Cleavable conjugates of catechol compounds and water-soluble polymers and methods of treatment using same

Abstract

The present invention relates to cleavable conjugates of catechol compounds and water-soluble polymers and methods of treatment using the same. Described are conjugates comprising a water-soluble polymer linked via a cleavable linkage to a compound comprising a catechol moiety wherein the cleavable linkage is formed between the water-soluble polymer and a first phenolic hydroxyl group of the catechol moiety and a second phenolic hydroxyl group of the catechol moiety is linked to a blocking group, wherein the hydrolysis release rate of the compound comprising the catechol moiety is controlled at least in part by the structure or design of the blocking group on the second phenolic hydroxyl group of the catechol moiety. Thus, the hydrolysis release rate of the compound comprising the catechol moiety can be adjusted by the structural design of the group on the second phenolic hydroxyl group of the catechol moiety. Compounds useful in the synthesis of the conjugates and methods of using the conjugates and other compounds in the treatment of dopamine-responsive disorders are also described.

Description

[0001] This invention is a divisional application. The filing date of the original application is July 27, 2019, the application number is 201980063964.1, and the invention title is "Cleavable Conjugates of Catechol Compounds and Water-Soluble Polymers and Therapeutic Methods Using Them". Technical Field

[0002] The present disclosure generally relates to conjugates comprising a water-soluble polymer and a compound, wherein the compound is linked to the water-soluble polymer via a cleavable linkage. The present disclosure more specifically relates to conjugates comprising a water-soluble polymer and a compound comprising a catechol moiety, wherein the compound is linked to the water-soluble polymer via a cleavable linkage involving one of the two phenolic hydroxyl groups on the catechol moiety of the compound, and the release of the compound from the conjugate is at least partially controlled by the structure of the group of the other of the two phenolic hydroxyl groups on the catechol moiety of the compound. The present disclosure also relates to intermediates for the synthesis of such conjugates, compounds having a catechol moiety comprising at least one blocking group, and methods of using such conjugates and compounds for treating diseases and disorders, including but not limited to dopamine-responsive conditions. Background of the Invention

[0004] Compounds comprising a catechol moiety have been shown to have many beneficial properties and can be used to treat human diseases. A particular class of compounds comprising a catechol moiety are dopamine receptor agonists. A representative compound is apomorphine. Apomorphine and other dopamine agonists can be used to treat dopamine-responsive conditions, such as but not limited to Parkinson's disease.

[0005] Common early treatment for Parkinson's disease utilizes levodopa. However, due to the short-acting nature of levodopa (and other orally administered drugs used to treat Parkinson's disease), treatment with levodopa often results in motor complications and "on-off" periods. Subcutaneous apomorphine has been shown to be very effective in rapidly reversing these "off-periods", but apomorphine delivered in this way is only effective for a limited period of time because the in vivo half-life of apomorphine is very short.

[0006] Oral apomorphine is not effective because the oral bioavailability is only 1.7%, mainly due to hepatic first-pass metabolism. Oral delivery formulations for apomorphine have also been developed, but the formulation requires frequent use and may cause stomatitis and dental caries. Lipid-based prodrugs have also been shown to improve the in vivo half-life of the drug, but have not significantly improved the hydrolysis characteristics (e.g., due to hepatic metabolism).

[0007] The delivery period of apomorphine can be extended by using a microneedle pump patch (obtained under the Apo-Go brand in Europe). The use of the microneedle pump patch requires daily repositioning of the patch and the involvement of a healthcare professional. This method is clearly inconvenient at best and may be uncomfortable due to the use of the microneedle patch. Additionally, this method may cause skin burning, skin nodules, and skin infections in the user.

[0008] There is clearly a need to improve the delivery of compounds containing a catechol moiety (exemplified by apomorphine) for the treatment of diseases and disorders, including but not limited to dopamine-responsive conditions. The present disclosure addresses the problems in the art by providing compounds containing a catechol moiety, polymeric conjugates of compounds containing a catechol moiety, wherein the catechol moiety comprises at least one blocking group on the phenolic hydroxyl group of the catechol moiety, and the polymeric conjugates provide sustained pharmacokinetics, increased bioavailability, ease of administration, and / or reduced side effects upon administration to a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 Shows the hydrolysis rates 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; solid circles), Example 12 (Apo-D; solid squares), Example 13 (Apo-E; triangles), and Example 15 (Apo-G; open circles). Also shown is the calculated t 1 / 2 value for each POZ-apomorphine conjugate.

[0010] Figure 2 Shows the PK curves of free apomorphine after subcutaneous infusion of apomorphine HCl and subcutaneous injection of POZ-apomorphine A and POZ-apomorphine B in female monkeys.

[0011] Figure 3 Shows the PK curves of total apomorphine after subcutaneous infusion of apomorphine HCl and subcutaneous injection of POZ-apomorphine A and POZ-apomorphine B in female monkeys.

[0012] Figure 4A Shows a graphical representation of the skin reaction on day 5 after administration following a single subcutaneous administration (by slow infusion) of free apomorphine (Group 1, animal 1502).

[0013] Figure 4B Shows a graphical representation of the skin reaction on day 5 after administration following a single subcutaneous administration (by injection) of POZ-apomorphine A (Group 2, animal 2502).

[0014] Figure 4CShown is a graphic representation of skin reactions following a single subcutaneous administration (by injection) of POZ-apomorphine B (Group 3, Animal 3502) on day 5 post-administration.

[0015] Figure 5A A graphical representation of the skin response 12 hours after the third dose of POZ-apomorphine A (Group 1) was administered via subcutaneous administration (by injection) on Day 14 is shown.

[0016] Figure 5B A graphical representation of the skin response 12 hours after the third dose of POZ-apomorphine B (Group 2) was administered via subcutaneous administration (by injection) on Day 14 is shown.

[0017] Figure 5C A graphical representation of the skin response 12 hours after the third dose of POZ-apomorphine G (Group 3) was administered via subcutaneous administration (by injection) on Day 14 is shown. DETAILED DESCRIPTION

[0018] Definition

[0019] As used herein, the term "active" or "activated" when used in conjunction with a specific functional group refers to a reactive functional group that readily reacts with an electrophile or nucleophile on another molecule. This is in contrast to those groups that require a catalyst or impractical reaction conditions to react (i.e., "non-reactive" or "inert" groups).

[0020] As used herein, the terms "bond," "link," "connected," or "linking" when used with respect to a polymer or compound described herein or a component thereof, refer to a bond, typically formed as a result of a chemical reaction, and typically a covalent bond.

[0021] As used herein, the terms "cleavable linkage," "cleavable linker," "hydrolyzable linker," "hydrolyzable functional group," "releasable linker," or "releasable functional group" refer to a chemical linkage containing a cleavable moiety. The terms "hydrolyzable" and "releasable" do not imply any particular mechanism for cleaving the linker.

[0022] As used herein, the term "cleavable moiety" refers to a group (such as in a cleavable linkage) that is cleavable in vivo in a subject under physiological conditions in the subject after the conjugate of the present disclosure has been 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 occurring or induced to occur 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 foregoing.

[0023] As used herein, the terms "inert" or "non-reactive" when used in connection with a particular functional group refer to a functional group that is not readily reactive with an electrophile or a nucleophile on another molecule and that requires a catalyst or impracticable reaction conditions to react.

[0024] As used herein, the term "first phenolic hydroxyl" or "first hydroxyl" refers to the hydroxyl group on the catechol moiety that is linked via a direct bond or a linking group to a water-soluble polymer including a polyoxazoline polymer. It should be understood that the term "first phenolic hydroxyl" or "first hydroxyl" does not refer to a specific hydroxyl group of the catechol moiety or to the specific position of the hydroxyl group on the compound.

