lack of dopamine, a neurotransmitter essential for normal coordination and movement. Striatal dopaminergic neurons fire randomly but continuously due to the stability of dopamine levels, allowing precise coordinated movements. In Parkinson's disease patients, presynaptic neurons degenerate. When dopamine agonists (e.g., dopamine agonists) are administered to control symptoms, postsynaptic neurons are discontinuously stimulated (e.g., caused by pulsatile stimulation of striatal dopamine receptors), promoting motor fluctuations (dyskinesias) that may worsen as the disease progresses. Early symptoms of dopamine deficiency in Parkinson's disease include tremor, rigidity, bradykinesia, and gait disturbances. In later stages of Parkinson's disease, cognitive and behavioral problems and dementia develop.

[0121] There is currently no cure for Parkinson's disease, but the symptoms of the disease are treated with a variety of drugs aimed at maintaining dopaminergic tone. Medications currently used to treat Parkinson's disease include levodopa, dopamine agonists, and adenosine A 2AThese drugs include antagonists, anticholinergics, monoamine oxidase B inhibitors and catechol-O-methyltransferase inhibitors and other drugs.These drugs have problems associated with them, including limited bioavailability, short in vivo half-life and fast first-pass and / or peripheral metabolism.Their short half-life requires frequent administration several times a day, resulting in pulsatile stimulation of striatal dopamine receptors, which can actually accelerate the disappearance of dopaminergic neurons in the CNS.

[0122] Apomorphine is a compound that contains a catechol moiety. The R-enantiomer of apomorphine is an agonist at both D1 and D2 dopamine receptors, with greater activity at D2. Members of the D2 subfamily, consisting of D2, D3, and D4 receptors, are inhibitory G protein-coupled receptors. The D4 receptor, in particular, is an important target in signal transduction pathways and is involved in the development of several neurological disorders. Apomorphine improves motor function by activating dopamine receptors in the nigrostriatal tract, limbic system, hypothalamus, and pituitary gland. It also increases blood flow to the supplementary motor area and dorsolateral prefrontal cortex, the stimulation of which has been found to reduce the tardive dyskinetic effects of L-DOPA. Subjects with Parkinson's disease have also been found to have excess iron at sites of neurodegeneration, and both the R- and S-enantiomers of apomorphine are potent iron chelators and radical scavengers. Apomorphine also reduces the breakdown of dopamine in the brain and inhibits its synthesis.

[0123] Apomorphine is typically delivered to patients by subcutaneous injection. Common side effects of apomorphine administration by subcutaneous injection are the development of subcutaneous nodules at the injection site and a burning sensation at the injection site. Because apomorphine is delivered at least once a day to different injection sites, patients often develop subcutaneous nodules in multiple locations on the body. These subcutaneous nodules may develop into open wounds or wounds that may become infected and require further treatment. In some cases, surgery may also be required. As a result, patients often require further treatment to treat the side effects of apomorphine administration. The presence of subcutaneous nodules is painful, limits available injection sites, and prevents absorption of the drug over time. By using the conjugates of the present invention, the side effects of apomorphine administration, including but not limited to the development of subcutaneous nodules, are eliminated or reduced.

[0124] In certain embodiments, the compound is represented by formula IV, or a pharma- ceutical acceptable salt thereof: [ka] During the ceremony, R 15 and R 16 is as described for compounds of formula III, R 19 is H, unsubstituted alkyl, alkenyl, or alkynyl, substituted alkyl, alkenyl, or alkynyl, benzyl, substituted benzyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinyl, or 1-aryltetrazolyl. 19 is a linear, substituted or unsubstituted alkyl group of 1 to 5 carbons in length. In one embodiment, R 19 is -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3, and [ka] is selected from the group consisting of:

[0125] In one embodiment, R 19 is CH3. R 19 is CH3 and R 15 and R 16 When both are H, the compound is apomorphine (sold under the trade names Apokyn, Ixense, Spontane, and Uprima).

[0126] Thus, in certain embodiments, the present disclosure provides conjugates of formula I, II, IIA, and IIB comprising a water-soluble polymer and a compound of formula IV. In certain preferred aspects, the water-soluble polymer is a polyoxazoline polymer. Such conjugates are useful for treating dopamine-responsive disorders, such as, but not limited to, Parkinson's disease. In certain embodiments, the present disclosure provides conjugates of formula I, II, IIA, and IIB comprising a water-soluble polymer and a compound of formula IV. In certain preferred aspects, the water-soluble polymer is a polyoxazoline polymer. Such conjugates are useful for treating dopamine-responsive disorders, such as, but not limited to, Parkinson's disease. 19 Conjugates of formula I, II, IIA, and IIB are provided, including compounds of formula IV where is CH3. In certain preferred embodiments, the water-soluble polymer is a polyoxazoline polymer. Such conjugates are useful for treating diseases or conditions described herein, including, but not limited to, dopamine-responsive disorders such as Parkinson's disease.

[0127] Representative polymer conjugates The following are representative polymer conjugates of the present disclosure. [ka] and Example conjugates. In any of the foregoing, o2 may be 0 and the polymer subunit of o1 may comprise a mixture of enantiomeric forms of the compound.

[0128] In the above embodiment, R, R, R, R 16 , and R 19 For any of the groups may be used. In certain preferred embodiments, the variables are selected as described below. R is selected from the group consisting of hydrogen, unsubstituted and substituted alkyl, C1-C4 unsubstituted alkyl, and H. R1 for each repeat unit is selected from the group consisting of unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclylalkyl groups, unsubstituted C1-C4 alkyl, and substituted C1-C4. R6 is a substituted or unsubstituted alkyl, a linear substituted or unsubstituted C1-C4 alkyl, a branched substituted or unsubstituted C1-C4 alkyl, -(CH2) d and d is selected from the group consisting of -, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, and -CH2(CH3)-, and d is an integer of 1 to 10. T is a thioalkyl carboxylic acid, a thiocarboxylic ester, or a hydroxyl group. Z is S, O, or N. B is an optional linking group. Q is a terminal nucleophile or a terminal portion of a nucleophile. Certain preferred combinations of Z, B, and Q are: Z is S and B is -(CH2) y -, Q is -NH-tBoc, -COOH, -COOCH3, or -NH2, and y is 1 to 4.

[0129] In certain embodiments, R 16 , CH3) y -(CH x )-(CH2) 0-6 -C(O)-, where when y is 1, x is 2, when y is 2, x is 1, or when y is 3, x is 0. In one embodiment, the blocking group is selected from the group consisting of the structure (CH3) y -(CH x )-C(O)-, where when y is 1, x is 2, when y is 2, x is 1, or when y is 3, x is 0. In one embodiment, the blocking group has the structure CH3-(CH2) 0-6 In one embodiment, the blocking group has the structure CH3-(CH2) 0-6 -C(O)-(CH2)0-6 In certain embodiments, R 16 are (CH3)-C(O)-, CH3-(CH2)2-C(O)-, CH3-CH2-C(O)-, (CH3)2-CH-C(O)-, (CH3)3-CC(O)-, CH3CH2-OC(O)-CH2CH2-C(O)- and [ka] is selected from the group consisting of:

[0130] R 19 is -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3, and [ka] is selected from the group consisting of:

[0131] In certain embodiments, R is C-C unsubstituted alkyl or H, R is unsubstituted C-C alkyl, and R is (CH) d -, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, or -CH2(CH3)-; d is an integer from 1 to 10; Z is S; B is -(CH2)2-; Q is -NH-tBoc, -COOH, -COOCH3, or -NH2; R 16 are (CH3)-C(O)-, CH3-(CH2)2-C(O)-, CH3-CH2-C(O)-, (CH3)2-CH-C(O)-, CH3CH2-OC(O)-CH2CH2-C(O)-, and [ka] and R 19 is -H, -CH3, -CH2-CH3.

[0132] Further compounds The present disclosure also provides various compounds (i.e., intermediates) useful in the preparation of the described polymer conjugates. Such compounds may be used as active agents by themselves (i.e., without being attached to a water-soluble polymer as a component of a polymer conjugate).

[0133] In one embodiment, the present disclosure provides an intermediate of formula V, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R 11 , R 12 , R 13 and R 14 are independently selected from H, OH, halogen, alkoxy, NO, unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl, substituted alkyl, heteroalkyl, alkenyl, or alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, heteroarylalkyl, substituted heteroarylalkyl, or adjacent to each other, R 11 , R 12 , R 13 and R 14 any two of may be taken together with the carbons to which they are attached to form an optionally substituted aryl, heteroaryl, or heterocyclyl ring; R 20 and R 21 is H or a blocking group, and R 20 and R 21 The other is H, a group containing an active functional group, or a blocking group, while R 20 and R 21 Both of them cannot be H.

[0134] In certain embodiments, a "substituted alkyl" or "substituted heteroalkyl" refers to a C-C alkyl group substituted with up to five groups selected from the group consisting of -OH, -NH, -NH-NH, =O(OH), substituted aryl, and =O. 14 It refers to a straight or branched chain alkyl or heteroalkyl group.

[0135] In one embodiment, R 20 and R 21 is a blocking group, and R 20 and R 21 The other of R is a group that contains an active functional group. 20 and R 21 One of them is H and the other is R 20 and R 21 The other of R is a group that contains an active functional group. 20 and R 21 One of them is H and the other is R 20 and R 21 The other of R is a blocking group. 20 and R 21 Each of is a blocking group.

[0136] R 20 and R 21 is a blocking group, and R 20 and R 21 is a group that contains an active functional group, the compound is suitably used as an intermediate in the preparation of the polymer conjugates of the present disclosure.

[0137] R 20 and R 21 is a blocking group, and R 20 and R 21 The other is H or R 20 and R 21 and R are each a blocking group, the compound is suitably used as an active agent in the therapeutic methods disclosed herein. Without being bound to any particular theory, it is believed that one or both of the first or second phenolic hydroxyl groups (i.e., R 20 and / or R21 ) is believed to result in a compound that is less irritating to the skin (compared to a compound having free hydroxyl groups at both the first and second phenolic hydroxyl groups).

[0138] R 20 and R 21 In embodiments where both R 20 and R 21 The blocking groups in R may be the same or different. 20 and R 21 In embodiments where both R 20 and R 21 The blocking groups of R may contain the same or different cleavable moieties. 20 and R 21 In embodiments where both R 20 and R 21 The blocking group of contains the same cleavable moiety, which can be an ester bond.

[0139] Exemplary cleavable moieties include, but are not limited to, an ester bond, a carboxylate bond (-C(O)-O-), a carbonate bond (-OC(O)-O-), a carbamate bond (-OC(O)-NH-), an amide bond (-C(O)-NH-), and a disulfide bond (SS). Other cleavable moieties are discussed herein. In certain embodiments, the first cleavable moiety is an ester bond. In another particular embodiment, the cleavable moiety is a carboxylate bond.

[0140] In one embodiment, the blocking group comprises a second cleavable moiety or the blocking group is R 20 and / or R 21 In one embodiment, the blocking group forms a second cleavable moiety upon forming a bond with the O atom of R 20 and / or R 21Upon forming a bond with the O atom of the cleavable moiety, the second cleavable moiety is formed. In one embodiment, the cleavable moiety is cleaved by a chemical reaction. In one aspect of this embodiment, the cleavage is by hydrolysis or reduction of an ester group, such as, but not limited to, reduction of a disulfide. In one embodiment, the cleavable moiety is cleaved by a substance that is naturally present or induced to be present in the subject. In one aspect of this embodiment, such a substance is an enzyme or a polypeptide. Thus, in one embodiment, the cleavable moiety is cleaved by an enzymatic reaction. In one embodiment, the cleavable moiety is cleaved by the combination of the above.

[0141] In one embodiment, the R 20 and / or R 21 The blocking group in is -R 22 -R 23 - and R 22 is -C(O)-, -OC(O)-, -C(O)-NH-cyclic-OC(O)- (cyclic represents substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl or cycloalkyl), -C(O)-NH-(CH)-OC(O)-, or -OP(O)(OR)(O)- (R is H or substituted or unsubstituted C-C alkyl); R 23 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

[0142] In one embodiment, R 22 is R 20 and / or R 21 forms a bond with the oxygen atom of R 22 and the O to which it is attached forms a cleavable moiety. In one embodiment, the cleavable moiety is -C(O)-O.

[0143] In one embodiment, R 23 is substituted or unsubstituted alkyl. In one embodiment, R 23is substituted or unsubstituted C1-C6 alkyl. In one embodiment, R 23 is a substituted or unsubstituted C1-C6 straight chain alkyl. In one embodiment, R 23 is a substituted or unsubstituted C1-C6 branched alkyl. In one embodiment, R 23 is a substituted or unsubstituted aralkyl. In one embodiment, R 23 is a substituted or unsubstituted aryl.

[0144] In one embodiment, the blocking group has the structure [ka] where when y is 1 then x is 2, or when y is 2 then x is 1, or when y is 3 then x is 0. In one embodiment, the blocking group has the structure [ka] where when y is 1 then x is 2, or when y is 2 then x is 1, or when y is 3 then x is 0. In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In the foregoing, the underlined portion represents the portion of the compound that contains the catechol moiety and is not considered part of the blocking group.

[0145] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In the foregoing, the underlined portion represents the portion of the compound that contains the catechol moiety and is not considered part of the blocking group.

[0146] In one embodiment, the group containing the active functional group is R 24 -R 25 -R 26 and R 24 is -C(O)-, -OC(O)-, -C(O)-NH-cyclic-OC(O)- (cyclic represents substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl or cycloalkyl), -C(O)-NH-(CH)-OC(O)-, or -OP(O)(OR)(O)- (R is H or substituted or unsubstituted C-C alkyl); R 25is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group; R 26 is an active functional group or a moiety that contains an active functional group capable of forming bonds with groups of the polymer, including groups at pendant positions of the polymer. In one embodiment, R 26 is an alkyne, amine, oxyamine, aldehyde, ketone, acetal, ketal, maleimide, ester, carboxylic acid, activated carboxylic acid (such as, but not limited to, N-hydroxysuccinimidyl (NHS) and 1-benzotriazinyl active ester), activated carbonate, chloroformate, alcohol, azide, vinyl sulfone, and orthopyridyl disulfide (OPSS). 26 is an azide group (N3) or an alkyne group. In one embodiment, R 24 forms a bond with the oxygen atom of the first phenolic hydroxyl group, and R 24 and the O to which it is attached form the first cleavable moiety. In one embodiment, the first cleavable moiety is -C(O)-O.

[0147] In one embodiment, R 25 is substituted or unsubstituted alkyl. In one embodiment, R 25 is substituted or unsubstituted C1-C6 alkyl. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 straight chain alkyl. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 branched alkyl.

[0148] In one embodiment, R 26 is N3. R 26When is N3, the compound of formula V can be coupled to a polymer containing an alkyne group (such as, but not limited to, acetylene) via copper(I) catalyzed azide-acetylene click chemistry. In such a reaction, the compound of formula V is coupled to an azide group as described herein, and a copper(I) catalyzed click reaction is carried out with the alkyne group of the polymer. In one embodiment of the foregoing, the alkyne group is at a pendant position of the polymer. In one embodiment of the foregoing, the polymer is a polyoxazoline polymer, and the alkyne group is at a pendant position of the polyoxazoline polymer.

[0149] In one embodiment, R 26 is an alkyne. R 26 When is an alkyne (such as, but not limited to, acetylene), the compound of formula V can be attached to a polymer containing an N group via copper(I) catalyzed azide-acetylene click chemistry. In such a reaction, the compound of formula V is attached to an alkyne group as described herein, and a copper(I) catalyzed click reaction is carried out with the azide group of the polymer. In one embodiment of the foregoing, the azide group is at a pendant position of the polymer. In one embodiment of the foregoing, the polymer is a polyoxazoline polymer and the azide group is at a pendant position of the polyoxazoline polymer.