[0025] As used herein, the term "second phenolic hydroxyl" or "second hydroxyl" refers to the hydroxyl group on the catechol moiety that is adjacent (i.e., ortho) to the first phenolic hydroxyl. It should be understood that the term "second phenolic hydroxyl" or "second hydroxyl" does not refer to a specific hydroxyl group of the catechol moiety or to the specific position of the hydroxyl group on the compound.

[0026] As used herein, the term "alkyl", whether used alone or as part of a substituent, is a term in the art and refers to a saturated aliphatic group, including straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyls, and cycloalkyl-substituted alkyls. In certain embodiments, the straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C 30 , for straight-chain, and C3-C 30 ) and / or about 20 or fewer or 10 or fewer carbon atoms. In certain embodiments, the term "alkyl" refers to a C1-C 10 straight-chain alkyl. In certain embodiments, the term "alkyl" refers to a C1-C6 straight-chain alkyl. In certain embodiments, the term "alkyl" refers to a C3-C 12Branched alkyl. In certain embodiments, the term "alkyl" refers to a C3-C8 branched alkyl. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0027] As used herein, the term "heteroalkyl" refers to a straight-chain or branched alkyl preferably having 2 to 14 carbons in the chain, one or more of which have been replaced by a heteroatom selected from S, O, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, etc., where the heteroatom may be optionally substituted.

[0028] As used herein, the term "alkenyl", whether used alone or as part of a substituent, is a term in the art and refers to an unsaturated aliphatic group, including a straight-chain or branched hydrocarbon group having 2 to 30 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. One or more of the unsaturated bonds of the alkenyl can be located at any position in the moiety and can have the (Z) or (E) configuration with respect to one or more double bonds. The alkenyl can be optionally substituted.

[0029] As used herein, the term "alkynyl", whether used alone or as part of a substituent, is a term in the art and refers to an unsaturated aliphatic group, including a straight-chain or branched hydrocarbon group having 2 to 30 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. The alkynyl can be optionally substituted.

[0030] The phrases "substituted alkyl", "substituted heteroalkyl", "substituted alkenyl", and "substituted alkynyl" refer to alkyl, heteroalkyl, alkenyl, and alkynyl as defined above, wherein one or more bonds to one or more carbon or hydrogen atoms are replaced by bonds to non-hydrogen or non-carbon atoms such as, but not limited to, halogen atoms in halides such as F, Cl, Br, and I; and oxygen atoms in groups such as: carbonyl, carboxyl, hydroxyl, alkoxy, aryloxy, heterocyclyloxy, and ester groups; sulfur atoms in groups such as: mercapto, alkylthio, and arylthio groups, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as: amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, enamine, imine, oxime, hydrazone, heterocyclic amine, (alkyl)(heterocyclic)-amine, (aryl)(heterocyclic)amine, diheterocyclic amine, and nitrile; silicon atoms in groups such as: trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl; and other heteroatoms in various other groups. In certain embodiments, the term "substituted alkyl" or "substituted heteroalkyl" refers to C1-C substituted with up to 5 groups selected from the group consisting of 14 a straight-chain or branched alkyl or heteroalkyl: -OH, -NH2, -NH-NH2, =O(OH), substituted aryl, and =O.

[0031] The term "halo" or "halogen", whether used alone or as part of a substituent, is a term in the art and refers to –F, –Cl, -Br, or –I.

[0032] The term "alkoxy", whether used alone or as part of a substituent, is a term in the art and refers to an alkyl as defined herein attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0033] The term "aralkyl" or "arylalkyl", whether used alone or as part of a substituent, is a term in the art and refers to an alkyl substituted with an aryl, wherein the moiety is attached to the parent molecule through the alkyl. The aralkyl may be optionally substituted. "Substituted aralkyl" has the same meaning with respect to unsubstituted aralkyl as substituted aryl has with respect to unsubstituted aryl. However, substituted aralkyl also includes groups in which a carbon or hydrogen bond in the alkyl portion of the group is replaced by a bond to a non-carbon or non-hydrogen atom.

[0034] The term "heteroarylalkyl" or "heteroaryl-alkyl", whether used alone or as part of a substituent, is a term in the art and refers to an alkyl group substituted by a heteroaryl group, wherein said moiety is attached to the parent molecular moiety through an alkyl group. The heteroarylalkyl may be optionally substituted. The term "substituted heteroarylalkyl" has the same meaning with respect to unsubstituted heteroarylalkyl as the meaning that substituted aryl has with respect to unsubstituted aryl.

[0035] The term "heterocyclic alkyl" or "heterocyclic-alkyl", whether used alone or as part of a substituent, is a term in the art and refers to an unsubstituted or substituted alkyl, alkenyl or alkynyl group, wherein a hydrogen or carbon bond of the unsubstituted or substituted alkyl, alkenyl or alkynyl group is replaced by a bond to a heterocyclic group. The heterocyclic alkyl may be optionally substituted. The term "substituted heterocyclic alkyl" has the same meaning with respect to unsubstituted heterocyclic alkyl as the meaning that substituted aryl has with respect to unsubstituted aryl. However, substituted heterocyclic alkyl also includes groups in which a non-hydrogen atom is bonded to a heteroatom in the heterocyclic group of the heterocyclic alkyl, such heteroatoms including but not limited to the nitrogen atom in the piperidine ring of piperidylalkyl.

[0036] The term "aryl", whether used alone or as part of a substituent, is a term in the 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, hydroxy, alkoxy, amino, nitro, mercapto, imino, acylamino, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term "aryl" also includes polycyclic ring systems having two or more rings, wherein two or more carbons are common to two adjacent rings (said rings being "fused rings"), wherein at least one ring is an aromatic hydrocarbon, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic group. In certain embodiments, the term "aryl" refers to phenyl. The aryl may be optionally substituted. "Substituted aryl" includes aryl in which one of the aromatic carbon atoms is bonded to a non-carbon or non-hydrogen atom (such as but not limited to those atoms described above with respect to substituted alkyl), and also includes aryl in which one or more aromatic carbon bonds of the aryl are bonded to substituted and / or unsubstituted alkyl, alkenyl or alkynyl groups as defined herein. This includes bonding arrangements in which two carbon atoms of the aryl are bonded to two atoms of the 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, etc.

[0037] The term "cycloalkyl", whether used alone or as part of a substituent, is a term in the art and refers to a saturated carbocyclic group containing three to six ring carbon atoms, wherein such a ring may optionally be substituted or unsubstituted by alkyl or a substituent as described for substituted alkyl. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclobutyl, and 4-ethylcyclohexyl.

[0038] The term "heteroaryl", whether used alone or as part of a substituent, is a term in the art and refers to monocyclic, bicyclic, and polycyclic aromatic groups having a total of 3 to 30 atoms in the ring structure (including one or more heteroatoms such as nitrogen, oxygen, or sulfur). Exemplary heteroaryls include azaindolyl, benzothiophenyl, 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, thienyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, etc. "Heteroaryl" may be substituted at one or more ring positions by one or more substituents such as: halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, mercapto, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term "heteroaryl" also includes polycyclic ring systems having two or more rings, wherein two or more carbons are common to two adjacent rings (the rings are "fused rings"), wherein at least one ring is an aromatic group having one or more heteroatoms in the ring structure. For example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic group.

[0039] The term "heterocyclic group", whether used alone or as part of a substituent, is a term in the art and refers to a group of non-aromatic ring systems, including but not limited to monocyclic, bicyclic and tricyclic rings, which may be fully saturated or which may contain one or more unsaturated units, and which, for the avoidance of doubt, do not result in an aromatic ring system due to the degree of unsaturation, and which have from 3 to 15 atoms, including at least one heteroatom such as nitrogen, oxygen or sulfur. For illustrative purposes, this should not be construed as limiting the scope of the invention, and the following are examples of heterocycles: aziridinyl, azirine, epoxyethyl, thiiranyl, thietene, dioxiranyl, diazirine, diazepane, 1,3-dioxolane, 1,3-dioxolanyl, 1,3-dithiolane, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azete, oxetanyl, oxete, thietanyl, thiete, diazetidinyl, dioxetanyl, dioxete, dithietanyl, dithiete, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxazolyl, azepine, azetidine, morpholinyl, oxadiazoline, oxadiazolyl, oxazoline, oxazolyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazoline, pyrazolyl, pyrroline, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazoline, thiadiazolyl, thiazoline, thiazolyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thiopyranyl and trithianyl. The heterocyclic group may be substituted at one or more ring positions with one or more substituents such as: halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, mercapto, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc.

[0040] The terms "treatment", "treat" and "treating" refer to a process of action (such as administering a conjugate as described herein or a pharmaceutical composition comprising a conjugate as described herein) to prevent, eliminate or reduce the symptoms, aspects or features of a disease or disorder. Such treatment is not necessarily absolutely effective. In one embodiment, treatment includes a process of action that is initiated simultaneously with or after the onset of the symptoms, aspects or features of a disease or disorder. In another embodiment, treatment includes a process of action that is initiated prior to the onset of the symptoms, aspects or features of a disease or disorder.

[0041] The term "in need of treatment" refers to a judgment made by a caregiver that a patient needs treatment or will benefit from treatment. This judgment is made based on a variety of factors within the caregiver's area of expertise, but this includes knowledge that the patient has or will develop a disease or disorder that can be treated by the methods or compounds of the present disclosure.

[0042] The terms "individual", "subject" or "patient" refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and humans. These terms may denote male or female or both, or may exclude male or female. In a preferred embodiment, the terms "individual", "subject" or "patient" refer to a human.

[0043] The term "therapeutically effective amount" refers to the amount of a conjugate or compound, either alone or as part of a pharmaceutical composition, that is capable of having any detectable positive effect on any symptom, aspect or feature of a disease or disorder. Such an effect is not necessarily absolutely beneficial.

[0044] Certain compounds contained in the conjugates and / or compositions of the present disclosure may exist in specific geometric or stereoisomeric forms. Additionally, the compounds contained in the conjugates and / or compositions of the present disclosure may also be optically active. The present disclosure encompasses all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, their racemic mixtures, and other mixtures thereof as fall within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are intended to be included in the present invention.

[0045] For example, if a specific enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis or by derivation with a chiral auxiliary, where the resulting mixture of diastereoisomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereoisomeric salts are formed with a suitable optically active acid or base, and the diastereoisomers thus formed are then resolved by fractional crystallization or chromatographic means well known in the art, and subsequently the pure enantiomer is recovered.

[0046] It should be understood that "substituted" or "substitued" includes the implicit proviso that such substitution is in accordance with the allowed valences of the atoms being substituted and the substituents, and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo transformation, such as by rearrangement, cleavage, decomposition, cyclization, elimination or other reactions.

[0047] It should be understood that when a group is designated as part of a compound, the substitution of the group can be adjusted to accommodate a particular bond. For example, when an alkyl group is joined to two other groups, the alkyl group is considered an alkylene group.

[0048] The term "substituted" is also intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched substituents of organic compounds, carbocyclic and heterocyclic groups, aromatic and non-aromatic substituents. Exemplary substituents include those described above, for example. For the purposes of this disclosure, heteroatoms (such as oxygen and nitrogen) can have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valence of the heteroatom. Exemplary substitutions include, but are not limited to, hydroxy, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, mercapto, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The present invention is not intended to be limited in any way by the permissible substituents of organic compounds.

[0049] Other chemical terms herein are used according to their conventional usage in the art, as exemplified by McGraw-Hill Dictionary of Chemical Terms (edited by Parker, S., 1985), McGraw-Hill, San Francisco, which is incorporated herein 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 pertains.

[0050] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from inorganic or organic acids, such 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, trifluoroacetic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms can include forms in which the ratio of molecules containing the salt is not 1:1. For example, the salt can contain more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of conjugate. As another example, the salt can contain less than one inorganic or organic acid molecule per molecule of base, such as two conjugate molecules per molecule of inorganic or organic acid molecule.

[0051] As used herein, the terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oil; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Additionally, adjuvants, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, which is incorporated herein by reference in its entirety.

[0052] Introduction

[0053] Previous patents from the applicant have addressed problems associated with the administration of dopamine agonists (exemplified by rotigotine and ropinirole) to a subject by providing conjugates comprising a polyoxazoline polymer linked via a linking group comprising a cleavable moiety (e.g., an ester group) to a dopamine agonist, wherein the structure of the linking group provides for controlled release of the dopamine agonist from the polyoxazoline polymer in vivo. In animal studies as well as in human clinical trials, the pharmacokinetics of rotigotine hydrolysis confirmed suitability for steady-state delivery by weekly subcutaneous injection.

[0054] In additional studies, when the method employed the dopamine agonist apomorphine (wherein apomorphine was linked to the polymer via a linking group comprising an ester moiety as the cleavable moiety at one of the two phenolic hydroxyls of the catechol moiety), the release rate of apomorphine in human plasma was much faster than expected or desired. Additionally, the structure of the linking group did not provide the desired control over the release rate as seen for the rotigotine polymer conjugates.

[0055] Apomorphine is a compound comprising a catechol moiety. The structure of apomorphine is provided below, and two adjacent phenolic hydroxyls characteristic of the catechol moiety are present at the 10- and 11-positions of apomorphine. Thus, apomorphine (and generally compounds comprising a catechol moiety) has a first phenolic hydroxyl and a second phenolic hydroxyl.

[0056]

[0057] While not bound by any particular theory, it is believed that the neighboring group participation of the free adjacent phenolic hydroxyls (hydroxyls not linked to the polymer via a linking group) contributes at least in part to the rapid cleavage of the cleavable moiety in the linking group (in this case, the ester group), and explains the fact that the structure of the linking group fails to provide the desired control over the release rate of apomorphine from the polyoxazoline polymer.

[0058] In the present disclosure, novel methods for administering compounds (including dopamine agonists) comprising a catechol moiety are provided. Specifically, the present disclosure provides a conjugate comprising a water-soluble polymer and a compound comprising a catechol moiety, wherein the compound is linked to the polymer via a linkage (e.g., a direct linkage or a linking group between the polymer and the first hydroxyl group) comprising a first cleavable moiety to the first phenolic hydroxyl group of the catechol moiety, and the cleavage of the first cleavable moiety on the linkage is at least partially controlled by the structure of a blocking group on the second phenolic hydroxyl group of the catechol moiety. In certain embodiments, the linkage is a linking group. In certain embodiments, when the first cleavable moiety is cleaved, a first phenolic hydroxyl group is generated. In certain embodiments, the blocking group contains a second cleavable moiety such that when the second cleavable moiety is cleaved, a second phenolic hydroxyl group is generated. The blocking group is not directly linked to the water-soluble polymer.

[0059] In one embodiment, when the second cleavable moiety is cleaved, a free hydroxyl group is generated at the second phenolic hydroxyl group of the catechol moiety. In one embodiment, when the first cleavable moiety is cleaved, a free hydroxyl group is generated at the first phenolic hydroxyl group of the catechol moiety. In one embodiment, when both the first cleavable moiety and the second cleavable moiety are cleaved, free hydroxyl groups are generated at both the first phenolic hydroxyl group and the second phenolic hydroxyl group of the catechol moiety. In one embodiment, at least one of the first cleavable moiety and the second cleavable moiety is positioned and / or structured such that when the first cleavable moiety and / or the second cleavable moiety is cleaved, a free hydroxyl group is generated at the first phenolic hydroxyl group and / or the second phenolic hydroxyl group of the catechol moiety. In one embodiment, each of the first cleavable moiety and the second cleavable moiety is positioned and / or structured such that when the first cleavable moiety and the second cleavable moiety are cleaved, free hydroxyl groups are generated at the first phenolic hydroxyl group and the second phenolic hydroxyl group of the catechol moiety.