[0150] In one embodiment, the group comprising the active functional group has the structure [ka] In one embodiment, the group comprising the active functional group has the structure [ka] In one embodiment, the group comprising the active functional group has the structure [ka] In one embodiment, the group comprising the active functional group has the structure [ka] In the foregoing, the underlined portion represents the portion of the compound that contains the catechol moiety and is not considered part of the group that contains the active functional group.

[0151] In one embodiment, R 20 and R 21 is a blocking group, and R 20 and R 21 and the other is H. In another embodiment, R 20 and R 21 is a blocking group, and each of R 20 and R 21 are the same. In another embodiment, the blocking groups in R 20 and R 21 each of R 20 and R 21 The blocking groups of R are different. 20 and R 21 In embodiments where both R 20 and R 21 The blocking groups of R 20 and R 21 In embodiments where both R 20 and R 21 The blocking groups of R 20 and R 21 In embodiments where both R 20 and R 21 The blocking group of R contains an ester bond as the cleavable moiety. 20 and R 21 Embodiments in which one or both are blocking groups may be used in the treatment methods described herein as active agents without being conjugated to a water-soluble polymer (i.e., not as a component of a polymer conjugate as described above).

[0152] In one embodiment, the present disclosure provides an intermediate of formula VI, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R 19 is H, unsubstituted alkyl, alkenyl, or alkynyl, substituted alkyl, alkenyl, or alkynyl, benzyl, substituted benzyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinyl, or 1-aryltetrazolyl; R 20 and R 21 is H or a blocking group, and R 20 and R 21 The other is H, a group containing an active functional group, or a blocking group, while R 20 and R 21 Both of them cannot be H.

[0153] In one embodiment, R 19 is a linear, substituted or unsubstituted alkyl group of 1 to 5 carbons in length. In one embodiment, R 19 is -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3, and [ka] In one embodiment, R 19 is CH3.

[0154] In one embodiment, R 20 and R 21 is a blocking group, and R 20 and R 21 The other of R is a group that contains an active functional group. 20 and R 21 One of them is H and the other is R 20 and R 21 The other of R is a group that contains an active functional group. 20 and R 21 One of them is H and the other is R 20 and R 21The other of R is a blocking group. 20 and R 21 Each of is a blocking group.

[0155] R 20 and R 21 In embodiments where both R 20 and R 21 The blocking groups in R may be the same or different. 20 and R 21 In embodiments where both R 20 and R 21 The blocking groups of R may contain the same or different cleavable moieties. 20 and R 21 In embodiments where both R 20 and R 21 The blocking group of contains the same cleavable moiety, which can be an ester bond.

[0156] Exemplary cleavable moieties include, but are not limited to, an ester bond, a carboxylate bond (-C(O)-O-), a carbonate bond (-OC(O)-O-), a carbamate bond (-OC(O)-NH-), an amide bond (-C(O)-NH-), and a disulfide bond (SS). Other cleavable moieties are discussed herein. In certain embodiments, the first cleavable moiety is an ester bond. In another particular embodiment, the cleavable moiety is a carboxylate bond.

[0157] In one embodiment, the blocking group comprises a second cleavable moiety or the blocking group is R 20 and / or R 21 In one embodiment, the blocking group forms a second cleavable moiety upon forming a bond with the O atom of R 20 and / or R 21Upon forming a bond with the O atom of the cleavable moiety, the second cleavable moiety is formed. In one embodiment, the cleavable moiety is cleaved by a chemical reaction. In one aspect of this embodiment, the cleavage is by hydrolysis or reduction of an ester group, such as, but not limited to, reduction of a disulfide. In one embodiment, the cleavable moiety is cleaved by a substance that is naturally present or induced to be present in the subject. In one aspect of this embodiment, such a substance is an enzyme or a polypeptide. Thus, in one embodiment, the cleavable moiety is cleaved by an enzymatic reaction. In one embodiment, the cleavable moiety is cleaved by the combination of the above.

[0158] In one embodiment, the blocking group is -R 22 -R 23 - and R 22 is -C(O)-, -OC(O)-, -C(O)-NH-cyclic-OC(O)- (cyclic represents substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl or cycloalkyl), -C(O)-NH-(CH)-OC(O)-, or -OP(O)(OR)(O)- (R is H or substituted or unsubstituted C-C alkyl); R 23 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

[0159] In one embodiment, R 22 forms a bond with the oxygen atom of the second phenolic hydroxyl group, and R 22 and the O to which it is attached form the second cleavable moiety. In one embodiment, the second cleavable moiety is -C(O)-O.

[0160] In one embodiment, R 23 is substituted or unsubstituted alkyl. In one embodiment, R 23 is substituted or unsubstituted C1-C6 alkyl. In one embodiment, R 23is a substituted or unsubstituted C1-C6 straight chain alkyl. In one embodiment, R 23 is a substituted or unsubstituted C1-C6 branched alkyl. In one embodiment, R 23 is a substituted or unsubstituted aralkyl. In one embodiment, R 23 is a substituted or unsubstituted aryl.

[0161] In one embodiment, the blocking group has the structure [ka] where when y is 1 then x is 2, or when y is 2 then x is 1, or when y is 3 then x is 0. In one embodiment, the blocking group has the structure [ka] where when y is 1 then x is 2, or when y is 2 then x is 1, or when y is 3 then x is 0. In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In the foregoing, the underlined portion represents the portion of the compound that contains the catechol moiety and is not considered part of the blocking group.

[0162] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In the foregoing, the underlined portion represents the portion of a compound that includes the catechol moiety. In the foregoing, the underlined portion represents the portion of a compound that includes the catechol moiety and is not considered part of the blocking group.

[0163] In one embodiment, the group containing the active functional group is R 24 -R 25 -R 26 and R 24 is -C(O)-, -OC(O)-, -C(O)-NH-cyclic-OC(O)- (cyclic represents substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl or cycloalkyl), -C(O)-NH-(CH)-OC(O)-, or -OP(O)(OR)(O)- (R is H or substituted or unsubstituted C-C alkyl); R 25 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group; R 26is a moiety that contains a reactive group capable of forming a bond with a group of the polymer, including groups at pendant positions of the polymer. In one embodiment, R 26 is an alkyne, amine, oxyamine, aldehyde, ketone, acetal, ketal, maleimide, ester, carboxylic acid, activated carboxylic acid (such as, but not limited to, N-hydroxysuccinimidyl (NHS) and 1-benzotriazinyl active ester), activated carbonate, chloroformate, alcohol, azide, vinyl sulfone, and orthopyridyl disulfide (OPSS). 26 is an azide group (N3) or an alkyne group. In one embodiment, R 24 forms a bond with the oxygen atom of the first phenolic hydroxyl group, and R 24 and the O to which it is attached form the first cleavable moiety. In one embodiment, the second cleavable moiety is -C(O)-O.

[0164] In one embodiment, R 25 is substituted or unsubstituted alkyl. In one embodiment, R 25 is substituted or unsubstituted C1-C6 alkyl. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 straight chain alkyl. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 branched alkyl.

[0165] In one embodiment, R 26 is N3. R 26When is N3, the compound of formula V can be coupled to a polymer containing an alkyne group (such as, but not limited to, acetylene) via copper(I) catalyzed azide-acetylene click chemistry. In such a reaction, the compound of formula V is coupled to an azide group as described herein, and a copper(I) catalyzed click reaction is carried out with the alkyne group of the polymer. In one embodiment of the foregoing, the alkyne group is at a pendant position of the polymer. In one embodiment of the foregoing, the polymer is a polyoxazoline polymer, and the alkyne group is at a pendant position of the polyoxazoline polymer.

[0166] In one embodiment, R 26 is an alkyne. R 26 When is an alkyne (such as, but not limited to, acetylene), the compound of formula V can be attached to a polymer containing an N group via copper(I) catalyzed azide-acetylene click chemistry. In such a reaction, the compound of formula V is attached to an alkyne group as described herein, and a copper(I) catalyzed click reaction is carried out with the azide group of the polymer. In one embodiment of the foregoing, the azide group is at a pendant position of the polymer. In one embodiment of the foregoing, the polymer is a polyoxazoline polymer and the azide group is at a pendant position of the polyoxazoline polymer.

[0167] In one embodiment, the group comprising the active functional group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In one embodiment, the group comprising the active functional group has the structure [ka] In one embodiment, the blocking group has the structure [ka] In the foregoing, the underlined portion represents the portion of the compound that contains the catechol moiety and is not considered part of the group that contains the active functional group.

[0168] Certain preferred compounds of the present disclosure for use as intermediates are set forth below. [ka] and the compounds of the examples.

[0169] In the aforementioned preferred compounds of the present disclosure, R 19 , R 23 , and R 25 may be as described herein.

[0170] In one embodiment, R 19 is -H, CH3, -CH2-CH3, -CH2-CH2-CH3, and [ka] R 23 (when present) is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group; R 25 If present, -(CH2) 1-6 - or -(CH2)3-.

[0171] In one embodiment, R 19 is -H, CH3, -CH2-CH3, -CH2-CH2-CH3, and [ka] R 23 (If present) is (CH3) y -(CH x )-(CH2) 0-6-C(O)- (when y is 1, x is 2, or when y is 2, x is 1, or when y is 3, x is 0), (CH3) y -(CH x )-C(O)-(when y is 1, x is 2, or when y is 2, x is 1, or when y is 3, x is 0), CH3-(CH2) 0-6 -C(O)-, or CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 - and R 25 If present, -(CH2) 1-6 - or -(CH2)3-.

[0172] In one embodiment, R 19 is -H, CH3, -CH2-CH3, -CH2-CH2-CH3, and [ka] R 23 (When present) is CH3-, CH3-(CH2)2-, CH3-CH2-, (CH3)2-CH-, (CH3)3-C-, or [ka] and R 25 If present, -(CH2) 1-6 - or -(CH2)3-.

[0173] In any of the above, R 19 is CH3.

[0174] Certain preferred compounds of the present disclosure for use as active agents are set forth below. [ka]

[0175] In the aforementioned preferred compounds of the present disclosure, R 19 and R 23may be as described herein. Without being bound to any particular theory, administration of a compound having a blocking group on at least one of the first or second phenolic hydroxyl groups results in a compound that is less irritating to the skin (compared to a compound having free hydroxyl groups on both the first and second phenolic hydroxyl groups).

[0176] In one embodiment, R 19 is -H, CH3, -CH2-CH3, -CH2-CH2-CH3, and [ka] R 23 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group (or two R 23 groups, if present, are independently selected from these.

[0177] In one embodiment, R 19 is -H, CH3, -CH2-CH3, -CH2-CH2-CH3, and [ka] R 23 is (CH3) y -(CH x )-(CH2) 0-6 -C(O)- (when y is 1, x is 2, or when y is 2, x is 1, or when y is 3, x is 0), (CH3) y -(CH x )-C(O)-(when y is 1, x is 2, or when y is 2, x is 1, or when y is 3, x is 0), CH3-(CH2) 0-6 -C(O)-, or CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 - (or two R 23 groups, if present, are independently selected from these.

[0178] In one embodiment, R 19 is -H, CH3, -CH2-CH3, -CH2-CH2-CH3, and [ka] R 23 is CH3-, CH3-(CH2)2-, CH3-CH2-, (CH3)2-CH-, (CH3)3-C-, or [ka] (or two R 23 groups, if present, are independently selected from these.

[0179] In any of the above, R 19 is CH3.

[0180] Treatment method The present disclosure also provides polymeric conjugates of formula I, II, IIA, and IIB for use as active agents in the therapeutic methods described herein. Such conjugates include a polymeric moiety attached to a compound comprising a catechol moiety via a first cleavable bond, the cleavable bond being formed between the polymer and a first phenolic hydroxyl group of the catechol moiety, and a second phenolic hydroxyl group of the catechol moiety being attached to a blocking group, and the cleavage (i.e., release rate) of the compound comprising the catechol moiety is controlled, at least in part, via the structure and / or design of the blocking group. The present disclosure further provides that the release of the compound from the polymeric conjugate can be controlled. In one embodiment, the compound is delivered with a pharmacokinetic / release profile that lacks the peaks and troughs seen in prior art therapeutics. In one embodiment, a near constant release of the compound from the polymeric conjugate is achieved over a period of time (e.g., 12 hours to 168 hours).

[0181] In one embodiment, the conjugate delivers a therapeutically effective amount of the compound to the subject for 12 hours to 24 hours, 24 hours to 48 hours, 24 hours to 72 hours, 24 hours to 96 hours, 24 hours to 120 hours, 24 hours to 144 hours, or 24 hours to 168 hours. In any of the foregoing embodiments, the delivery is controllable delivery or sustained controllable delivery. In any of the foregoing embodiments, the compound is delivered with a pharmacokinetic / release profile lacking peaks and troughs.

[0182] In one embodiment, the conjugate delivers a therapeutically effective amount of the compound to the subject for a period of 1 week or more. In one embodiment, the conjugate delivers a therapeutically effective amount of the compound to the subject for a period of 1-2 weeks, 1-3 weeks, or 1-4 weeks. In any of the foregoing embodiments, the delivery is controllable delivery or sustained controllable delivery. In any of the foregoing embodiments, the compound is delivered with a pharmacokinetic / release profile lacking peaks and troughs.

[0183] In one embodiment, the delivery provides a release profile that provides a therapeutically effective amount of the compound over such a period of time.As a result, the polymer conjugates of the present disclosure are useful for treating human diseases through appropriate selection of the compound and / or blocking group.In addition, the polymer conjugates of the present disclosure reduce the frequency of administration to achieve a therapeutically effective amount of the compound in a subject compared to the art.In one embodiment, the polymer conjugates of the present disclosure are administered once a day, every other day, once a week, once every two weeks, once every three weeks, once a month, or at other desired intervals.

[0184] The present disclosure also provides a compound of formula V or VI for use as an active agent in the methods of treatment described herein. The generation of one or both of the free hydroxyl groups of a compound of formula V or VI is controlled, at least in part, through the structure of the blocking group of the first and / or second hydroxyl groups.

[0185] The present disclosure provides various treatment methods using the conjugates and compounds of the present disclosure.The present disclosure provides a method for treating a disease or condition, comprising administering to a subject an amount of the polymer conjugate or compound of the present disclosure (e.g., the compound of formula V and / or VI), and the disease or condition is selected based on the compound that is part of the polymer conjugate.For example, if the compound is a dopamine agonist, the disease or condition to be treated can be a disease or condition related to dopamine deficiency in the peripheral nervous system or central nervous system.In another example, if the compound is a dopamine agonist, the disease or condition to be treated can be hypodopaminergic condition, pituitary tumor (prolactinoma), Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, hypodopaminergic condition, SSRI-induced sexual dysfunction, depression, obesity, and type II diabetes. Other diseases and conditions that may be treated are described in Rubi et al. (Endocrinology, 151(12), 5570-5581, 2010, which is incorporated by reference for such disclosure).

[0186] Compounds containing the catechol moiety have been reported to treat a variety of diseases and conditions, as described in Yang et al. (Molecules, 2007, 12, 878-884), which is incorporated by reference for such disclosure.

[0187] The present disclosure provides a method for treating dopamine-responsive disease or condition, comprising administering to a subject an amount of the polymer conjugate or compound of the present disclosure (e.g., compound of formula V and / or VI), wherein the agent is a dopamine agonist.In one embodiment, the dopamine-responsive disease or condition is hypodopaminergic condition, pituitary tumor (prolactinoma), Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, hypodopaminergic condition, SSRI-induced sexual dysfunction, depression, obesity, and type II diabetes.In another embodiment, such disease or condition is Parkinson's disease.In another embodiment, such disease or condition is restless legs syndrome.