[0060] Although not bound by any particular theory, it is believed that the blocking group blocks or inhibits the neighboring group participation of the second phenolic hydroxyl group and slows the cleavage of the first cleavable moiety in the linkage. The structure of the blocking group can be varied to provide control over the cleavage of the first cleavable moiety and the release kinetics of the compound from the polymer.

[0061] The conjugate provides sustained pharmacokinetics, increased bioavailability, and / or ease of administration of the compound comprising the catechol moiety. In certain embodiments, when administered to a subject, the conjugate provides reduced side effects (compared to the unconjugated compound administered in a suitable formulation). In one aspect of this embodiment, the side effect is a skin reaction at the site of administration.

[0062] Water-soluble polymer conjugate

[0063] The present disclosure provides a polymer conjugate comprising a water-soluble polymer and a compound comprising a catechol moiety, consisting essentially of a water-soluble polymer and a compound comprising a catechol moiety, or consisting of a water-soluble polymer and a compound comprising a catechol moiety. In one embodiment, the linkage is a direct linkage, and the compound is attached to the polymer backbone via a direct linkage through a reactive group on the compound (preferably a first phenolic hydroxyl group) and a reactive group on the polymer. In one embodiment, the direct linkage contains at least a first cleavable moiety such that, under physiological conditions in a subject (such as but not limited to a human), after administration of the polymer conjugate to the subject, the compound is released from the polymer. The direct linkage may form the first cleavable moiety in the reaction that attaches the polymer to the compound. Such cleavable moieties are discussed herein.

[0064] In an alternative embodiment, the linkage is via a linking group, and the compound is attached to the polymer through a linking group to a reactive group on the compound (preferably a first phenolic hydroxyl group). In one embodiment, the linking group contains at least a first cleavable moiety such that, under physiological conditions in a subject (such as but not limited to a human), after administration of the polymer conjugate to the subject, the compound is released from the polymer. Such cleavable moieties are discussed herein. In one embodiment, in addition to the first cleavable moiety, the linking group further contains a group capable of forming a linkage with a reactive group on the polymer and a group capable of forming a linkage with a reactive group on the compound.

[0065] As discussed herein, cleavage of the first cleavable moiety of the linkage is at least partially controlled by the structure of the blocking group on the second phenolic hydroxyl group of the catechol moiety.

[0066] For convenience and clarity, this specification describes a direct linkage or a 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.

[0067] In a general embodiment, the polymer conjugate of the present disclosure can be represented by Formula I, or a pharmaceutically acceptable salt thereof.

[0068] POL n –(L–A) b I

[0069] Wherein,

[0070] POL is a water-soluble polymer;

[0071] n is 1 - 1000 and represents the number of monomer units constituting the water-soluble polymer;

[0072] b is 1 to 50, provided that n is always greater than or equal to b;

[0073] A is a compound comprising a catechol moiety, said catechol moiety comprising at least a first phenolic hydroxyl group and a second phenolic hydroxyl group, wherein said compound is linked to the polymer via said first phenolic hydroxyl group, and said second phenolic hydroxyl group is optionally linked to a blocking group; and

[0074] L is a linkage comprising a first cleavable moiety that links compound (A) and polymer (POL).

[0075] In certain embodiments, L is a linking group comprising a first cleavable moiety. In certain embodiments, L is a direct linkage, wherein the direct linkage comprises a first cleavable moiety (in some aspects, the direct linkage forms a first cleavable moiety in the reaction that links the polymer to the compound).

[0076] 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, wherein R 19 is CH3.

[0077] In one embodiment, the first phenolic hydroxyl group is modified by forming a linkage with the polymer moiety. In one embodiment, the oxygen atom of the first phenolic hydroxyl group participates in the formation of the linkage with the polymer moiety. The formation of the linkage can include forming a chemical bond between the first phenolic hydroxyl group (e.g., the oxygen atom) and an atom or group or linking group on the polymer. In one embodiment, the second phenolic hydroxyl group is modified by reacting with a blocking group. In one embodiment, the oxygen atom of the second phenolic hydroxyl group participates in the formation of the bond with the blocking group. The formation of the chemical bond can be between the first phenolic hydroxyl group (e.g., the oxygen atom) and an atom or group on the blocking group. In each of the foregoing embodiments, the modification of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group can result in the formation of an ester linkage, wherein the ester linkage comprises the oxygen atom of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group. In each of the foregoing embodiments, the modification of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group can result in the formation of an ester linkage, wherein the ester linkage comprises the oxygen atom of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group and the ester linkage forms a first cleavable moiety and / or a second cleavable moiety. Thus, in certain embodiments, the first cleavable moiety and the second cleavable moiety are the same. Thus, in certain embodiments, the first cleavable moiety is an ester linkage, the second cleavable moiety is an ester linkage, or both the first cleavable moiety and the second cleavable moiety are ester linkages.

[0078] The polymer portion of the disclosed polymer conjugates can take a variety of forms. In certain embodiments, the polymer is poly(oxazoline) (POZ), poly(5,6-dihydro-4H-1,3-oxazine), dextran, dextran modified by oxidation, polyethylene glycol (PEG), poly(hydroxypropyl methacrylate), polyglutamic acid, poly(lactic acid)-polyglutamic acid mixture, polysialic acid, polycaprolactone, polyvinylpyrrolidone, glycosaminoglycan, polyglycerol, poly(acryloyloxyethyl phosphorylcholine) or a methacrylate-based copolymer with synthetic form of phosphorylcholine; also included are combinations of the foregoing.

[0079] 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 a dextran polymer modified by oxidation.

[0080] In one embodiment where the water-soluble polymer is a copolymer, the copolymer can be made 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 can optionally be a water-soluble polymer). Such copolymers include both block copolymers and random copolymers. In certain aspects, the copolymer includes a POZ polymer and at least a second polymer. In certain aspects, the copolymer comprises a POZ polymer and at least a second polymer, wherein the POZ polymer portion accounts for greater than 25%, 50%, 75%, 85%, 95%, 98%, 99% or 99.5% of the polymer (based on the weight ratio with respect to the total polymer components). In certain aspects, the copolymer comprises a POZ polymer and at least a second polymer, wherein the POZ polymer accounts for greater than 25%, 50%, 75%, 85%, 95%, 98%, 99% or 99.5% of the polymer (based on the weight ratio with respect to the total polymer components) and at least one additional polymer is a water-soluble polymer. In any of the foregoing cases, one or more additional water-soluble polymers can be any of the above water-soluble polymers. In any of the foregoing cases, one or more additional polymers can be PEG, dextran and / or dextran modified by oxidation. In certain aspects, the copolymer comprises a POZ polymer and at least a second polymer, wherein the POZ polymer accounts for greater than 25%, 50%, 75%, 85%, 95%, 98%, 99% or 99.5% (based on the weight ratio) and one or more additional polymers are not water-soluble polymers.

[0081] L can form a linkage with any reactive group on the polymer and a reactive group on the compound, suitably with the first phenolic hydroxyl group on the catechol moiety of the compound. In one embodiment, L is a linkage between the compound and the terminus of the polymer. In one embodiment, L is a linkage between the compound and a side chain group of the polymer (referred to herein as a “lateral attachment” position or “side group”). Additionally, L can include one or more components of groups originally present on the polymer and / or the compound.

[0082] Suitable parameters for L are described herein. In certain embodiments, L is a linking group containing a first cleavable moiety.

[0083] In certain embodiments, the polymer conjugate of the present disclosure can be represented by Formula II, or a pharmaceutically acceptable salt thereof.

[0084] R-POZ n –(L–A) b II

[0085] Wherein,

[0086] R is a starting group;

[0087] POZ is a polyoxazoline polymer;

[0088] n is 1 - 1000 and represents the number of monomer units constituting the polyoxazoline polymer;

[0089] b is 1 to 50, provided that n is always greater than or equal to b;

[0090] A is a compound containing a catechol moiety, the catechol moiety comprising at least a first phenolic hydroxyl group and a second phenolic hydroxyl group, wherein the compound is linked to the polymer via the first phenolic hydroxyl group, and the second phenolic hydroxyl group is optionally linked to a blocking group; and

[0091] L is a linkage containing a first cleavable moiety that links the compound (A) and the polymer (POL).

[0092] In certain embodiments, the POZ conjugate of the present disclosure is represented by Formula IIA, or a pharmaceutically acceptable salt thereof, wherein the linkage between the compound and the polymer is formed at a “lateral attachment” position.

[0093]

[0094] Wherein

[0095] R is a starting group;

[0096] POZ is a polyoxazoline polymer;

[0097] n is from 1 to 1000 and represents the number of monomer units constituting the polyoxazoline polymer;

[0098] b is from 1 to 50, provided that n is always greater than or equal to b;

[0099] A is a compound containing a catechol moiety, the catechol moiety containing at least a first phenolic hydroxyl group and a second phenolic hydroxyl group, wherein the compound is linked to the polymer via the first phenolic hydroxyl group, and the second phenolic hydroxyl group is optionally linked to a blocking group;

[0100] L is a linkage containing a first cleavable moiety that links compound (A) and polymer (POL); and

[0101] T is a capping group.

[0102] In another specific embodiment, the POZ conjugate of the present disclosure can be represented by Formula IIB, or a pharmaceutically acceptable salt thereof, wherein the linkage between the compound and the polymer is formed at a "lateral" position.

[0103] R-{[N(COX)CH2CH2] o1 -[N(COY)CH2CH2] o2 -[N(COR1)CH2CH2] n} a -T IIB

[0104] wherein

[0105] R is a starting group;

[0106] A is a compound containing a catechol moiety, the catechol moiety containing at least a first phenolic hydroxyl group and a second phenolic hydroxyl group, wherein the compound is linked to the polymer via the first phenolic hydroxyl group, and the second phenolic hydroxyl group is optionally linked to a blocking group;

[0107] L is a linkage containing a first cleavable moiety that links compound (A) and polymer (POL);

[0108] R1 is a non-reactive lateral moiety and is independently selected for each repeating unit;

[0109] X is independently selected from –L-A for each repeating unit;

[0110] Y is independently selected from –L-A, a non-reactive lateral moiety, or a lateral moiety containing a reactive functional group for each repeating unit;

[0111] a is ran representing a random copolymer or block representing a block copolymer

[0112] o1 is an integer from 1 to 50;

[0113] o2 ranges from 0 to 49, provided that the sum of o1 and o2 is less than or equal to 50;

[0114] n is an integer from 1 to 1000; and

[0115] T is a capping group.

[0116] Unless otherwise specified, the following description applies to each of the conjugates of Formula II, Formula IIA, and Formula IIB.

[0117] In certain embodiments, L is a linking group comprising a first cleavable moiety. In certain embodiments, L is a direct bond, where the direct bond comprises a first cleavable moiety (in some aspects, the direct bond forms the first cleavable moiety in the reaction that attaches the polymer to the compound).

[0118] 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, where R 19 is CH3.

[0119] 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 forming 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 a blocking group. In one embodiment, the second phenolic hydroxyl group is modified by forming 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 phenolic hydroxyl group and / or the second phenolic hydroxyl group can result in the formation of an ester linkage, where the ester linkage comprises the oxygen atom of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group. In each of the foregoing embodiments, modification of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group can result in the formation of an ester linkage, where the ester linkage comprises the oxygen atom of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group and the ester linkage forms the first cleavable moiety and / or the second cleavable moiety. Thus, in certain embodiments, the first cleavable moiety is an ester linkage, the second cleavable moiety is an ester linkage, or each of the first cleavable moiety and the second cleavable moiety is an ester linkage.

[0120] Exemplary R groups include, but are not limited to, hydrogen, alkyl, and substituted alkyl. In one embodiment, R is alkyl, such as C1 to C4 alkyl. In the foregoing specific embodiment, the starting group is methyl. In another embodiment, the starting group is H. In yet another embodiment, the starting group is selected to be lacking in functional groups. Additional exemplary starting 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 teachings.

[0121] L can form a linkage with any reactive group on the polymer and a reactive group on the compound, suitably the first phenolic hydroxyl group on the catechol moiety of the compound. In one embodiment, L is a linkage between the terminal of the compound and the polymer. In one embodiment, L is a linkage between the compound and a side chain group of the polymer (referred to herein as a "side-attached" position or "side group"). Additionally, L can include one or more components of groups initially present on the polymer and / or the compound.

[0122] Suitable parameters for L are described herein. In certain embodiments, L is a linking group containing a first cleavable moiety.

[0123] In certain embodiments, the polymer conjugate of the present disclosure can be represented by Formula IIB, or a pharmaceutically acceptable salt thereof.

[0124] In one embodiment of the conjugates of Formula IIA and Formula IIB, T is a thioalkylcarboxylic acid, a thiocarboxylate, or a hydroxyl group. In one embodiment of the conjugates of Formula IIA and Formula IIB, T is Z-B-Q, where Z is S, O, or N; B is an optional linking group; and Q is a capped nucleophile or part of a capped nucleophile. In certain embodiments of the conjugates of Formula IIA and Formula IIB, Q is non-reactive (i.e., does not contain a functional group); in other embodiments, Q contains a functional group.

[0125] Exemplary B groups include, but are not limited to, alkylene groups. In certain embodiments, B is -(CH2) 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 Formula IIB, Z is S. The sulfur-containing polyoxazoline conjugates described herein can be prepared by cationic capping at the terminus of the polyoxazoline polymer with a thiolate reagent such as, but not limited to, a thiol ester (e.g., -S-CH2CH2-CO2CH3 or -S-CH2CH2-CO2H), an amine (e.g., –S-CH2CH2-NH2) or a thiol-protected amine (e.g., –S-CH2CH2-NH-tBoc). Such POZ conjugates provide efficient large-scale purification by ion-exchange chromatography (to remove secondary amines), as well as allow control of the polydispersity value (the polydispersity value is 1.10 or less) and the production of conjugates with higher molecular weight POZ polymers. In another embodiment of the conjugates of Formula IIA and Formula IIB, Z is N. In yet another embodiment of the conjugates of Formula IIA and Formula IIB, Z is O.

[0126] As described above, Q can be non-reactive or can 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-benzotriazole active ester), active carbonate, chloroformate, alcohol, azide, vinyl sulfone or o-pyridyl disulfide (OPSS). When Q contains a functional group, the functional group can be chemically orthogonal to one or more or all of the other functional groups present on the conjugate. When Q is a non-reactive group, any non-reactive group can be used, including, but not limited to, an unsubstituted alkyl group and -C6H5.

[0127] In one embodiment of the conjugates of Formula IIA-IIB, L is a linking group and contains a first cleavable moiety, Z is S, B is -(CH2) y - and Q is -COOH. In another specific embodiment, L is a linking group and contains a first cleavable moiety, Z is O, B is -(CH2) y - and Q is -COOH. In yet another specific embodiment, L is a linking group and contains a first cleavable moiety, Z is N, B is -(CH2) y - and Q is -COOH. In any of the foregoing embodiments, the first cleavable moiety can be an ester group. In any of the foregoing cases, y is 2.