[0188] The present disclosure provides a method for treating Parkinson's disease, the method comprising administering to a subject an amount of a polymer conjugate or compound of the present disclosure (e.g., a compound of Formula V and / or VI), where the agent is a dopamine agonist.

[0189] The present disclosure provides a method for treating dopamine deficiency in the peripheral or central nervous system, the method comprising administering to a subject an amount of a polymer conjugate or compound of the present disclosure (e.g., a compound of Formula V and / or VI), where the agent is a dopamine agonist.

[0190] In any of the aforementioned methods of treatment, one or more of the following may apply to each method of treatment described.

[0191] In any of the foregoing embodiments, any polymer conjugate described herein may be used, and the compound may be selected based on the disease or condition being treated.

[0192] In any of the foregoing embodiments in which the polymer conjugate is a poly(oxazoline) polymer conjugate, the poly(oxazoline) polymer conjugate may have the general formula shown for Formulas II-IIB.

[0193] In any of the preceding embodiments, the polymer is a polyoxazoline polymer.

[0194] In any of the foregoing embodiments, the compound is a compound of formula III or IV, or a compound of Figure 1 or Table 1S of Yang et al. (Molecules, 2007, 12, 878-884). In one embodiment, the compound containing a catechol moiety is a compound described in Yang et al. (e.g., particularly Figure 1 and Table S1), which is useful for treating dopamine-responsive conditions, such as, but not limited to, Parkinson's disease. In one embodiment, the compound containing a catechol moiety is apomorphine, fenoldopam, entacapone, or tolcapone.

[0195] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is a compound of formula III or IV, or a compound in Figure 1 or Table 1S of Yang et al. (Molecules, 2007, 12, 878-884). In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is a compound of formula III or IV, or a compound described in Yang et al. (e.g., particularly Figure 1 and Table S1), which is useful for treating dopamine-responsive conditions, such as, but not limited to, Parkinson's disease. In one embodiment, the compound is apomorphine, albutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levopoda, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam.In another embodiment, the compound is apomorphine, fenoldopam, entacapone, tolcapone, chf-1303, dopamantine, dopamine, droxipoda, etilevodopa, exifon, or levodopa.In another embodiment, the compound is apomorphine, fenoldopam, entacapone, tolcapone, or levodopa. In the preceding list of exemplary compounds, the first phenolic hydroxyl group of the catechol moiety is R 15 Qualified with OR 15 and the second phenolic hydroxyl group of the catechol moiety is R 16 Qualified with OR 16 In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is a compound of formula III or IV, or is apomorphine, fenoldopam, entacapone, or tolcapone.

[0196] In any of the preceding embodiments, the polymer is a polyoxazoline polymer.

[0197] In any of the foregoing embodiments, the compound is a dopamine agonist, such as, but not limited to, apomorphine.

[0198] In any of the foregoing embodiments, the compound is fenoldopam, entacapone, or tolcapone.

[0199] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is a dopamine agonist, for example, but not limited to, apomorphine.

[0200] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is fenoldopam, entacapone, or tolcapone.

[0201] In any of the preceding embodiments, the compound is apomorphine.

[0202] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is apomorphine.

[0203] In any of the foregoing embodiments, the polymer conjugate or compound (e.g., a compound of formula V and / or VI) may be administered alone or as part of a pharmaceutical composition described herein. In any of the foregoing embodiments, the subject may be determined to be in need of such treatment. In any of the foregoing embodiments, the polymer conjugate or compound (e.g., a compound of formula V and / or VI) is administered in a therapeutically effective amount. In any of the foregoing embodiments, the subject may be a mammal. In the foregoing embodiments, the subject may be a human.

[0204] In any of the foregoing embodiments, the method of treatment may be accomplished by subcutaneous administration (e.g., subcutaneous injection) of a polymer conjugate or compound of the present disclosure (e.g., compounds of Formula V and / or VI) or a pharmaceutical composition comprising such a polymer conjugate or compound.

[0205] In any of the above-mentioned embodiments, the method of treatment can be achieved by subcutaneous administration of a compound of the present disclosure (e.g., a compound of formula V and / or VI) or a pharmaceutical composition comprising such a compound. Suitable routes of subcutaneous administration include, but are not limited to, subcutaneous injection or infusion. In a particular embodiment, the compound of formula V and / or VI is a compound comprising a blocking group at one or both (preferably both) of the first and second phenolic hydroxyl groups, and the cleavable portion of the blocking group(s) is an ester bond. In another particular embodiment, the compound of formula V and / or VI is apomorphine comprising a blocking group at one or both (preferably both) of the first and second phenolic hydroxyl groups, and the cleavable portion of the blocking group(s) is an ester bond. Without being limited to any particular theory, the compounds of formulas V and VI, which contain a blocking group on one or both (preferably both) of the first and second phenolic hydroxyl groups and the cleavable portion of the blocking group(s) is an ester bond, are advantageously administered to a subject via subcutaneous injection without side effects (such as, but not limited to, skin irritation) seen with the administration of prior art compounds. Since the enzyme required for cleaving the ester bond is not present in the blood of a human subject, the cleavable portion of the blocking group(s) is not cleaved upon subcutaneous administration (including subcutaneous injection or infusion). As a result, the hydroxyl group of the catechol moiety is not exposed on the compound until the compound leaves the subcutaneous space, thereby reducing the side effects of administration seen in the prior art (especially when the compound is apomorphine).

[0206] Preferred apomorphine compounds for administration by subcutaneous injection or infusion include, but are not limited to, the following compounds: [ka] .

[0207] In any of the foregoing embodiments, the polymer conjugate is administered once a day, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered every other day, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered every second, third, fourth or fifth day, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered once a week, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered once every two weeks, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered once every four weeks, either alone or as part of a pharmaceutical composition. Other dosing frequencies may be used based on the nature of the selected polymer conjugate and the release rate of the compound.

[0208] In any of the foregoing embodiments, the polymer conjugate is administered subcutaneously once a day, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered subcutaneously every other day, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered subcutaneously every second, third, fourth or fifth day, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered subcutaneously once a week, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered subcutaneously once every two weeks, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered subcutaneously once every four weeks, either alone or as part of a pharmaceutical composition. Other dosing frequencies may be used based on the nature of the selected polymer conjugate and the release rate of the compound.

[0209] In any of the above embodiments, the polymer conjugate is a polyoxazoline polymer, the compound is apomorphine, and the polymer conjugate is administered subcutaneously once a day, either alone or as part of a pharmaceutical composition. In any of the above embodiments, the polymer conjugate is a polyoxazoline polymer, the compound is apomorphine, and the polymer conjugate is administered subcutaneously every other day, either alone or as part of a pharmaceutical composition. In any of the above embodiments, the polymer conjugate is a polyoxazoline polymer, the compound is apomorphine, and the polymer conjugate is administered subcutaneously every second, third, fourth, or fifth day, either alone or as part of a pharmaceutical composition. In any of the above embodiments, the polymer conjugate is a polyoxazoline polymer, the compound is apomorphine, and the polymer conjugate is administered subcutaneously once a week, either alone or as part of a pharmaceutical composition. In any of the above embodiments, the polymer conjugate is a polyoxazoline polymer, the compound is apomorphine, and the polymer conjugate is administered subcutaneously once every two weeks, either alone or as part of a pharmaceutical composition. In any of the above embodiments, the polymer conjugate is a polyoxazoline polymer, the compound is apomorphine, and the polymer conjugate is administered subcutaneously once every four weeks, either alone or as part of a pharmaceutical composition. Other dosing frequencies may be used, depending on the nature of the selected polymer conjugate and the release rate of the compound.

[0210] In any of the foregoing embodiments, the polymer conjugates described herein can also be administered in combination with other therapeutic agents, such as other agents useful for treating dopamine-responsive disorders, including, but not limited to, Parkinson's disease or any other condition described herein. When administered with other therapeutic agents, the polymer conjugates of the present disclosure can be administered before, after, or simultaneously with the additional therapeutic agent. Thus, in one embodiment, the present disclosure also provides a composition comprising a polymer conjugate described herein, at least one other therapeutic agent, and a pharma- ceutically acceptable diluent or carrier.

[0211] kit The disclosure provides kits comprising, consisting essentially of, or consisting of a water-soluble polymer, such as, but not limited to, a polyoxazoline polymer, and a compound of general formula V or VI and one or more of the following: reagents for coupling the intermediate to the polymer, packaging materials, and instructions for coupling the intermediate to the polymer.

[0212] The present disclosure provides kits comprising, consisting essentially of, or consisting of a compound comprising a catechol moiety, a reagent for forming a blocking group on one of the phenolic hydroxyl groups of the catechol moiety and / or a functional group on the other of the phenolic hydroxyl groups of the catechol moiety, and one or more of the following: a water soluble polymer such as, but not limited to, a polyoxazoline polymer, packaging materials, and instructions for forming a blocking group on one of the phenolic hydroxyl groups of the catechol moiety and / or a functional group on the other of the phenolic hydroxyl groups of the catechol moiety.

[0213] The present disclosure provides a kit comprising, consisting essentially of, or consisting of the polymer conjugate of the present disclosure and one or more of the following: packaging material and instructions for administering the polymer conjugate to a subject for the treatment of a disease or condition. The disease or condition is selected based on the compound that is part of the polymer conjugate. For example, if the compound is a dopamine agonist, the disease or condition to be treated may be Parkinson's disease. Compounds that include the catechol moiety have been reported to treat various diseases and conditions, as described in Yang et al. (Molecules, 2007, 12, 878-884). This document is incorporated by reference for its disclosure.

[0214] The present disclosure provides a kit comprising, consisting essentially of, or consisting of a polymer conjugate of the present disclosure and one or more of the following: packaging material and instructions for administering the polymer conjugate to a subject for the treatment of a dopamine-responsive disease or condition. In one embodiment, the dopamine-responsive disease or condition is a hypodopaminergic condition, Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, pituitary tumor (prolactinoma), hypodopaminergic condition, SSRI-induced sexual dysfunction, depression, obesity, and type II diabetes. In one embodiment, such disease or condition is Parkinson's disease. In one embodiment, such disease or condition is restless legs syndrome.

[0215] The present disclosure provides kits comprising, consisting essentially of, or consisting of a polymer conjugate of the present disclosure and one or more of the following: packaging materials and instructions for administering the polymer conjugate to a subject for the treatment of a hypodopaminergic condition.

[0216] The present disclosure provides kits comprising, consisting essentially of, or consisting of a polymer conjugate of the present disclosure and one or more of the following: packaging material and instructions for administering the polymer conjugate to a subject for the treatment of Parkinson's disease.

[0217] The present disclosure provides kits comprising, consisting essentially of, or consisting of a polymer conjugate of the present disclosure and one or more of the following: packaging materials and instructions for administering the polymer conjugate to a subject for the treatment of restless legs syndrome.

[0218] In any of the above kits, one or more of the following may also be applied: i) the kit further comprises an additional active agent; ii) the kit further comprises an additional active agent, and the instructions describe the administration of the additional active agent in conjunction with administration of the polymer conjugate; iii) the instructions describe the polymer conjugate being administered by subcutaneous administration; iv) the instructions describe the polymer conjugate being administered by subcutaneous administration once a day, every other day, every second day, every third day, every fourth day, or every fifth day, once a week, once every two weeks, or once every four weeks; v) the kit further comprises a delivery system, or a part thereof, for administration of the polymer conjugate; vi) the polymer conjugate is, in one embodiment of the general formula shown for formula II or III, a poly(oxazoline) polymer conjugate. vii) the compound is of formula II or III or is a compound of Figure 1 or Table 1S of Yang et al. (Molecules, 2007, 12, 878-884). viii) the polymer is a polyoxazoline polymer and the compound is of formula II or III or is a compound of Figure 1 or Table 1S of Yang et al. (Molecules, 2007, 12, 878-884). ix) the compound is fenoldopam, entacapone, or tolcapone. x) the compound is fenoldopam, entacapone, or tolcapone and the polymer is a polyoxazoline polymer. xi) the compound is apomorphine. xii) the compound is apomorphine and the polymer is a polyoxazoline polymer. xiii) the compound is a dopamine agonist. xiv) The compound is a dopamine agonist and the polymer is a polyoxazoline polymer.

[0219] In certain embodiments, all of i)-xiv) apply. In certain embodiments, one, two, three, or four or more of i)-xiv) apply. In certain embodiments, at least one of iii), iv), and vi)-xiv) apply. In certain embodiments, two of iii), iv), and vi)-xii) apply.

[0220] Pharmaceutical Compositions and Routes of Administration A pharmaceutical composition is provided that includes an amount of the polymer conjugate or compound of the present disclosure (e.g., a compound of formula V and / or VI). In one embodiment, such a pharmaceutical composition includes a therapeutically effective amount of the conjugate or compound of the present disclosure (e.g., a compound of formula V and / or VI). In certain embodiments, the conjugate of the present disclosure is a conjugate of formula I, II, IIA, or IIB. In certain embodiments, the conjugate of the present disclosure is a conjugate of formula I, II, IIA, or IIB, and the polymer is a polyoxazoline polymer. In addition, such a pharmaceutical composition may include other active agents. The additional active agents included may be selected based on the disease or condition to be treated.

[0221] Pharmaceutical compositions of the present disclosure may include one or more of the conjugates or compounds of the present disclosure (e.g., compounds of formula V and / or VI), alone or in combination with additional active agents, in combination with a pharma- ceutical acceptable carrier. Examples of such carriers and methods of formulation are described in Remington: The Science and Practice of Pharmacy (2006). th Ed., Lippincott, Williams & Wilkins, Daniel Limmer, editor). Such conjugates and pharmaceutical compositions may be used in the manufacture of medicaments for use in the methods of treatment described herein. The conjugates or compounds of the present disclosure (e.g., compounds of formula V and / or VI) are useful both in the free form and in the form of pharma- ceutical acceptable salts.

[0222] The pharma- ceutically acceptable carriers described herein, including but not limited to vehicles, adjuvants, excipients, or diluents, are well known to those skilled in the art. Pharmaceutically acceptable excipients are also well known to those skilled in the art. The choice of excipients depends in part on the specific conjugate(s) and on the specific method used to administer the formulation. Thus, there are a wide variety of suitable formulations of the pharmaceutical composition. The following methods and excipients are merely exemplary and in no way limiting. Suitable carriers and excipients include solvents, such as water, alcohol, and propylene glycol, solid adsorbents and diluents, surfactants, suspending agents, tableting binders, lubricants, flavoring agents, and coloring agents. The pharma- ceutically acceptable carriers can include polymers and polymer matrices. Examples of acceptable pharmaceutical carriers include carboxymethylcellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powder, saline, sodium alginate, sucrose, starch, talc, and water, among others. Generally, the pharma- ceutical acceptable carrier is chemically inert to the active agent in the composition and has no harmful side effects or toxicity under the conditions of use.In some embodiments, the term "pharma- ceutical acceptable" means approved by the regulatory agency of the federal or state government for use in animals, more particularly in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias.

[0223] In one embodiment, such pharmaceutical compositions comprise a therapeutically effective amount of the conjugate or compound of the present disclosure (e.g., a compound of formula V and / or VI). In certain embodiments, the conjugate is a conjugate of formula I, II, IIA, or IIB. In addition, such pharmaceutical compositions may comprise other active agents. The additional active agents included may be selected based on the disease or condition to be treated.