[0128] In one embodiment of the conjugates of Formula IIA-IIB, L is a linking group and contains a first cleavable moiety, Z is S, B is -(CH2) y- And Q is -COOCH3. In another specific embodiment, L is a linking group and contains a first cleavable moiety, Z is O, B is -(CH2) y - And Q is -COOCH3. In yet another specific embodiment, L is a linking group and contains a first cleavable moiety, Z is N, B is -(CH2) y - And Q is -COOCH3. In any of the foregoing embodiments, the first cleavable moiety can be an ester group. In any of the foregoing cases, y is 2.

[0129] In one embodiment of the conjugate of formulae IIA-IIB, L is a linking group and contains a first cleavable moiety, Z is S, B is -(CH2) y - And Q is -NH2. In another specific embodiment, L is a linking group and contains a first cleavable moiety, Z is O, B is -(CH2) y - And Q is -NH2. In yet another specific embodiment, L is a linking group and contains a first cleavable moiety, Z is N, B is -(CH2) y - And Q is -NH2. In any of the foregoing embodiments, the first cleavable moiety can be an ester group. In any of the foregoing cases, y is 2.

[0130] In one embodiment of the conjugate of formulae IIA-IIB, L is a linking group and contains a first cleavable moiety, Z is S, B is -(CH2) y - And Q is NH-tBoc. In another specific embodiment, L is a linking group and contains a first cleavable moiety, Z is O, B is -(CH2) y - And Q is NH-tBoc. In yet another specific embodiment, L is a linking group and contains a first cleavable moiety, Z is N, B is -(CH2) y - And Q is -NH-tBoc. In any of the foregoing embodiments, the first cleavable moiety can be an ester group. In any of the foregoing cases, y is 2.

[0131] In one embodiment of the conjugate of formulae IIA-IIB, R1 is independently selected for each repeating unit from unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted heterocyclic alkyl. In one embodiment, R1 is unsubstituted alkyl or substituted alkyl, such as C1-C4 unsubstituted alkyl or substituted alkyl. In a particular embodiment, 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 teachings.

[0132] In one embodiment of the conjugate of formula IIB, Y is –L-A. When Y is –L-A, the –L-A group on Y can be the same as the –L-A group on X. When Y is –L-A, the –L-A group on Y can be different from the –L-A group on X.

[0133] In one embodiment of the conjugate of formula IIB, Y is a linking moiety. When Y is a linking moiety, Y can be a non-reactive linking moiety or a linking moiety containing a reactive functional group. In one embodiment, when Y is a linking moiety, Y is independently selected, for each repeating unit, from unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclic alkyl. In one embodiment, Y is alkyl or substituted alkyl. In a particular embodiment, Y is methyl, ethyl, propyl, or butyl. In a particular embodiment, Y is a linking moiety containing a reactive functional group. Suitable reactive functional groups include, but are not limited to, alkyne, amine, oxyamine, aldehyde, ketone, acetal, ketal, maleimide, ester, carboxylic acid, activated carboxylic acids (such as, but not limited to, N-hydroxysuccinimidyl (NHS) and 1-benzotriazolyl active esters), active carbonates, chloroformates, alcohol, azide, vinyl sulfone, and ortho-pyridyl disulfide (OPSS). In some embodiments, the reactive functional group of Y is chemically orthogonal to one or more or all of the other functional groups on the conjugate. In some embodiments, the reactive functional group of Y is not chemically orthogonal to one or more or all of the other functional groups on the conjugate. In one embodiment, Y is absent or is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclic alkyl.

[0134] In one embodiment of the conjugate of formula II-IIB, L is a linking group and contains 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 a first phenolic hydroxyl group.

[0135] In one embodiment of the conjugate of formula IIB, o1 is from 1 to less than or equal to 20, and o2 is 0. In one embodiment, o1 is from 1 to less than or equal to 20, and o2 is from 1 to 30. In one embodiment, o1 is from 1 to less than or equal to 20, and o2 is from 1 to 30, and at least a portion of Y is a linking moiety containing a functional group. In one embodiment, o1 is from 1 to less than or equal to 10, and o2 is from 1 to 30, and at least a portion of Y is –L-A, where the –L-A of X and Y are the same as each other. In one embodiment, o1 is from 1 to less than or equal to 10, and o2 is from 1 to 30, and at least a portion of Y is –L-A, where the –L-A of X and Y are different from each other.

[0136] In a specific embodiment of the conjugate of Formula IIA-IIB, T is ZBQ

[0137] In one embodiment of the conjugate of Formula IIA-IIB, L is a linker and contains a first cleavable moiety, Z is S, B is -CH2CH2-, and Q is -COOH. In another specific embodiment, L is a linker and contains a first cleavable moiety, Z is O, B is -CH2CH2- 2- and Q is -COOH. In yet another specific embodiment, L is a linking group and contains a first cleavable moiety, Z is N, B is -CH2CH2- and Q is -COOH. In any of the foregoing embodiments, the first cleavable moiety can be an ester group.

[0138] In the aforementioned embodiment that polymer is polyoxazoline polymer, multiple polyoxazoline polymer can be used for conjugate of the present disclosure.Polyoxazoline polymer can contain the functional group of single type or classification, or can contain the functional group that exceeds a type or classification.Polyoxazoline polymer is linear polyoxazoline polymer, branched polyoxazoline polymer or multi-arm polyoxazoline polymer, wherein any of the aforementioned can contain side group.Various representative polyoxazoline polymers are described herein.POZ polymer can be prepared by living cationic polymerization or by additives known in the art.Representational POZ polymer is described in U.S. Patent number 7,943,141,8,088,884,8,110,651 and 8,101,706, and each in these patents is incorporated herein by introduction for this type of instruction.In one embodiment, prepare POZ polymer by living cationic polymerization.

[0139] In the foregoing embodiments where the polymer is a polyoxazoline polymer, n is 1-500. In one embodiment, n is 1-250. In one embodiment, n is 1-100. In one embodiment, n is 1 to 50. In one embodiment, n is greater than 25 and less than 250. In one embodiment, n is greater than 25 and less than 150.

[0140] In the aforementioned embodiment that polymer is polyoxazoline polymer, polyoxazoline polymer part (not including A and L) has the molecular weight of 2kDa to 100kDa.In one embodiment, polyoxazoline polymer part (not including A and L) has the molecular weight of 10kDa to 30kDa.In one embodiment, polyoxazoline polymer part (not including A and L) has the molecular weight of 15kDa to 25kDa.In one embodiment, polyoxazoline polymer part (not including A and L) has the molecular weight of 20kDa.In this manual, when for polymer, particularly for polyoxazoline polymer molecular weight is provided, unless otherwise specifically stated, otherwise molecular weight is number-average molecular weight.

[0141] In the foregoing embodiments of the conjugates of Formula I, Formula II, and Formula IIA, b is from 1 to 40. In one embodiment, b is from 1 to 30. In one embodiment, b is from 1 to 20. In one embodiment, b is from 1 to 15. In one embodiment, b is from 1 to 10. In one embodiment, b is greater than or equal to 5 and less than or equal to 15. In one embodiment, b is 10.

[0142] In any of the foregoing embodiments of the conjugates of Formula I and Formula II-IIB, L can form a linkage with any reactive group on the polymer and any reactive group on the compound (preferably the first phenolic hydroxyl group). In any of the foregoing embodiments, L is a linkage between the terminus of the compound and the polymer. In any of the foregoing embodiments, L is a linkage between the side chain group of the compound (referred to herein as the "side-attached" position or "side group") and the polymer. In any of the foregoing embodiments, L can include components of groups initially 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 containing a first cleavable moiety.

[0143] In any of the foregoing embodiments of the conjugates of Formula I and Formula II-IIB, regardless of the form of the linkage (whether a direct linkage or via a linking group), the linkage is a cleavable bond that allows the compound to be released from the polymer via cleavage of the first cleavable moiety after administration of the conjugate to a subject. The cleavage of the first cleavable moiety of the compound from the conjugate (release kinetics) (at least in part) is controlled by the structure of the blocking group on the second phenolic hydroxyl group, providing a controlled delivery of the compound. In any of the foregoing embodiments, cleavage of the first cleavable moiety results in the formation of a free phenolic hydroxyl group at the first phenolic hydroxyl group.