[0224] Pharmaceutical compositions of the disclosure may include one or more conjugates or compounds of the disclosure (e.g., compounds of Formula V and / or VI), alone or in combination with additional active agents, in combination with a pharma- ceutically acceptable carrier.

[0225] The conjugates of the present disclosure and pharmaceutical compositions comprising such conjugates or compounds (e.g., compounds of formula V and / or VI) can be administered by any conventional method available for use with pharmaceutical agents, either as individual therapeutic agents or in combination with additional therapeutic agents. Those skilled in the art will understand that suitable methods of administering the conjugates of the present disclosure, either alone or in pharmaceutical formulations, to a patient are available, and that although multiple routes can be used, certain routes may provide a more rapid and effective response than other routes.

[0226] In one embodiment, the conjugates or compounds of the present disclosure (e.g., compounds of formula V and / or VI), whether alone or as part of a pharmaceutical composition, are administered in a therapeutically effective amount. The therapeutically effective amount and the dose administered will, of course, vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its method and route of administration, the age, health and weight of the recipient, the severity and stage of the disease state or condition, type of concurrent therapy, frequency of treatment, and the desired effect.

[0227] The total amount of the conjugate or compound (e.g., compound of formula V and / or VI) administered, whether alone or as part of a pharmaceutical composition, will also depend on the route, timing, and frequency of administration, as well as the existence, nature, and extent of any adverse side effects that may accompany the administration of the conjugate or compound, and the desired physiological effect. Those skilled in the art will appreciate that various conditions or medical conditions, particularly chronic conditions or medical conditions, may require long-term treatment, including multiple administrations.

[0228] In one embodiment of the pharmaceutical composition, the conjugate(s) or compound(s) of the present disclosure (e.g., compounds of formula V and / or VI) are typically present in an amount of about 0.5-95% by weight based on the total weight of the composition. Multiple dosage forms may be administered as part of a single treatment.

[0229] The conjugates or compounds of the present disclosure (e.g., compounds of formula V and / or VI), alone or as part of a pharmaceutical composition, can be administered enterally in solid dosage forms, such as capsules, tablets, and powders, or liquid dosage forms, such as milks, elixirs, syrups, and suspensions. The conjugates or compounds of the present disclosure (e.g., compounds of formula V and / or VI), alone or as part of a pharmaceutical composition, can also be administered parenterally, in sterile liquid dosage forms, intranasally (nose drops) or by inhalation via the pulmonary system, for example, by a propellant-based metered-dose inhaler or dry powder inhalation device. Other dosage forms include topical administration, for example, transdermal administration via a patch mechanism or ointment.

[0230] Formulations suitable for enteral or oral administration may be liquid solutions, such as those in which a therapeutically effective amount of the conjugate or compound (e.g., a compound of formula V and / or VI) is dissolved in a diluent, such as milk, water, saline, buffer, infant formula, other suitable carrier, or a combination thereof. The conjugate or compound may then be mixed with the diluent immediately prior to administration. In alternative embodiments, formulations suitable for enteral or oral administration may be capsules, sachets, tablets, lozenges, and pastilles. In each embodiment, the formulation may include a predetermined amount of the conjugate or compound of the present disclosure as a solid or granule, powder, suspension, and suitable emulsion. Liquid formulations may include diluents, such as water and alcohol, such as ethanol, benzyl alcohol, propylene glycol, glycerin, and polyethylene alcohol, with or without the addition of a pharma- ceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms may be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms may contain one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, as well as other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavorings, and pharmacologically compatible carriers.

[0231] Lozenge forms can contain conjugates in a flavoring, usually sucrose and acacia or tragacanth; pastilles contain the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels which contain, in addition to the active ingredient, such carriers as are known in the art.

[0232] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the patient's blood, and aqueous and non-aqueous sterile suspensions which may contain suspending agents, solubilizing agents, thickening agents, stabilizers, and preservatives. The conjugates or compounds can be administered alone or as part of a pharmaceutical composition in a physiologically acceptable diluent, a pharma- ceutically acceptable carrier, for example, a sterile liquid or mixture of liquids, i.e., water, saline, aqueous dextrose and related sugar solutions, alcohols, for example, ethanol, isopropanol, or hexadecyl alcohol, glycols, for example, propylene glycol or polyethylene glycols, for example, poly(ethylene glycol) 400, glycerol ketals, for example, 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides, with or without the addition of a pharma- ceutically acceptable surfactant, for example, a soap or detergent, a suspending agent, for example, pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifiers and other pharmaceutical adjuvants.

[0233] The oil that can be used in parenteral formulations includes mineral oil, animal oil, vegetable oil, or synthetic oil.Specific examples of oil include peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil.The fatty acid suitable for use in parenteral formulations includes oleic acid, stearic acid, and isostearic acid.Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Soaps suitable for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include: (a) cationic detergents, such as dimethyldialkylammonium halides, and alkylpyridinium halides; (b) anionic detergents, such as alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; (c) nonionic detergents, such as fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers; (d) amphoteric detergents, such as alkyl beta-aminopropionates, and 2-alkylimidazoline quaternary ammonium salts; and (e) mixtures thereof.

[0234] Parenteral formulations usually contain about 0.5% to about 50% by weight of the conjugate or compound in solution. Suitable preservatives and buffers may be used in such formulations. To minimize or eliminate irritation at the injection site, such compositions may contain one or more non-ionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations is about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and the high molecular weight adducts of ethylene oxide with hydrophobic bases formed by the condensation of propylene oxide and propylene glycol. EXAMPLES

[0235] The following examples provide a description of the methods for preparing the conjugates and compounds of the present disclosure, using polyoxazoline as an exemplary polymer and apomorphine as an exemplary compound containing a catechol moiety. The polymer conjugates are shown to include two different linkages of the compound to the polymer moiety as a result of a particular synthesis method of the compound with the necessary linkage and blocking group (i.e., in the case of apomorphine, the compound is shown to be linked to the polymer moiety via a linkage between both hydroxyl groups at the 10th and 11th positions). For example, in Example 4, apomorphine-10,11-[(4'-azidobutyrate)(isobutyrate)] hydrochloride is synthesized with a linkage group and an isobutyrate blocking group, where in compound 3a, the linkage group is at the 10th position of the apomorphine molecule and the blocking group is at the 11th position (reversed in compound 3b). By conjugating compounds 3a and 3b to the polymer moiety (see Example 7), apomorphine is linked to the polymer moiety through the hydroxyl groups at both positions 10 and 11. However, if a particular form of a compound (e.g., either 3a or 3b) is desired, these compounds can be separated using conventional techniques (e.g., chromatography). The following examples also provide methods for analyzing these conjugates and measuring the hydrolysis rates of these conjugates in human plasma.

[0236] material Apomorphine hydrochloride was obtained from Johnson Matthey. POZ 10p-acid 20K and 4-azidobutyryl chloride were synthesized by Serina Therapeutics, Inc. Butyryl chloride, isobutyl chloride, benzoyl chloride, and triethylamine (TEA) were purchased from Sigma-Aldrich. Trifluoroacetic acid (TFA), hydrochloric acid (HCl), anhydrous sodium sulfate, dichloromethane (DCM), acetonitrile (ACN), and diethyl ether were purchased from EMD Millipore. L(+)-ascorbic acid sodium salt, copper sulfate pentahydrate (CuSO4·5H2O), and sodium chloride (NaCl) were purchased from Fluka. Dimethyl sulfoxide (DMSO) was purchased from Acros Organics. Ambersep M4195 (or Dowex M4195) was purchased from Supelco. SNAP Ultra C18 30 g columns and the Isolera System for column purification were from Biotage.

[0237] Example 1 - Synthesis of apomorphine mono-(4'-azidobutyrate) hydrochloride. [ka] Apomorphine hydrochloride (4.00 grams, 12.72 mmol, 1 equiv.) was weighed into a 500 mL RB flask containing 385 mL of DCM. Triethylamine (3.546 mL, 25.44 mmol, 2 equiv.) was added under argon, followed by a solution of 4-azidobutyryl chloride (1.877 grams, 12.72 mmol, 1 equiv.) in 15 mL of DCM to the reaction mixture. The solution was stirred at room temperature under argon for 30 minutes, after which the solution was washed with 0.1 N HCl (1271 mL). After phase separation, NaCl (147 grams) was added to the aqueous phase, which was extracted with DCM (3×200 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (200 grams). After filtration to remove sodium sulfate, the filtrate was evaporated to dryness. The residue was further dried in vacuum to give 2.90 grams of off-white crude product. Reverse phase HPLC analysis of the crude product showed 97.8% apomorphine mono-(4'-azidobutyrate) hydrochloride. The crude product was purified on a Biotage Isolera System using a Biotage SNAP Ultra C18 30 g column with 2 mM HCl and ACN as the mobile phase. After column purification, the ACN of the product fraction was evaporated and NaCl was added to the remaining aqueous solution to make 15% brine. The solution was extracted with DCM (4 x 200 mL). The DCM phase was dried with anhydrous sodium sulfate (150 grams). After filtration, the filtrate was concentrated to dryness by rotary evaporation and further dried in vacuum overnight to give 2.65 grams of a light gray solid (1a + 1b, 50% yield). Purity by HPLC was >99.9%.

[0238] Example 2 - Synthesis of Apomorphine-10,11-[(4'-azidobutyrate)(butyrate)] Hydrochloride [ka] Apomorphine-(4'-azidobutyrate) hydrochloride (1a+1b, 0.40 grams, 0.964 mmol) was weighed into a 100 mL round bottom flask containing anhydrous DCM (40 mL). Under argon, trifluoroacetic acid (4 mL) was added to the solution followed by butyryl chloride (1.00 mL, 9.64 mmol, 10 equiv). The solution was stirred overnight at room temperature under argon. Reverse phase HPLC analysis of the reaction mixture indicated that the reaction had proceeded to completion. The solution was evaporated to dryness and the remaining syrup was dissolved in DCM (100 mL) and washed with deionized water (200 mL) followed by 0.1 N HCl (200 mL). The DCM phase was dried over anhydrous sodium sulfate (40 grams) and then filtered. The filtrate was evaporated to dryness. The residue was further dried in vacuum to give 0.58 grams of an amber waxy solid (2a+2b).

[0239] Example 3 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(isobutyrate)] hydrochloride [ka]

[0240] Example 4 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(isobutyrate)] hydrochloride [ka] Apomorphine-(4'-azidobutyrate) hydrochloride (1a+1b, 0.10 grams, 0.241 mmol) was weighed into a 25 mL round bottom flask containing anhydrous DCM (10 mL). Under argon, trifluoroacetic acid (1 mL) was added followed by isobutyryl chloride (0.25 mL, 2.41 mmol, 10 equiv). The solution was stirred overnight at room temperature under argon and then evaporated to dryness. The remaining syrup was dissolved in DCM (25 mL) and washed with 0.1 N HCl (50 mL). The DCM phase was dried over anhydrous sodium sulfate (10 grams) and filtered. The filtrate was evaporated to dryness and further dried under vacuum to give 0.12 grams of an amber residue (3a+3b). HPLC analysis of the product showed 100% purity. Apomorphine-(4'-azidobutyrate) hydrochloride (1a+1b, 0.50 grams, 1.205 mmol) was weighed into a 100 mL round bottom flask containing anhydrous DCM (50 mL). Triethylamine (0.34 mL, 2.410 mmol, 2 equiv.) was added under argon, followed by isobutyryl chloride (0.155 mL, 1.446 mmol, 1.2 equiv.). The solution was stirred overnight at room temperature under argon. The solution was then washed twice with 0.1 N HCl (145 mL). The DCM phase was dried over anhydrous sodium sulfate (25 grams) and then filtered. The filtrate was evaporated to dryness. Further drying under vacuum gave 0.49 grams of an amber residue (3a+3b). HPLC analysis of the product indicated 99.4% purity.

[0241] Example 5 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(benzoate)] hydrochloride [ka] Apomorphine-(4'-azidobutyrate) hydrochloride (1a+1b, 0.50 grams, 1.205 mmol) was weighed into a 100 mL round bottom flask containing anhydrous DCM (50 mL). Triethylamine (0.34 mL, 2.410 mmol, 2 equiv.) was added under argon, followed by benzoyl chloride (0.168 mL, 1.446 mmol, 1.2 equiv.). The solution was stirred overnight at room temperature under argon. After 30 minutes of reaction, the solution was washed twice with 0.1 N HCl (145 mL). The DCM phase was dried over anhydrous sodium sulfate (25 grams) and then filtered. The filtrate was evaporated to dryness. Further drying under vacuum gave 0.55 grams of an amber residue (4a+4b). HPLC analysis of the product indicated 97.7% purity.

[0242] Example 6 - POZ10p20k [apo(4-butanoate)(4-triazolebutanoate)] via click reaction 10 Synthesis of (5) Apomorphine-10,11-[(4'-azidobutyrate)(butyrate)] hydrochloride (2a+2b, 0.10 grams, 0.21 mmol, 11.6 equiv.) and POZ 10p-acid 20K (0.37 grams, 0.018 mmol, 1 equiv.) were dissolved in DMSO (10 mL) and deionized water (5 mL) in a 50 mL round bottom flask. Under argon, Na ascorbate (0.017 grams, 0.085 mmol, 4.64 equiv.) was then added to the flask, followed immediately by CuSO4·5H2O (0.021 grams, 0.085 mmol, 4.64 equiv.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl containing 10 wt% NaCl (150 mL) and extracted twice with DCM (50 mL). The DCM phase was evaporated to dryness and the residue was dissolved in 2 mM HCl (10 mL). The aqueous solution was passed through Ambersep M4195 media packed in a glass column to remove copper. The column was eluted with 2 mM HCl (50 mL). NaCl (9 grams) was added to the collected eluent (60 mL) and the cloudy solution was extracted with DCM (2×50 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (30 grams). After filtration to remove sodium sulfate, the filtrate was concentrated to near dryness by rotary evaporation. The residue was dissolved in DCM (4 mL) and precipitated in diethyl ether (60 mL). The precipitate was collected after filtration and dried in vacuum to give 0.39 grams of a white powder (POZ10p20k [apo(4-butanoate)(4-triazolebutanoate)] 10 , 5, to obtain POZ-apomorphine A). [ka]

[0243] Example 7 - POZ10p20k [apo(4-methylpropanoate)(4-triazolebutanoate)] via click reaction 10 Synthesis of (6) Apomorphine-10,11-[(4'-azidobutyrate)(isobutyrate)] hydrochloride (3a+3b, 0.086 grams, 0.178 mmol, 11.6 equiv.) and POZ 10p-acid 20K (0.31 grams, 0.015 mmol, 1 equiv.) were dissolved in DMSO (8 mL) and deionized water (4 mL) in a 50 mL round bottom flask. Under argon, Na ascorbate (0.014 grams, 0.071 mmol, 4.64 equiv.) was then added to the flask, followed immediately by CuSO4·5H2O (0.018 grams, 0.071 mmol, 4.64 equiv.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl containing 10 wt% NaCl (150 mL) and extracted twice with DCM (50 mL). The DCM phase was evaporated to dryness and the residue was dissolved in 2 mM HCl (10 mL). The aqueous solution was passed through Ambersep M4195 media packed in a glass column to remove copper. The column was eluted with 2 mM HCl (40 mL). NaCl (7.5 grams) was added to the collected eluent (50 mL) and the cloudy solution was extracted with DCM (2×50 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (30 grams). After filtration to remove sodium sulfate, the filtrate was concentrated to near dryness by rotary evaporation. The residue was dissolved in DCM (4 mL) and precipitated in diethyl ether (50 mL). The precipitate was collected after filtration and dried in vacuum to give 0.36 grams of a white powder (POZ10p20k [apo(4-methylpropanoate)(4-triazolebutanoate)] 10 , 6, to obtain POZ-apomorphine B). [ka]

[0244] Example 8 - POZ10p20k [apo(4-butanoate)(4-triazolebutanoate)] via click reaction 10 Synthesis of (7) Apomorphine-10,11-[(4'-azidobutyrate)(benzoate)] hydrochloride (4a+4b, 0.129 grams, 0.238 mmol, 11.6 equiv.) and POZ 10p-acid 20K (0.42 grams, 0.021 mmol, 1 equiv.) were dissolved in DMSO (10 mL) and deionized water (5 mL) in a 50 mL round bottom flask. Under argon, Na ascorbate (0.019 grams, 0.095 mmol, 4.64 equiv.) was then added to the flask, followed immediately by CuSO4·5H2O (0.024 grams, 0.095 mmol, 4.64 equiv.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl containing 10 wt% NaCl (150 mL) and extracted twice with DCM (50 mL). The DCM phase was evaporated to dryness and the residue was dissolved in 2 mM HCl (10 mL). Copper in the aqueous solution was removed by passing it through Ambersep M4195 media packed in a glass column. The column was eluted with 2 mM HCl. NaCl (11.3 grams) was added to the collected eluent (75 mL) and the cloudy solution was extracted with DCM (2×50 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (50 grams). After filtration to remove sodium sulfate, the filtrate was concentrated to near dryness by rotary evaporation. The residue was dissolved in DCM (5 mL) and precipitated in diethyl ether (50 mL). The precipitate was collected after filtration and dried in vacuum to give 0.5 grams of a white powder (POZ10p20k [apo(4-benzoate)(4-triazolebutanoate)] 10 , 7, POZ-apomorphine C) was obtained. [ka]

[0245] Example 9 - POZ10p20k [apo(4-triazole-4-butanoate)] via click reaction 10 Synthesis of (8) Apomorphine-(4'-azidobutyrate) hydrochloride (1a+1b, 0.069 grams, 0.166 mmol, 11.3 equiv.) and POZ 10p-acid 20K (0.30 grams, 0.0146 mmol, 1 equiv.) were dissolved in deionized water (10 mL) in a 50 mL round bottom flask. Under an argon atmosphere, Na ascorbate (0.013 grams, 0.066 mmol, 4.54 equiv.) was then added to the flask, followed immediately by CuSO4·5H2O (0.017 grams, 0.066 mmol, 4.54 equiv.). The solution was then stirred overnight at room temperature under an argon atmosphere. Copper in the aqueous solution was removed by passing the solution through Ambersep M4195 media packed in a glass column. The column was eluted with 2 mM HCl. NaCl (7.5 grams) was added to the collected eluent (75 mL) and the cloudy solution was extracted with DCM (4 x 20 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (30 grams). After filtration to remove sodium sulfate, the filtrate was concentrated to near dryness by rotary evaporation. The residue was dissolved in DCM (5 mL) and precipitated in diethyl ether (60 mL). The precipitate was collected after filtration, dried in vacuum and gave 0.3 grams of a white powder (POZ10p20k [apo(4-triazole-4-butanoate)] 10 , 8, POZ-apomorphine F) was obtained. [ka]

[0246] Example 10 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(acetate)] hydrochloride [ka] Apomorphine-(4'-azidobutyrate) hydrochloride (1a+1b, 0.18 grams, 0.434 mmol) was weighed into a 50 mL round bottom flask containing anhydrous DCM (20 mL). Triethylamine (0.12 mL, 0.868 mmol, 2 equiv.) was added under argon, followed by acetyl chloride (0.035 mL, 0.477 mmol, 1.1 equiv.). The solution was stirred at room temperature under argon for 30 minutes. The solution was then washed twice with 0.1 N HCl (87 mL). The DCM phase was dried over anhydrous sodium sulfate (10 grams) and then filtered. The filtrate was evaporated to dryness. Further drying under vacuum gave 0.13 grams of an off-white residue (9a+9b). HPLC analysis of the product indicated a purity of 99.8%.

[0247] Example 11 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(propionate)] hydrochloride [ka] Apomorphine-(4'-azidobutyrate) hydrochloride (1a+1b, 0.20 grams, 0.482 mmol) was weighed into a 50 mL round bottom flask containing anhydrous DCM (20 mL). Triethylamine (0.13 mL, 0.964 mmol, 2 eq.) was added under argon, followed by propionyl chloride (0.047 mL, 0.530 mmol, 1.1 eq.). The solution was stirred at room temperature under argon for 30 minutes. The solution was then washed twice with 0.1 N HCl (96 mL). The DCM phase was dried over anhydrous sodium sulfate (10 grams) and then filtered. The filtrate was evaporated to dryness. Further drying under vacuum gave 0.19 grams of an off-white residue (6a+6b). HPLC analysis of the product indicated a purity of 98.8%.

[0248] Example 12 - POZ10p20k [apo(acetate)(4-triazolebutanoate)] via click reaction 10 Synthesis of (11) Apomorphine-10,11-[(4'-azidobutyrate)(acetate)] hydrochloride (9a+9b, 0.13 grams, 0.27 mmol, 11.6 equiv.) and POZ 10p-acid 20K (0.48 grams, 0.024 mmol, 1 equiv.) were dissolved in DMSO (8 mL) and deionized water (4 mL) in a 50 mL round bottom flask. Under argon, Na ascorbate (0.022 grams, 0.110 mmol, 4.66 equiv.) was then added to the flask, followed immediately by CuSO4·5H2O (0.027 grams, 0.110 mmol, 4.66 equiv.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl containing 10 wt% NaCl (84 mL) and extracted twice with DCM (30 mL). The DCM phase was evaporated to dryness and the residue was dissolved in 2 mM HCl (10 mL). The aqueous solution was passed through Ambersep M4195 media packed in a glass column to remove copper. The column was eluted with 2 mM HCl (90 mL). NaCl (10 grams) was added to the collected eluent (100 mL) and the cloudy solution was extracted with DCM (2×40 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (40 grams). After filtration to remove sodium sulfate, the filtrate was concentrated to near dryness by rotary evaporation. The residue was dissolved in DCM (5 mL) and precipitated in diethyl ether (55 mL). The precipitate was collected after filtration and dried in vacuum to give 0.44 grams of a white powder (POZ10p20k [apo(acetate)(4-triazolebutanoate)] 10 , 11, POZ-apomorphine D) was obtained. [ka]

[0249] Example 13 - POZ10p20k [apo(propionate)(4-triazolebutanoate)] via click reaction 10 Synthesis of (12) Apomorphine-10,11-[(4'-azidobutyrate)(propionate)] hydrochloride (10a+10b, 0.19 grams, 0.39 mmol, 11.7 equiv.) and POZ 10p-acid 20K (0.68 grams, 0.033 mmol, 1 equiv.) were dissolved in DMSO (11 mL) and deionized water (5.5 mL) in a 50 mL round bottom flask. Under argon, Na ascorbate (0.031 grams, 0.156 mmol, 4.66 equiv.) was then added to the flask, followed immediately by CuSO4·5H2O (0.039 grams, 0.156 mmol, 4.66 equiv.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl containing 10 wt% NaCl (120 mL) and extracted twice with DCM (40 mL). The DCM phase was evaporated to dryness and the residue was dissolved in 2 mM HCl (14 mL). The aqueous solution was passed through Ambersep M4195 media packed in a glass column to remove copper. The column was eluted with 2 mM HCl. NaCl (11 grams) was added to the collected eluent (110 mL) and the cloudy solution was extracted with DCM (2×40 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (40 grams). After filtration to remove sodium sulfate, the filtrate was concentrated to near dryness by rotary evaporation. The residue was dissolved in DCM (7 mL) and precipitated in diethyl ether (76 mL). The precipitate was collected after filtration and dried in vacuum to give 0.70 grams of a white powder (POZ10p20k [apo(propionate)(4-triazolebutanoate)] 10 , 12, POZ-apomorphine E) was obtained. [ka]

[0250] Example 14 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(mono-ethylsuccinate)] hydrochloride [ka] Apomorphine-(4'-azidobutyrate) hydrochloride (1a+1b, 0.60 grams, 1.446 mmol) was weighed into a 100 mL round bottom flask containing anhydrous DCM (60 mL). Triethylamine (0.40 mL, 2.892 mmol, 2 eq.) was added under argon, followed by ethyl 4-chloro-4-oxobutanoate (0.31 grams, 1.591 mmol, 1.1 eq.) in 2 mL of anhydrous DCM. The solution was stirred overnight at room temperature under argon. After 30 minutes of reaction, the solution was washed twice with 0.1 N HCl (289 mL). The DCM phase was dried over anhydrous sodium sulfate (30 grams) and filtered. The filtrate was evaporated to dryness and dried in vacuum to give 0.72 grams of solid (11a+11b). HPLC analysis of the product showed a purity of 99.8%.

[0251] Example 15 - POZ10p20k [apo(4'-triazolebutanoate)(mono-ethylsuccinate)] via click reaction 10 Synthesis of (13) Apomorphine-10,11-[(4'-azidobutyrate)(mono-ethylsuccinate)] hydrochloride (5a+5b, 0.34 grams, 0.631 mmol, 11.7 equiv.) and POZ 10p-acid 20K (1.1 grams, 0.054 mmol, 1 equiv.) were dissolved in DMSO (18 mL) and deionized water (9 mL) in a 50 mL round bottom flask. Under argon, Na ascorbate (0.05 grams, 0.253 mmol, 4.66 equiv.) was then added to the flask, followed immediately by CuSO4·5H2O (0.063 grams, 0.253 mmol, 4.66 equiv.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl containing 10 wt% NaCl (195 mL) and extracted twice with DCM (70 mL). The DCM phase was evaporated to dryness and the residue was dissolved in 2 mM HCl (22 mL). The aqueous solution was passed through Ambersep M4195 media packed in a glass column to remove copper. The column was eluted with 2 mM HCl (160 mL). NaCl (18 grams) was added to the collected eluent (182 mL) and the cloudy solution was extracted with DCM (2×100 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (30 grams). After filtration to remove sodium sulfate, the filtrate was concentrated to near dryness by rotary evaporation. The residue was dissolved in DCM (12 mL) and precipitated in diethyl ether (124 mL). The precipitate was collected after filtration and dried in vacuum to give 1.16 grams of a white powder (POZ10p20k [apo(4'-triazolebutanoate)(mono-ethylsuccinate)] 10 , 13, POZ-apomorphine G) was obtained. [ka]

[0252] Example 16 - Random H-[(Ptyn) 10 (EOZ) 190 Exemplary synthesis of ]-T-CO2H (POZ10p20k) [ka] The synthesis of POZ polymers with various pendant groups is described in U.S. Patent Nos. 8,110,651 and 8,101,706, each of which is incorporated herein by reference for such disclosure. In a specific embodiment, H-[(Ptyn) 10 (EOZ) 190 The synthesis of POZ polymers having different molecular weights, different initiating and end groups, and different groups at the pendant positions may be prepared in the same manner. Furthermore, in addition to the random copolymers described in this example, block copolymers may be prepared. Methods for preparing random and block copolymers are described in U.S. Patent Nos. 8,110,651 and 8,101,706, each of which is incorporated herein by reference for such disclosure.

[0253] H-[(Ptyn) 10 (EOZ) 190 For the synthesis of ]-T-CO2H, triflic acid (HOTf, 173.3 μL, 1.96 mmol) was added to a solution of 2-pentynyl-2-oxazoline (PtynOZ, 3.76 g, 27.4 mmol, 14 equiv.) and 2-ethyl-2-oxazoline (EOZ, 46.61 g, 470.2 mmol, 240 equiv.) in chlorobenzene (124 mL). After stirring at room temperature for 5 min, the mixture was heated to 80 °C for 10 h and then cooled to room temperature. In a separate flask, the terminating reagent was prepared by adding methyl 3-mercaptopropionate (1.23 mL, 0.0114 mol) dropwise to a suspension of sodium hydride (60% in mineral oil, 0.272 g, 0.0068 mol) in chlorobenzene (34 mL). After stirring the mixture for 7 h, the living polymer H-(Ptyn) 10 (EOZ) 200 +A solution of was added. The resulting mixture was then stirred for 18 hours. The solvent was removed by rotary evaporation to give a white residue. The residue was dissolved in water and the pH was adjusted to 12.0. The resulting aqueous solution was purified by ion exchange chromatography using DEAE Sepharose FF. The aqueous solution was saturated with NaCl (15% w / w) and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated using a rotary evaporator. The residue was precipitated by adding the dichloromethane concentrate to diethyl ether. The precipitated material was collected and dried in vacuum to give 22.8 g of the desired product as a white powder (50% yield).

[0254] 1 H NMR (Varian, 500 MHz, 10 mg / mL CDCl3) showed the usual backbone peaks at 1.13 ppm (m, 3H, CH3CH2CO-), 2.32 ppm (m), and 2.41 (s) (total area 2H, CH3CH2CO-), and 3.47 ppm (m, 4H, -NCH2CH2N-). End group peaks appear at 2.63 ppm (m, 2H, -SCH2CH2CO2H), 2.74 ppm (m, 2H, -CH2SCH2CH2CO2H), and 2.85 ppm (m, 2H, -SCH2CH2CO2H). Pendant pentynyl group peaks appear at 1.85 ppm (m, 2H, -CH2CH2C≡CH) and 2.03 ppm (br s, 1H, -CH2CH2C≡CH). The number of pendant Ptyn groups was determined to be 8.5 by comparing the integrals of the terminal acetylene protons and the polymer backbone protons. GPC gave Mn=19,500 Da and Mp=20,800 Da with a PDI of 1.07.

[0255] Example 17 - Hydrolysis of POZ20K10p mono- and diesters of apomorphine in human plasma at 37°C Human female plasma was placed in a cryotube (BioIVT), thawed in a 37°C water bath, and gently mixed by inversion several times. The tube was then placed in an ice bath until use. The following POZ-apomorphine conjugates were examined in this example: POZ-apomorphine A (Example 6, drug loading 10.1% by weight), POZ-apomorphine B (Example 7, drug loading 10.3% by weight), POZ-apomorphine C (Example 8, drug loading 12.0% by weight), POZ-apomorphine D (Example 12, drug loading 10.2%), POZ-apomorphine E (Example 13, drug loading 10.2%), POZ-apomorphine F (Example 9, drug loading 14.2% by weight), and POZ-apomorphine G (Example 15, drug loading 10.7% by weight).

[0256] Approximately 50 mg of each POZ-apomorphine conjugate was weighed into a 5 mL volumetric flask and dissolved in 5% dextrose solution. In a biosafety laminar flow hood, 300 μL of this solution was added to 3 mL of chilled human female plasma. This was done in triplicate. After gently inverting the tube several times to mix the contents of the tube, an Eppendorf pipette was used to aliquot (200 μL) the plasma solution into separate screw-cap microcentrifuge tubes, and the samples were placed in a horizontal shaking water bath and incubated at 37°C.

[0257] At each time point, the tubes of plasma solution were quenched with 1000 μL of acetonitrile (ACN) containing 0.1% trifluoroacetic acid (TFA). The solution was vortexed to extract the POZ-apomorphine conjugate from the precipitated proteins. After centrifugation at 14000 RPM for 5 minutes, 500 μL of the supernatant was removed and added to 500 μL of purified water (HO) containing 0.1% TFA, and the mixture was then transferred to an HPLC vial.