[0144] In any of the foregoing embodiments of the conjugates of Formula I and Formula II-IIB, the cleavage of the first cleavable moiety of the compound from the polymer (release kinetics) is at least in part controlled by the structure of the blocking group on the second phenolic hydroxyl group. In any of the foregoing embodiments, the cleavage of the first cleavable moiety of the compound from the polymer (release kinetics) is at least in part controlled by the structure of the linking group and the structure of the blocking group on the second phenolic hydroxyl group. In any of the foregoing embodiments, the blocking group contains 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 cleavable moiety and the second cleavable moiety are the same. In any of the foregoing embodiments, the first cleavable moiety and the second cleavable moiety are different. In any of the foregoing embodiments, at least one of the first cleavable moiety and the second cleavable moiety is an ester linkage. In any of the foregoing embodiments, both the first cleavable moiety and the second cleavable moiety are ester linkages.

[0145] In any of the foregoing embodiments of the conjugates of Formula I and Formulas II-IIB, the conjugate provides delivery of a therapeutically effective amount of the compound to a subject over a period of time of: 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 controlled delivery or sustained controlled delivery. In any of the foregoing embodiments, the compound is delivered with a pharmacokinetic / release profile that is peakless and valley-free.

[0146] In any of the foregoing embodiments of the conjugates of Formula I and Formulas II-IIB, the conjugate provides delivery of a therapeutically effective amount of the compound to a subject over a period of one week or longer. In any of the foregoing embodiments, the conjugate provides delivery of a therapeutically effective amount of the compound to a subject over a period of time of: one to two weeks; one to three weeks; or one to four weeks. In any of the foregoing embodiments, the delivery is controlled delivery or sustained controlled delivery. In any of the foregoing embodiments, the compound is delivered with a pharmacokinetic / release profile that is peakless and valley-free.

[0147] In the embodiments described above for the conjugates of Formula I and Formulas II-IIB, specific linking groups are as described below. For clarity, any of the linking groups described herein can be used in the above general formulas.

[0148] L

[0149] In the above embodiments, L is a linking group that forms or contains a first cleavable moiety, or a direct bond that forms or contains a first cleavable moiety. In those embodiments where L forms the first cleavable moiety, the interaction of L with a group on the polymer or compound forms the first cleavable moiety. In certain preferred embodiments, the reaction between L and the oxygen atom on the first phenolic hydroxyl group forms the first cleavable moiety. Thus, L is a cleavable bond between the compound and the polymer. In other words, after administration of the polymer conjugate of the present disclosure to a subject, the first cleavable moiety can be cleaved in vivo in 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 occurring 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 foregoing. L can contain portions of the polymer and / or the compound, since such portions have reacted to form a linking group or direct bond with the polymer and / or the compound, as discussed herein.

[0150] Exemplary first cleavable moieties include, but are not limited to, ester linkages, carboxylate ester linkages (-C(O)-O-), carbonate linkages (-O-C(O)-O-), carbamate linkages (-O-C(O)-NH-), amide linkages (-C(O)-NH-), and disulfide linkages (S-S); other cleavable moieties are discussed herein. In certain embodiments, the first cleavable moiety is an ester linkage. In another specific embodiment, the cleavable moiety is a carboxylate ester linkage. In the following description, for illustrative purposes, it is assumed that the polymer is a polyoxazoline polymer. However, the following reactions are equally applicable to other polymer types.

[0151] In one embodiment, the linking group is a disubstituted triazole containing the first cleavable moiety in one of the R3 or R4 groups. In one embodiment, the first cleavable moiety is present in the R4 group. In a specific embodiment, the disubstituted triazole has the following structure:

[0152]

[0153] In another embodiment, the disubstituted triazole has the following structure:

[0154]

[0155] In each of the foregoing structures:

[0156] R3 is a linker that attaches the triazole moiety to the polymer chain. R3 may be partially defined by a functional group on the polymer chain; in other words, R3 may contain a portion of the functional group on the polymer chain. In one embodiment, R3 is -C(O)-R5-, where R5 is absent or is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclic alkyl. In one embodiment, R5 is absent or is a substituted or unsubstituted alkyl having 1 to 10 carbons. In one embodiment, R5 is absent or is an unsubstituted straight-chain alkyl having 1 to 10 carbons.

[0157] R4 is a linker that attaches the triazole moiety to the compound, wherein the bond between R4 and the compound occurs between the first phenolic hydroxyl group on the catechol portion of the compound. R4 may be partially defined by a functional group on the compound. In other words, R4 may contain a portion of a group / functional group on the compound, such as 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., -(CH2CH2O) e-, where e is from 1 - 10 or 1 - 4), R7 is a group containing a first cleavable moiety or a part of the first cleavable moiety, and R8 is absent or is O. In certain embodiments, R7 and R8 can 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 -O-C(O)-R b -, -R a -C(O)-O-R b -, -R a -C(O)-NH-cyclo-O-C(O)-R b -(where cyclo represents substituted or unsubstituted aryl, heterocylalkyl, heteroaryl, heterocyclic or cycloalkyl), -R a -C(O)-NH-(C6H4)-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 -, where R 10 is H or substituted or unsubstituted C1-C5 alkyl) and R a and R b are each independently absent or are substituted or unsubstituted alkyl. In another embodiment, R a and R b are each independently absent or are substituted or unsubstituted C1-C16 alkyl.

[0158] In one of the foregoing embodiments, R6 is a substituted or unsubstituted C1-C10 straight-chain alkyl or a substituted or unsubstituted C1-C10 branched-chain alkyl, R7 is -R a -C(O)-R b - and R8 is -O-. In one of the foregoing embodiments, R6 is a substituted or unsubstituted C1-C10 straight-chain alkyl or a substituted or unsubstituted C1-C10 branched-chain alkyl, R7 is -R a -C(O)-O-R b - and R8 is absent.

[0159] In one of the foregoing embodiments, R6 is a substituted or unsubstituted C1-C4 straight-chain alkyl or a substituted or unsubstituted C1-C4 branched-chain alkyl, and R7 is -R a -C(O)-R b - and R8 is -O-. In one of the foregoing embodiments, R6 is a substituted or unsubstituted C1-C4 straight-chain alkyl or a substituted or unsubstituted C1-C4 branched-chain alkyl, and R7 is -R a -C(O)-O-R b - and R8 is absent.

[0160] In a particular embodiment, 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 from 1 to 10.

[0161] In a particular embodiment, 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 from 1 to 10.

[0162] In each of the foregoing cases, the first cleavable moiety can be chemically cleaved under physiological conditions in a subject, cleaved by a substance that is naturally present or induced to be present in the subject under physiological conditions in the subject, or cleaved by a combination of the foregoing. In one embodiment, such a substance is an enzyme or a polypeptide, and the cleavage is enzymatic cleavage.

[0163] Compound containing a catechol moiety

[0164] In the embodiments for the general formula I, general formula II, general formula IIA and general formula IIB above, the specific compound (A) is as described below. For clarity, any compound (A) described herein can be used in the above general formulas.

[0165] Compounds containing a catechol moiety can be any compound known in the art that can be used for diagnosing or treating a disease or disorder. It has been reported that compounds containing a catechol moiety have a wide range of activities, including but not limited to adrenergic agonist activity, antiviral activity, anti-inflammatory activity, emetic activity, cardiotonic activity, antiasthmatic activity, enzyme inhibitory activity, antibiotic activity, antitumor activity, anticholinergic activity, spasmolytic activity, bronchodilator activity, antihypertensive activity, dopamine receptor agonist activity, antioxidant activity, spermicidal activity, and pesticidal activity. Compounds containing a catechol moiety can be diagnostic agents or therapeutic agents.