[0258] The mixture was analyzed by the following HPLC method: Agilent 1260 diode array HPLC with Zorbax 300SB C-8 column (5mmx4.6x150mm). Mobile phase A: HO with 0.1% TFA, Mobile phase B: ACN with 0.1% TFA, Gradient: 0.0-7.5 min 32% B, 7.5-10.5 min 75% B, Run time: 12 min, Post time: 3 min, Flow rate: 1.8mL / min, Injection volume: 100μL, UV λmax: 274nm.

[0259] A calibration curve (concentration vs. peak area) of POZ20K10p-apomorphine in 5% dextrose was constructed. The concentration of the conjugate at each time point was calculated by integrating the peak area of ​​the conjugate at a retention time of 10.8 min.

[0260] The hydrolysis rate of apomorphine from each of the POZ-apomorphine conjugates was calculated using the rate of disappearance of that conjugate and is shown in FIG. 1. These values ​​were normalized to % release using the % drug loading of each compound. As shown in FIG. 1, the half-life of POZ-apomorphine F (lacking a blocking group at the second phenolic hydroxyl group) was calculated to be approximately 6 minutes. The addition of a blocking group to the second phenolic hydroxyl group increased the half-lives of POZ-apomorphine conjugates A, B, C, D, and E in a manner dependent on the structure of the blocking group. The half-life of each conjugate was as follows: 2 hours (POZ-apomorphine D), 6 hours (POZ-apomorphine E), 8 hours (POZ-apomorphine G), 9 hours (POZ-apomorphine A), 20 hours (POZ-apomorphine B), and 66 hours (POZ-apomorphine C). The length of the in vitro release half-life is benzoate>methylpropanoate>butanoate>ethylsuccinate>propionate>acetate>uncapped monoester. Figure 1 clearly shows that the release rate of apomorphine from the described POZ conjugates is dependent on the structure of the blocking group of the second phenolic hydroxyl group, and the release rate (release profile) can be selected based on the selection of the blocking group (blocking group structure) of the second phenolic hydroxyl group of the catechol moiety of apomorphine. Such a result is surprising and unexpected.

[0261] Example 18 - Pharmacokinetic studies of POZ-apomorphine conjugates and unconjugated free apomorphine In vivo pharmacokinetic studies of apomorphine HCl (hemihydrate) and the POZ-apomorphine conjugates of the present disclosure were conducted in primates to determine free (all test articles) and total (for the POZ-apomorphine conjugates) plasma apomorphine levels following a single subcutaneous (SC) injection (apomorphine HCl) and a single SC injection (POZ-apomorphine conjugates), as well as skin responses to each test article.

[0262] POZ-Apomorphine Conjugates The POZ-apomorphine conjugates used in this study were those described in Example 6 (POZ-apomorphine A) and Example 7 (POZ-apomorphine B).

[0263] Administration Non-naive female cynomolgus monkeys were used in this study. The animals had been treated with drugs for a minimum of 4 weeks in a previous study. One animal, C3503, had an 18-day washout period. They were assigned to three groups, three per group. Animals in group 1 received a single 12-hour SC infusion of apomorphine HCl at a dose of 1.5 mg / kg. Animals in groups 2 and 3 received a single SC injection of POZ-apomorphine A and POZ-apomorphine B conjugates at a dose of 1.5 mg / kg (based on apomorphine equivalents). The dosing schedule is shown in Table 1. [Table 1]

[0264] The test articles were administered subcutaneously to the right shoulder of each monkey (as described in Table 1). Animals were observed for signs of ill health, general side effects, inflammation at the injection site, and mortality in response to the treatments described herein.

[0265] Blood collection and plasma preparation All animals were dosed at 0 hours. Blood samples from group 1 were taken at 1, 2, 4, 8, 12, 18, 24 and 48 hours post-dose. Blood samples from groups 2 and 3 were taken at 1, 3, 6, 12, 24, 48, 72, 120, 168 and 240 hours post-dose.

[0266] Approximately 1.0 mL of blood was collected from each animal via the cephalic vein into tubes containing anticoagulant mixture NaF / Na2EDTA (25 μL, containing 60 mg / mL NaF and 120 mg / mL Na2EDTA) and 0.5 M sodium ascorbate solution (100 μL) on ice and processed to obtain plasma. The tubes were mixed by gentle wrist rotation and placed in an ice bath. Samples were centrifuged (3,000 RPM, 15 min, 2-8°C) within 20 min after collection. At least 500 μL of plasma was obtained at each time point in all groups. Two aliquots of at least 250 μL were obtained and processed as follows:

[0267] Aliquot 1 (used for analysis of free drug, groups 1, 2 and 3). Plasma was transferred to a sample tube and mixed gently. After mixing, the samples were frozen and stored at -70 to -80 °C before being transferred to the bioanalytical laboratory for measurement of free drug concentration.

[0268] Aliquot 2 (used for total drug analysis, groups 2 and 3 only). Plasma was transferred to a sample tube and mixed gently. After mixing, samples were frozen and stored at -70 to -80 °C before being transferred to the bioanalytical laboratory for measurement of total drug concentrations.

[0269] Sample analysis All plasma samples were analyzed for free apomorphine (for groups 2 and 3, this assay measured the amount of apomorphine released from the polymer) and groups 2 and 3 for total apomorphine (drug that remained bound to the polymer in addition to the released drug). Analysis was performed by liquid chromatography triple quadrupole mass spectrometry (LC-MS / MS) analysis. Using 30.0 μL plasma aliquots, the lower limit of quantification (LLOQ) for the free apomorphine assay in plasma was 0.1 ng / mL for animals in group 1 and 0.2 ng / mL for animals in groups 2 and 3. The LLOQ for the total apomorphine assay in plasma was 0.5 ng / mL for groups 2 and 3. The upper limit of quantification was 300 ng / mL for free apomorphine in plasma and 1000 ng / mL for total apomorphine in all groups.

[0270] The formulated dosing solutions were also examined for accuracy of test article concentration and dose.

[0271] observation All animals were weighed the day before dosing to determine the dose volume administered. During the study, cage observations were made twice daily (approximately 9:30 a.m. and 4:00 p.m.) to determine general health and appearance. A physical examination of the animals was performed before the start of the study to ensure their health. Additionally, the animals were observed before and after the first dose and at the time of each sample collection. General condition, behavior, activity, excretion, respiration or other abnormal observations noted throughout the study were recorded. A staff veterinarian or animal nurse evaluated the clinical observations of each animal.

[0272] The body weight of each non-naive female monkey at the start of the study is shown in Table 2. [Table 2]

[0273] Example 19 - POZ-apomorphine conjugates provide enhanced pharmacokinetic properties compared to unconjugated free apomorphine Pharmacokinetic analysis The plasma concentration-time profiles of free and total apomorphine were analyzed by a validated WinNonlin® program (Pharsight, version 6.3) using a non-compartmental model. Maximum plasma concentrations (C max ) and C max Time to reach (T max ) were obtained from the plasma concentration versus time profiles. To access how drug loading (% w / w) affects the pharmacokinetic profile, the area under the plasma concentration-time curve (AUC) from 0 to 168 hours post-dose (AUC 0-168 ) was identified as the treatment phase, and the AUC from time zero to the last observation time point (AUC 0-last) was similarly calculated using the linear up / log down trapezoidal rule (Gabrielsson et al., Non-compartmental analysis in “Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts & Applications”, 4th edition, Chapter 2.8., pages 161-180. Swedish Pharmaceutical Press; 2006).

[0274] T max and C max Values ​​were reported for each plasma concentration-time profile. Elimination half-life, t 1 / 2 Z scores were calculated and reported along with correlation coefficients for the excretion phase using at least three points.

[0275] To understand the difference in exposure of released drug relative to total drug in groups 2 and 3, the percentage of apomorphine released (PR) was calculated using the following formula: PR%=[AUC 0-last (Free) ÷ AUC 0-last (Total)] x 100. As there were no conditions with deviations in the sampling times, the nominal sampling times were used to calculate all parameters.

[0276] Pharmacokinetics of free apomorphine The pharmacokinetics of free apomorphine was investigated in female monkeys following a single SC injection of apomorphine HCl (1.5 mg / kg) and single SC injections of POZ-apomorphine A and POZ-apomorphine B conjugates at a dose of 1.5 mg / kg (based on apomorphine equivalents). The mean plasma concentrations of free apomorphine are shown in Figure 2 for each test article.

[0277] The calculated pharmacokinetic parameters of free apomorphine in plasma are shown in Table 3 (mean, SD for n=3). These parameters were max , T max , t 1 / 2z Vz / F, CL / F and AUC values ​​are infinity (AUC 0-inf ), 1 week (AUC 0-168 ) and until the last measurable time point (AUC 0-last ). [Table 3]

[0278] Inspection of the concentration-time plots (Figure 2) and calculated pharmacokinetic results (Table 3) shows clear differences between apomorphine HCl and the POZ-apomorphine A and POZ-apomorphine B conjugates. Free apomorphine concentrations (ng / mL) following a single 12-hour SC injection of 1.5 mg / kg apomorphine HCl were T max Shows the average C max The AUC is approximately 10.6 ng / mL. 0-last The value was calculated to be 89.8 h*ng / ml. After infusion, the drug was completely cleared, falling below the limit of quantification (BLQ) by 24 hours after infusion. The terminal half-life of apomorphine HCl was calculated to be 1.7 hours.

[0279] On the other hand, free apomorphine levels after SC injection of POZ-apomorphine A and POZ-apomorphine B conjugates show differences in the concentration-time profile for each conjugate. Free apomorphine concentrations (ng / mL) after a single SC injection of 1.5 mg / kg (apomorphine equivalent) of POZ-apomorphine A conjugate increased gradually over the first 3 days, with a mean T max and C max were 88 hours and 6.6 ng / mL, respectively. AUC 0-last The value was calculated to be 656 h*ng / ml. The drug was completely eliminated and became BLQ by 240 h after injection. Free apomorphine concentrations (ng / mL) after a single SC injection of 1.5 mg / kg (apomorphine equivalent) of POZ-apomorphine B conjugate gradually increased over the first 5 days, reaching a mean T max and C maxwere 104 h and 3.5 ng / mL, respectively. AUC 0-last The value was calculated to be 640 h*ng / ml. The drug is not cleared until 240 hours after injection. The terminal half-lives of apomorphine released from POZ-apomorphine A and B conjugates were 22.5 and 143.4 hours, respectively.

[0280] In vivo t determined for POZ-apomorphine A and B conjugates 1 / 2 z values ​​were determined for POZ-apomorphine A and B conjugates in an in vitro human plasma release assay. 1 / 2 The values ​​show the same trend, with the POZ-apomorphine A conjugate having a shorter half-life in each assay compared to the POZ-apomorphine B conjugate. This comparison shows that the in vitro plasma assay reliably predicts the half-life in the in vivo studies.

[0281] Pharmacokinetics of total apomorphine The pharmacokinetics of total apomorphine was investigated in female monkeys following a single SC injection at a dose of 1.5 mg / kg based on the apomorphine equivalent of POZ-apomorphine A and POZ-apomorphine B conjugates. The mean plasma concentrations of free apomorphine are shown in Figure 3 for each condition.

[0282] The calculated pharmacokinetic parameters of total apomorphine in plasma are shown in Table 4. These parameters are max , T max , t 1 / 2 z Vz / F, CL / F and AUC values ​​are infinity (AUC 0-inf ), 1 week (AUC 0-168 ) and until the last measurable time point (AUC 0-last ). [Table 4]

[0283] Examination of the concentration-time plots (Figure 3) and calculated pharmacokinetic results (Table 4) for the POZ-apomorphine A and POZ-apomorphine B conjugates at a dose of 1.5 mg / kg (apomorphine equivalents) reveals differences in their concentration-time profiles. Total drug levels of the POZ-apomorphine A conjugate increased gradually over the first 3 days, with a mean T max and C max were 88 hours and 151.3 ng / mL, respectively. AUC 0-las The value was calculated to be 13835 h*ng / ml. The drug was completely cleared at 240 h and reached BLQ. Total drug levels of POZ-apomorphine B conjugate increased gradually over the first 5 days, with a mean T max and C max were 107 hours and 72.6 ng / mL, respectively. AUC 0-last The value was calculated to be 11610 h*ng / ml. The drug is not cleared by 240 hours. The terminal half-lives of apomorphine released from POZ-apomorphine A and B conjugates were 20.9 and 106.9 hours, respectively.

[0284] The ratio of released apomorphine to total apomorphine is reported as percent apomorphine released (PR, calculated as described herein). The PR values ​​for POZ-apomorphine A and B conjugates were 4.8 and 5.5, respectively. The released and total apomorphine values ​​for Group 1 are the same (shown in Table 3).

[0285] Summary of Pharmacokinetic Data The pharmacokinetic profiles of released apomorphine and total apomorphine following a single SC injection of apomorphine HCl and single SC injections of POZ-apomorphine A and POZ-apomorphine B conjugates are summarized as follows:

[0286] Attachment of apomorphine to the POZ polymer allows for sustained delivery of apomorphine over a period of 5-10 days. maxThe values ​​were increased by 22-fold and 26-fold for the POZ-apomorphine A and POZ-apomorphine B conjugates, respectively, compared to apomorphine HCl. 1 / 2 z was increased 13.2- and 84.3-fold for the POZ-apomorphine A and POZ-apomorphine B conjugates, respectively, compared to apomorphine HCl.

[0287] Furthermore, the binding of apomorphine to the POZ polymer resulted in a higher C max was reduced from 10.6 ng / mL to 6.6 and 3.5 ng / mL for POZ-apomorphine A and POZ-apomorphine B, respectively. Furthermore, the AUC 0-last , drug exposure was increased by more than 7-fold when apomorphine was released from the POZ-apomorphine A and B conjugates. These data indicate that the total drug exposure of apomorphine was significantly increased when apomorphine was released from the POZ-apomorphine A and B conjugates.

[0288] These data show the surprising effect that the nature of the blocking group of the second phenolic hydroxyl group of the catechol moiety of apomorphine has on the release rate of apomorphine from the POZ conjugates. The POZ-apomorphine A conjugate provides a sustained release of apomorphine over a period of 5 days, and the POZ-apomorphine B conjugate provides a steady release of apomorphine over a period of 10 days. This result clearly demonstrates that the release rate of apomorphine from the described POZ conjugates can be controlled to provide a release rate (release profile) based on the selection of the blocking group of the second phenolic hydroxyl group of the catechol moiety of apomorphine.

[0289] Total apomorphine plasma levels reflect the released apomorphine levels in the concentration-time profile. The released-to-total apomorphine ratio (PR) was found to be 4.8-5.5%. There was no evidence of excessive release (burst effect) following administration of POZ-apomorphine A and B conjugates.

[0290] Example 20 - POZ-apomorphine conjugate did not cause skin irritation when administered by subcutaneous route Subcutaneous injection of apomorphine (Apo-Go, 10 mg / mL formulation) has been reported in the literature to produce red, irritating lumps (nodules). All animals were observed daily for these skin reactions. Photographs were taken to assess the severity of the reactions and observations were recorded. Based on the presence of erythema and swelling, skin reactions were scored as none, slight, well-defined, moderate, and severe.

[0291] Observation of skin reactions Visual observations for each test animal are summarized in Table 5. [Table 5] TIFF2025041852000095.tif155158

[0292] Figures 4A-C show the difference between group 1 animals (1502), group 2 animals (2502), and group 3 animals (3502) 5 days after injection. As shown in Figure 4A, animal 1502 shows wounds with yellow discharge at the injection site as well as redness and swelling, while animals 2502 and 3502 show no wounds, discharge, swelling or redness (Figures 4B and C, respectively).

[0293] In summary, animals in Group 1 had significant redness, swelling and yellow exudate at and around the injection site from days 1 through 7, whereas animals in Groups 2 and 3 had no skin reactions throughout the study.

[0294] These results demonstrated that POZ-apomorphine A and B conjugates were well tolerated in primates following SC injection.

[0295] Example 21 - POZ-apomorphine conjugates did not cause skin irritation when administered via the subcutaneous route after multiple doses were administered In vivo pharmacokinetic studies of the POZ-apomorphine conjugates of the present disclosure were conducted in primates to determine free (all test articles) and total (for POZ-apomorphine conjugates) plasma apomorphine levels following a single subcutaneous (SC) injection (apomorphine HCl) and a single SC injection (POZ-apomorphine conjugates), as well as skin responses to each test article.

[0296] POZ-Apomorphine Conjugates The POZ-apomorphine conjugates used in this study were those described in Example 6 (POZ-apomorphine A), Example 7 (POZ-apomorphine B) and Example 15 (POZ-apomorphine G).

[0297] Administration Non-naive female cynomolgus monkeys were used in this study. The animals had been at least 4 weeks since their last drug treatment in a previous study. They were assigned to three groups, three per group. Animals in groups 1, 2 and 3 received four weekly SC injections of POZ-apomorphine A, POZ-apomorphine B and POZ-apomorphine G conjugates at a dose of 3.0 mg / kg (based on apomorphine equivalents). The dosing schedule is shown in Table 6. [Table 6]

[0298] Test articles were administered subcutaneously to each monkey's right shoulder on days 0 and 14 and to the left shoulder on days 7 and 21 (as described in Table 6). Animals were observed for signs of ill health, general side effects, inflammation at the injection site, and mortality in response to treatments described herein and in Example 18. Photographs were taken to assess the severity of reactions and observations were recorded.

[0299] Blood collection and plasma preparation All animals were dosed at 0 hours. Blood samples from groups 1-3 were taken at 3, 6, 12, 24, 48, 72, 120, 168, 171, 174, 180, 192, 216, 240, 288, 336, 339, 342, 348, 360, 384, 408, 456, 504, 507, 510, 516, 528, 552, 576, 624, 672, 720, 768, 840, 888, 936, and 1008 hours after dosing. Blood samples were collected and processed as described in Example 18.

[0300] Sample analysis All plasma samples were analyzed for free apomorphine (this assay measures the amount of apomorphine released from the polymer) and total apomorphine (drug that remains bound to the polymer in addition to the drug released). The assays were performed as described in Example 18.

[0301] Pharmacokinetic analysis The plasma concentration-time profiles of free and total apomorphine are analyzed by a validated WinNonlin® program (Pharsight, version 6.3) using a non-compartmental model as described in Example 18.

[0302] observation All animals are weighed the day before dosing and the dose volume administered is determined and performed / will be carried out as described in Example 18.

[0303] Observation of skin reactions As discussed in Example 20, apomorphine (Apo-Go, 10 mg / mL formulation) has been reported to cause severe skin irritation following administration to humans. To determine whether Apo-A, Apo-B, and Apo-G conjugates induced skin reactions at a concentration of 3.0 mg / kg (compared to the 1.5 mg / kg dose described in Examples 18 and 20), all animals were / will be observed daily for these skin reactions. Photographs were taken to assess skin reactions and observations were / will be recorded. Based on the presence of erythema and swelling, skin reactions were / will be recorded as none, slight, clear, moderate, and severe.

[0304] After the third dose of Apo-A, Apo-B, and Apo-G conjugates (day 14), photographs were taken 12 hours after dosing. The skin at the injection site (referred to as the raised area) for each animal in groups 1-3 appeared normal, without signs of erythema and swelling. Figures 5A-C show the skin area for one animal from each group, 12 hours after the third dose, free of sores, discharge, swelling, or redness.

[0305] These results demonstrated that POZ-apomorphine A, B, and G conjugates were well tolerated in primates following SC injection at a dose of 3.0 mg / kg (based on apomorphine equivalents).

[0306] Further Aspects Further exemplary claims supported by this specification include, but are not limited to, the following: Aspect 1: A compound of formula V, or a pharma- ceutically acceptable salt thereof, [ka] During the ceremony, R 11 , R 12 , R 13 and R 14 are independently selected from H, OH, halogen, alkoxy, NO, unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl, substituted alkyl, heteroalkyl, alkenyl, or alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, heteroarylalkyl, substituted heteroarylalkyl, or adjacent to each other, R 11 , R 12 , R 13 and R 14 any two of may be taken together with the carbons to which they are attached to form an optionally substituted aryl, heteroaryl, or heterocyclyl ring; R 20and R 21 is H or a blocking group, and R 20 and R 21 The other is H, a group containing an active functional group, or a blocking group, while R 20 and R 21 and wherein both are not each H, the group that includes the active functional group comprises a first cleavable moiety, and the blocking group comprises a second cleavable moiety.

[0307] Aspect 2: R 20 and R 21 is the blocking group, and R 20 and R 21 the other of which is the group that contains the active functional group.

[0308] Aspect 3: The group containing the active functional group is R 24 -R 25 -R 26 and R 24 is -C(O)-, -OC(O)-, -C(O)-NH-cyclic-OC(O)-, -C(O)-NH-(CH)-OC(O)-, or -OP(O)(OR)(O)-; Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R9 is H or substituted or unsubstituted C1-C5 alkyl; R 25 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group; R 26 is an active functional group or a moiety that includes an active functional group capable of forming a bond with a group of the polymer.

[0309] Aspect 4: The compound of aspect 3, wherein the active functional group is an azide group or an alkyne group.

[0310] Aspect 5: R 24-R 25 -R 26 But N3-(CH2) 1-6 -C(O)-, [ka] N3-(CH2)3-C(O), or [ka] 4. The compound according to embodiment 3, wherein

[0311] Aspect 6: R 24 But R 20 or R 21 It forms a bond with the oxygen of R 24 and the O to which it is attached forms the first cleavable moiety.

[0312] Aspect 7: A compound according to aspect 2, which is a compound of formula VI, or a pharma- ceutically acceptable salt thereof, [ka] During the ceremony, R 19 is H, unsubstituted alkyl, alkenyl, or alkynyl, substituted alkyl, alkenyl, or alkynyl, benzyl, substituted benzyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinyl, or 1-aryltetrazolyl.

[0313] Aspect 8: R 19 is -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3, or [ka] 8. The compound of embodiment 7, wherein

[0314] Aspect 9: The group containing the active functional group is R 24 -R25 -R 26 and R 24 is -C(O)-, -OC(O)-, -C(O)-NH-cyclic-OC(O)-, -C(O)-NH-(CH)-OC(O)-, or -OP(O)(OR)(O)-; Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R9 is H or substituted or unsubstituted C1-C5 alkyl; R 25 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group; R 26 is an active functional group or a moiety that includes an active functional group capable of forming a bond with a group of the polymer.

[0315] Example 10: The compound of example 9, wherein the active functional group is an azide group or an alkyne group.

[0316] Aspect 11: R 24 -R 25 -R 26 But N3-(CH2) 1-6 -C(O)-, [ka] , N3-(CH2)3-C(O), or [ka] 10. The compound according to embodiment 9, wherein

[0317] Aspect 12: R 24 But R 20 or R 21 It forms a bond with one of the oxygen atoms of R 24 and the O to which it is attached forms the first cleavable moiety.

[0318] Aspect 13: The blocking group is -R 22 -R 23 and R 22 are -C(O)-, -C(O)-O-, -C(O)-NH-cyclic-OC(O)-, -C(O)-NH-(C6H4)-OC(O)-, CH3(CH2) 1-4 -OC(O)-(CH2) 1-4 -C(O)- or -OP(O)(OR9)-; Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R9 is H or substituted or unsubstituted C1-C5 alkyl; R 23 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

[0319] Aspect 14: R 22 But R 20 or R 21 It forms a bond with one of the oxygen atoms of R 22 and the O to which it is attached forms the second cleavable moiety.

[0320] Embodiment 15: The blocking group has the structure (CH3): y -(CH x )-(CH2) 0-6 -C(O)-, (CH3) y -(CH x )-C(O)-, CH3-(CH2) 0-6 -C(O)-, CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 - wherein when y is 1, then x is 2; or when y is 2, then x is 1; or when y is 3, then x is 0.

[0321] Embodiment 16: The blocking group has the structure CH3-C(O)-, CH3-(CH2)2-C(O)-, CH3-CH2-C(O)-, (CH3)2-CH-C(O)-, (CH3)3-CC(O)-, CH3CH2-OC(O)-CH2CH2-C(O)-, [ka] ,or [ka] 16. The compound according to any one of aspects 1 to 15, having the following structure:

[0322] Aspect 17: R 20 and R 21 each of which is said blocking group, or R 20 and R 21 is the blocking group, and R 20 and R 21 and the other is H.

[0323] Aspect 18: The blocking group is -R 22 -R 23 and R 22 are -C(O)-, -C(O)-O-, -C(O)-NH-cyclic-OC(O)-, -C(O)-NH-(C6H4)-OC(O)-, CH3(CH2) 1-4 -OC(O)-(CH2) 1-4 -C(O)- or -OP(O)(OR9)-; Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R9 is H or substituted or unsubstituted C1-C5 alkyl; R 23 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

[0324] Aspect 19: R 22But R 20 or R 21 It forms a bond with one or both oxygens of R 22 and the O to which it is attached forms the second cleavable moiety.

[0325] Embodiment 20: The blocking group has the structure (CH3): y -(CH x )-(CH2) 0-6 -C(O)-, (CH3) y -(CH x )-C(O)-, CH3-(CH2) 0-6 -C(O)-, CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 - when y is 1 then x is 2, or when y is 2 then x is 1, or when y is 3 then x is 0.

[0326] Embodiment 21: The blocking group has the structure CH3-C(O)-, CH3-(CH2)2-C(O)-, CH3-CH2-C(O)-, (CH3)2-CH-C(O)-, (CH3)3-CC(O)-, CH3CH2-OC(O)-CH2CH2-C(O)-, [ka] ,or [ka] The compound according to any one of aspects 17 to 19, or the compound according to aspect 81, having the following formula:

[0327] Aspect 22: A compound according to aspect 17, which is a compound of formula VI, or a pharma- ceutically acceptable salt thereof, [ka] During the ceremony, R 19is H, unsubstituted alkyl, alkenyl, or alkynyl, substituted alkyl, alkenyl, or alkynyl, benzyl, substituted benzyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinyl, or 1-aryltetrazolyl.

[0328] Aspect 23: R 19 is -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3, or [ka] 23. The compound according to embodiment 22, wherein

[0329] Aspect 24: The blocking group is -R 22 -R 23 and R 22 are -C(O)-, -C(O)-O-, -C(O)-NH-cyclic-OC(O)-, -C(O)-NH-(C6H4)-OC(O)-, CH3(CH2) 1-4 -OC(O)-(CH2) 1-4 -C(O)- or -OP(O)(OR9)-; Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R9 is H or substituted or unsubstituted C1-C5 alkyl; R 23 24. The compound according to any one of aspects 22 to 23, wherein is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

[0330] Aspect 25: R 22 But R 20 or R 21 It forms a bond with one or both oxygens of R 22and the O to which it is attached forms the second cleavable moiety.

[0331] Embodiment 26: The blocking group has the structure (CH3): y -(CH x )-(CH2) 0-6 -C(O)-, (CH3) y -(CH x )-C(O)-, CH3-(CH2) 0-6 -C(O)-, CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 - wherein when y is 1, then x is 2; or when y is 2, then x is 1; or when y is 3, then x is 0.

[0332] Embodiment 27: The blocking group has the structure CH3-C(O)-, CH3-(CH2)2-C(O)-, CH3-CH2-C(O)-, (CH3)2-CH-C(O)-, (CH3)3-CC(O)-, CH3CH2-OC(O)-CH2CH2-C(O)-, [ka] ,or [ka] 26. The compound according to any one of aspects 22 to 25, having the formula:

[0333] Aspect 28: A method for treating a dopamine-responsive disease or condition in a subject, the method comprising administering to the subject an amount of a compound of any one of aspects 1 to 27, wherein the agent is a dopamine agonist.

[0334] Aspect 29: The method of aspect 28, wherein said dopamine-responsive disease or condition is a hypodopaminergic state, a pituitary tumor (prolactinoma), Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, a hypodopaminergic state, SSRI-induced sexual dysfunction, depression, obesity, or type II diabetes.

[0335] Aspect 30: The method of aspect 28, wherein said dopamine responsive disease or condition is Parkinson's disease.

[0336] Aspect 31: The method of any one of aspects 28 to 30, wherein the dopamine agonist is apomorphine, albutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levopoda, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam.

Claims

1. A conjugate of formula I or a pharma- ceutically acceptable salt thereof, POL ｎ -(L-A) ｂ I During the ceremony, POL is a water soluble polymer, n represents the number of repeat units of the polymer and is 1 to 1000; b is 1 to 50, with the proviso that n is always greater than or equal to b; L is a bond that includes a first cleavable moiety that connects A and POL; The conjugate, wherein A is a compound comprising a catechol moiety, said catechol moiety comprising at least a first and a second phenolic hydroxyl group, wherein said compound is attached to said polymer via said first phenolic hydroxyl group and said second phenolic hydroxyl group is attached to a blocking group comprising a second cleavable moiety.

2. The conjugate of claim 1 , wherein the water-soluble polymer is a poly(oxazoline) polymer.

3. The conjugate of claim 1 , wherein the water-soluble polymer is a copolymer.

4. 2. The conjugate of claim 1, wherein the water-soluble polymer is a copolymer, the copolymer comprising 50% to 99.5% (based on the weight of all polymer components) of a poly(oxazoline) polymer.

5. The conjugate of any one of claims 1 to 4, wherein L is a direct bond or a linking group.

6. 6. The conjugate of any one of claims 1 to 5, wherein the first cleavable moiety and the second cleavable moiety are each independently an ester, a carboxylate bond (-C(O)-O-), a carbonate bond (-O-C(O)-O-), a carbamate bond (-O-C(O)-NH-), an amide bond (-C(O)-NH-), or a disulfide bond (S-S).

7. 6. The conjugate of any one of claims 1 to 5, wherein the first cleavable moiety is an ester bond, the second cleavable moiety is an ester bond, or both the first and second cleavable moieties are each an ester bond.

8. 8. The conjugate of claim 1, wherein a free hydroxyl group is generated upon cleavage of the first cleavable moiety at the first phenolic hydroxyl group of the catechol moiety.

9. 9. The conjugate of any one of claims 1 to 8, wherein a free hydroxyl group is generated upon cleavage of the second cleavable moiety at the second phenolic hydroxyl group of the catechol moiety.

10. The conjugate according to any one of claims 1 to 9, wherein the first cleavable moiety and the second cleavable moiety are the same.

11. The conjugate of any one of claims 1 to 10, wherein the release rate of the compound from the polymer is controlled, at least in part, by the structure of the blocking group.

12. 12. The conjugate of any one of claims 1 to 11, which delivers a therapeutically effective amount of the compound for a period of 24 to 168 hours.

13. 12. The conjugate of any one of claims 1 to 11, wherein the conjugate delivers a therapeutically effective amount of the compound for a period of 1 to 4 weeks.

14. 14. The conjugate according to any one of claims 1 to 13, wherein A is a compound of formula III or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, R １１ , R １２ , R １３ and R １４ are independently H, OH, halogen, alkoxy, NO ２ , unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl, substituted alkyl, heteroalkyl, alkenyl, or alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, heteroarylalkyl, substituted heteroarylalkyl, or adjacent to each other. １１ , R １２ , R １３ and R １４ any two of may be taken together with the carbons to which they are attached to form an optionally substituted aryl, heteroaryl, or heterocyclyl ring; R １５ Or R １６ One of the is L, R １５ Or R １６ the other of which is the blocking group.

15. The blocking group is -R １７ -R １８ and R １７ -C(O)-, -C(O)-O-, -C(O)-NH-cyclic -O-C(O)-, -C(O)-NH-(C ６ H ４ )-OC(O)-, CH ３ (CH ２ ) １－４ -O-C(O)-(CH ２ ) １－４ -C(O)- or -O-P(O)(OR ９ )(O)-, Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R ９ is H or substituted or unsubstituted C1-C5 alkyl; R １８ is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

16. R １７ forms a bond with the oxygen of the second phenolic hydroxyl group, and R １７ and the O to which it is attached form the second cleavable moiety.

17. 17. The conjugate of claim 16, wherein the second cleavable moiety is -C(O)-O.

18. The blocking group has the structure (CH ３ ) ｙ - (CH ｘ )-(CH ２ ) ０－６ -C(O)-, (CH ３ ) ｙ - (CH ｘ )-C(O)-, CH ３ - (CH ２ ) ０－６ -C(O)-, CH ３ - (CH ２ ) ０－６ -C(O)-(CH ２ ) ０－６ -, and when y is 1, x is 2, or when y is 2, x is 1, or when y is 3, x is 0.

19. The blocking group has the structure CH ３ -C(O)-, CH ３ - (CH ２ ) ２ -C(O)-, CH ３ -CH ２ -C(O)-, (CH ３ ) ２ -CH-C(O)-, (CH ３ ) ３ -C-C(O)-, CH ３ CH ２ -O-C(O)-CH ２ CH ２ -C(O)-, 【Chemistry 2】 15. The conjugate of claim 14, having the formula:

20. 15. The conjugate of claim 14, wherein the compound is arbutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levopoda, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam.

21. 14. The conjugate according to any one of claims 1 to 13, wherein the compound is a compound of formula IV or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】 During the ceremony, R １５ Or R １６ One of the is L, R １５ Or R １６ the other is the blocking group, R １９ is H, unsubstituted alkyl, alkenyl, or alkynyl, substituted alkyl, alkenyl, or alkynyl, benzyl, substituted benzyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinyl, or 1-aryltetrazolyl.

22. R １９ is -H, -CH ３ , -CH ２ -CH ３ , -CH ２ -CH ２ -CH ３ , -CH(CH ３ ) ２ -CH ２ -CH ２ -CH ２ -CH ３ , and 【Chemistry 4】 22. The conjugate of claim 21, selected from the group consisting of:

23. The blocking group is -R １７ -R １８ and R １７ -C(O)-, -C(O)-O-, -C(O)-NH-cyclic -O-C(O)-, -C(O)-NH-(C ６ H ４ )-OC(O)-, CH ３ (CH ２ ) １－４ -O-C(O)-(CH ２ ) １－４ -C(O)- or -O-P(O)(OR ９ )(O)-, Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R ９ is H or substituted or unsubstituted C1-C5 alkyl; R １８ 23. The conjugate of claim 22, wherein is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

24. R １７ forms a bond with the oxygen of the second phenolic hydroxyl group, and R １７ and the O to which it is attached form the second cleavable moiety.

25. 25. The conjugate of claim 24, wherein the second cleavable moiety is -C(O)-O.

26. The blocking group has the structure (CH ３ ) ｙ - (CH ｘ )-(CH ２ ) ０－６ -C(O)-, (CH ３ ) ｙ - (CH ｘ )-C(O)-, CH ３ - (CH ２ ) ０－６ -C(O)-, CH ３ - (CH ２ ) ０－６ -C(O)-(CH ２ ) ０－６ -, and when y is 1, x is 2, or when y is 2, x is 1, or when y is 3, x is 0.

27. The blocking group has the structure CH ３ -C(O)-, CH ３ - (CH ２ ) ２ -C(O)-, CH ３ -CH ２ -C(O)-, (CH ３ ) ２ -CH-C(O)-, (CH ３ ) ３ -C-C(O)-, CH ３ CH ２ -O-C(O)-CH ２ CH ２ -C(O)-, 【Chemistry 5】 22. The conjugate of claim 21 , having the formula:

28. 22. The conjugate of claim 21 , wherein the compound is apomorphine.

29. A conjugate of formula IIB or a pharma- ceutical acceptable salt thereof, 【Chemistry 6】 During the ceremony, R is an initiating group; L is a bond that includes a first cleavable moiety that connects A to the polymer; A is a compound comprising a catechol moiety, said catechol moiety comprising at least a first and a second phenolic hydroxyl group, said compound being attached to said polymer via said first phenolic hydroxyl group and said second phenolic hydroxyl group being attached to a blocking group comprising a second cleavable moiety; R １ is independently selected for each repeat unit from unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups; X is independently selected for each repeat unit from -L-A; Y is independently selected for each repeat unit from -L-A, a non-reactive pendant moiety, or a pendant moiety that includes an active functional group; a is ran indicating a random copolymer or block indicating a block copolymer; o1 is an integer from 1 to 50, The sum of o1 and o2 is equal to or less than 50, and o2 is between 0 and 49. n is an integer from 1 to 1000, The conjugate, wherein T is a terminal group.

30. 30. The conjugate of claim 29, wherein L is a direct bond or a linking group.

31. The linking group has the structure 【Chemistry 7】 31. The conjugate of claim 30, having the formula: R ３ is a linker attaching the triazole moiety to the polymer; R ４ is a linker that attaches the triazole moiety to the compound, the linker forming a bond with the first phenolic hydroxyl group of the compound.

32. R ３ HA -C(O)-R ５ - and R ５ is absent or is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl group; R ４ is -R ６ -R ７ -R ８ - and R ６ is a substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, or oligo(ethylene oxide); R ７ is -R ａ -C(O)-R ｂ -, -R ａ -O-C(O)-R ｂ -, -R ａ -C(O)-O-R ｂ , -R ａ -C(O)-NH-cyclic-O-C(O)-R ｂ , -R ａ -C(O)-NH-(C ６ H ４ )-O-C(O)-R ｂ , -R ａ -O-C(O)-NR １０ -R ｂ , -R ａ -CH(OH)-O-R ｂ , -R ａ -S-S-R ｂ , -R ａ -O-P(O)(OR １０ )-O-R ｂ , or -R ａ -C(O)-NR １０ -R ｂ - and Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R ８ is absent or is O, R １０ is H or substituted or unsubstituted C1-C5 alkyl; R ａ and R ｂ are each independently absent or substituted or unsubstituted alkyl; R ７ comprises at least a portion of the first cleavable moiety.

33. R ７ and R ８ The conjugate of claim 32, wherein:

34. R ６ is a straight chain substituted or unsubstituted C1-C4 alkyl or a branched substituted or unsubstituted C1-C4 alkyl; R ７ is —C(O)—O—, and R ８ The conjugate of claim 32, wherein is absent.

35. R ６ is a straight chain substituted or unsubstituted C1-C4 alkyl or a branched substituted or unsubstituted C1-C4 alkyl; R ７ is —C(O)—, and R ８ The conjugate of claim 32, wherein is -O- or absent.

36. R ３ is -C(O)-(CH ２ ) ３ and R ４ is -(CH ２ ) ｄ -C(O)-O-, -CH ２ -C(O)-O-, -CH ２ -CH ２ -C(O)-O-, -CH ２ -CH ２ -CH ２ -C(O)-O-, or -CH ２ (CH ３ 32. The conjugate of claim 31 , wherein:

37. R ３ is -C(O)-(CH ２ ) ３ and R ４ is -(CH ２ ) ｄ -C(O)-, -CH ２ -C(O)-, -CH ２ -CH ２ -C(O)-, -CH ２ -CH ２ -CH ２ -C(O)- or -CH ２ (CH ３ 32. The conjugate of claim 31 , wherein:

38. 38. The conjugate of any one of claims 29 to 37, wherein T is Z-B-Q, Z is S, O, or N, B is an optional linking group, and Q is a terminal nucleophile or part of a terminal nucleophile.

39. B is -(CH ２ ) １－１６ -, Z is S, and Q is -COOH, -COOCH ３ , -NH ２ or NH-tBoc.

40. R １ The conjugate of any one of claims 29 to 39, wherein is a C1-C4 unsubstituted alkyl or substituted alkyl.

41. 41. The conjugate of any one of claims 29 to 40, wherein the first cleavable moiety and the second cleavable moiety are each independently an ester bond, a carboxylate bond (-C(O)-O-), a carbonate bond (-O-C(O)-O-), a carbamate bond (-O-C(O)-NH-), an amide bond (-C(O)-NH-), or a disulfide bond (S-S).

42. 41. The conjugate of any one of claims 29 to 40, wherein the first cleavable moiety is an ester bond, the second cleavable moiety is an ester bond, or both the first and second cleavable moieties are each an ester bond.

43. 43. The conjugate of any one of claims 29 to 42, wherein a free hydroxyl group is generated upon cleavage of the first cleavable moiety at the first phenolic hydroxyl group of the catechol moiety.

44. 44. The conjugate of any one of claims 29 to 43, wherein a free hydroxyl group is generated upon cleavage of the second cleavable moiety at the second phenolic hydroxyl group of the catechol moiety.

45. The conjugate of any one of claims 29 to 44, wherein the first cleavable moiety and the second cleavable moiety are the same.

46. The conjugate of any one of claims 29 to 45, wherein the release rate of the compound from the polymer is controlled, at least in part, by the structure of the blocking group.

47. 47. The conjugate of any one of claims 29 to 46, wherein the conjugate delivers a therapeutically effective amount of the compound for a period of 24 to 168 hours.

48. 47. The conjugate of any one of claims 29 to 46, wherein the conjugate delivers a therapeutically effective amount of the compound for a period of 1 to 4 weeks.

49. 49. The conjugate of any one of claims 29 to 48, wherein A is a compound of formula III or a pharma- ceutically acceptable salt thereof: 【Chemistry 8】 During the ceremony, R １１ , R １２ , R １３ and R １４ are independently H, OH, halogen, alkoxy, NO ２ , unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl, substituted alkyl, heteroalkyl, alkenyl, or alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, heteroarylalkyl, substituted heteroarylalkyl, or adjacent to each other. １１ , R １２ , R １３ and R １４ any two of may be taken together with the carbons to which they are attached to form an optionally substituted aryl, heteroaryl, or heterocyclyl ring; R １５ Or R １６ One of the is L, R １５ Or R １６ the other of which is the blocking group.

50. R １６ Ga-R １７ -R １８ and R １７ -C(O)-, -C(O)-O-, -C(O)-NH-cyclic -O-C(O)-, -C(O)-NH-(C ６ H ４ )-OC(O)-, CH ３ (CH ２ ) １－４ -O-C(O)-(CH ２ ) １－４ -C(O)- or -O-P(O)(OR ９ )(O)-, Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R ９ is H or substituted or unsubstituted C1-C5 alkyl; R １８ is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

51. R １７ forms a bond with the oxygen of the second phenolic hydroxyl group, and R １７ and the O to which it is attached form the second cleavable moiety.

52. 52. The conjugate of claim 51 , wherein the second cleavable moiety is -C(O)-O.

53. The blocking group has the structure (CH ３ ) ｙ - (CH ｘ )-(CH ２ ) ０－６ -C(O)-, (CH ３ ) ｙ - (CH ｘ )-C(O)-, CH ３ - (CH ２ ) ０－６ -C(O)-, CH ３ - (CH ２ ) ０－６ -C(O)-(CH ２ ) ０－６ -, and when y is 1, x is 2, or when y is 2, x is 1, or when y is 3, x is 0.

54. The blocking group has the structure CH ３ -C(O)-, CH ３ - (CH ２ ) ２ -C(O)-, CH ３ -CH ２ -C(O)-, (CH ３ ) ２ -CH-C(O)-, (CH ３ ) ３ -C-C(O)-, CH ３ CH ２ -O-C(O)-CH ２ CH ２ -C(O)-, 【Chemistry 9】 50. The conjugate of claim 49, having the formula:

55. 50. The conjugate of claim 49, wherein the compound is arbutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levopoda, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam.

56. 49. The conjugate according to any one of claims 29 to 48, wherein the compound is a compound of formula IV or a pharma- ceutically acceptable salt thereof: 【Chemistry 10】 During the ceremony, R １５ Or R １６ One of the is L, R １５ Or R １６ the other is the blocking group, R １９ is H, unsubstituted alkyl, alkenyl, or alkynyl, substituted alkyl, alkenyl, or alkynyl, benzyl, substituted benzyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinyl, or 1-aryltetrazolyl.

57. R １９ is -H, -CH ３ , -CH ２ -CH ３ , -CH ２ -CH ２ -CH ３ , -CH(CH ３ ) ２ -CH ２ -CH ２ -CH ２ -CH ３ , and 【Chemistry 11】 57. The conjugate of claim 56, selected from the group consisting of:

58. The blocking group is -R １７ -R １８ and R １７ -C(O)-, -C(O)-O-, -C(O)-NH-cyclic -O-C(O)-, -C(O)-NH-(C ６ H ４ )-OC(O)-, CH ３ (CH ２ ) １－４ -O-C(O)-(CH ２ ) １－４ -C(O)- or -O-P(O)(OR ９ )(O)-, Cyclic represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclyl, or cycloalkyl; R ９ is H or substituted or unsubstituted C1-C5 alkyl; R １８ 58. The conjugate of claim 57, wherein is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl group.

59. R １７ forms a bond with the oxygen of the second phenolic hydroxyl group, and R １７ and the O to which it is attached form the second cleavable moiety.

60. 60. The conjugate of claim 59, wherein said second cleavable moiety is -C(O)-O.

61. The blocking group has the structure (CH ３ ) ｙ - (CH ｘ )-(CH ２ ) ０－６ -C(O)-, (CH ３ ) ｙ - (CH ｘ )-C(O)-, CH ３ - (CH ２ ) ０－６ -C(O)-, CH ３ - (CH ２ ) ０－６ -C(O)-(CH ２ ) ０－６ -, and when y is 1, x is 2, or when y is 2, x is 1, or when y is 3, x is 0.

62. The blocking group has the structure CH ３ -C(O)-, CH ３ - (CH ２ ) ２ -C(O)-, CH ３ -CH ２ -C(O)-, (CH ３ ) ２ -CH-C(O)-, (CH ３ ) ３ -C-C(O)-, CH ３ CH ２ -O-C(O)-CH ２ CH ２ -C(O)-, 【Chemistry 12】 57. The conjugate of claim 56, having the formula:

63. 57. The conjugate of claim 56, wherein the compound is apomorphine.

64. 57. The conjugate of claim 56, having the structure 【Chemistry 13】 The conjugate having the formula:

65. 65. A method of treating a dopamine responsive disease or condition in a subject, the method comprising administering to the subject an amount of a polymer conjugate of any one of claims 1 to 64, wherein the agent is a dopamine agonist.

66. 66. The method of claim 65, wherein the dopamine-responsive disease or condition is a hypodopaminergic state, Parkinson's disease, restless legs syndrome, pituitary tumor (prolactinoma), schizophrenia, attention deficit hyperactivity disorder, hypodopaminergic state, SSRI-induced sexual dysfunction, depression, obesity, or type II diabetes.

67. 66. The method of claim 65, wherein the dopamine responsive disease or condition is Parkinson's disease.

68. 68. The method of any one of claims 65 to 67, wherein the dopamine agonist is apomorphine, albutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levopoda, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam.

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