[0166] In one embodiment, the compound containing a catechol moiety is represented by Formula III, or a pharmaceutically acceptable salt thereof:

[0167]

[0168] wherein

[0169] R 11 、R 12 、R 13 and R 14 are independently selected from H, OH, halogen, alkoxy, NO2, unsubstituted alkyl, heteroalkyl, alkenyl or alkynyl, substituted alkyl, heteroalkyl, alkenyl or alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic group, substituted heterocyclic group, heteroaryl, substituted heteroaryl, heterocyclic alkyl, substituted heterocyclic alkyl, heteroaryl alkyl, substituted heteroaryl alkyl, or any two of R 11 、R 12 、R 13 and R 14 adjacent to each other together with the carbon to which they are attached can form an optionally substituted aryl, heteroaryl, heterocyclic ring;

[0170] R 15 or R 16 one of is L; and

[0171] R 15 or R 16 the other of is a closed group.

[0172] In certain embodiments, "substituted alkyl" or "substituted heteroalkyl" means a C1-C 14 linear or branched alkyl or heteroalkyl substituted with up to 5 groups selected from the group consisting of: -OH, -NH2, -NH-NH2, ═O(OH), substituted aryl, and ═O.

[0173] As discussed herein, in one embodiment, the first phenolic hydroxyl group (formed by R 15 or R 16is modified by forming a linkage with L. In one embodiment, the oxygen atom of the first phenolic hydroxyl group participates in the formation of the linkage with L. The formation of the linkage may include forming a chemical bond between the first phenolic hydroxyl group (e.g., the oxygen atom) and an atom or group or linking group on the polymer. In one embodiment, the second phenolic hydroxyl group (represented by the other of R 15 or R 16 is modified by forming a bond with a blocking group. In one embodiment, the oxygen atom of the second phenolic hydroxyl group participates in the formation of the bond with the blocking group. The formation of the chemical bond may be between the first phenolic hydroxyl group (e.g., the oxygen atom) and an atom or group on the blocking group. In each of the foregoing embodiments, the modification of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group may result in the formation of an ester linkage, wherein the ester linkage contains the oxygen atom of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group. In each of the foregoing embodiments, the modification of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group may result in the formation of an ester linkage, wherein the ester linkage contains the oxygen atom of the first phenolic hydroxyl group and / or the second phenolic hydroxyl group and the ester linkage forms a first cleavable moiety and / or a second cleavable moiety. Thus, in certain embodiments, the first cleavable moiety and the second cleavable moiety are the same. Thus, in certain embodiments, the first cleavable moiety is an ester linkage, the second cleavable moiety is an ester linkage, or each of the first cleavable moiety and the second cleavable moiety is an ester linkage.

[0174] In one embodiment, the blocking group contains a second cleavable moiety or forms a second cleavable moiety when forming a bond with the second phenolic hydroxyl group (i.e., modifying the second phenolic hydroxyl group). In one embodiment, the blocking group forms a second cleavable moiety when forming a bond 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 naturally present or induced in a 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 foregoing.

[0175] Exemplary second cleavable moieties include but are not limited to ester linkages, carboxylate ester linkages (-C(O)-O-), carbonate ester linkages (-O-C(O)-O-), carbamate linkages (-O-C(O)-NH-), amide linkages (-C(O)-NH-), and disulfide linkages (S-S); other cleavable moieties are discussed herein. In a particular embodiment, the first cleavable moiety is an ester linkage. In another particular embodiment, the cleavable moiety is a carboxylate ester linkage.

[0176] In one embodiment, the blocking group is -R 17 -R18 , wherein R 17 is -C(O)-, -C(O)-O-, -C(O)-NH-cyclo-O-C(O)- (wherein cyclo represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic or cycloalkyl), -C(O)-NH-(C6H4)-O-C(O)-, CH3(CH2) 1-4 -O-C(O)-(CH2) 1-4 -C(O)- or -O-P(O)(OR9)(O)- (wherein R9 is H or a substituted or unsubstituted C1-C5 alkyl) and R 18 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl.

[0177] In one embodiment, R 17 forms a bond with the oxygen atom of the second phenolic hydroxyl group, and R 17 and the O connected thereto form a second cleavable moiety. In one embodiment, the second cleavable moiety is -C(O)-O.

[0178] In one embodiment, R 18 is a substituted or unsubstituted alkyl. In one embodiment, R 18 is a substituted or unsubstituted C1-C6 alkyl. In one embodiment, R 18 is a substituted or unsubstituted C1-C6 straight-chain alkyl. In one embodiment, R 18 is a substituted or unsubstituted C1-C6 branched-chain alkyl. In one embodiment, R 18 is a substituted or unsubstituted aralkyl. In one embodiment, R 18 is a substituted or unsubstituted aryl.

[0179] In one embodiment, the blocking group has the structure (CH3) y -(CH x )-(CH2) 0-6 -C(O)- O- Compound, wherein 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) y -(CH x )-C(O)- O- Compound, wherein 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 -C(O)- O- Compound. In one embodiment, the blocking group has the structure CH3-(CH2)0-6 -C(O)-(CH2) 0-6 - O- Compound. In the foregoing, the underlined portion represents a part of the compound containing the catechol moiety and is not considered part of the blocking group.

[0180] In one embodiment, the blocking group has the structure CH3-C(O)- O- Compound. In one embodiment, the blocking group has the structure CH3-(CH2)2-C(O)- O- Compound. In one embodiment, the blocking group has the structure CH3-CH2-C(O)- O- Compound. In one embodiment, the blocking group has the structure (CH3)2-CH-C(O)- O- Compound. In one embodiment, the blocking group has the structure (CH3)3-C-C(O)- O- Compound. In one embodiment, the blocking group has the structure CH3CH2-O-C(O)-CH2CH2-C(O)- O -Compound. In one embodiment, the blocking group has the structure In one embodiment, the blocking group has the structure In the foregoing, the underlined portion represents a part of the compound containing the catechol moiety and is not considered part of the blocking group.

[0181] Accordingly, in certain embodiments, the present disclosure provides conjugates of Formula I, Formula II, Formula IIA and Formula IIB, which comprise a water-soluble polymer and a compound of Formula III. In certain preferred aspects, the water-soluble polymer is a polyoxazoline polymer. Such conjugates can be used to treat diseases or disorders as described herein, including but not limited to dopamine-responsive conditions such as, but not limited to, Parkinson's disease.

[0182] In one embodiment, the compound is the compound described in Yang et al. (Molecules, 2007, 12, 878 - 884, specifically including Figure 1 and Table S1). In one embodiment, the compound is apomorphine, dopamine, norepinephrine, levodopa, levoisoproterenol, isoproterenol, epinephrine, isoprenaline, (r)-(+)-fenoldopam, fenoldopam, isoetharine, carbidopa, dobutamine, tolcapone and entacapone. In one embodiment, the compound is Yang et al. (specifically including Figure 1Compounds useful for treating dopamine-responsive disorders (such as but not limited to Parkinson's disease) as described in Tables S1. In one embodiment, the compound is apomorphine, abutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoproterenol, isoprenaline, 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, exifone or levodopa. In another embodiment, the compound is apomorphine, fenoldopam, entacapone, tolcapone or levodopa. In the foregoing list of exemplary compounds, it should be understood that the first phenolic hydroxyl of the catechol moiety is modified by one of R 15 or R 16 and the second phenolic hydroxyl of the catechol moiety is modified by the other of R 15 and R 16 . For example, consider the compound entacapone having the following structure:

[0183] When entacapone is compound (A) as described herein, the conjugate should be understood to contain both, unless a specific form of entacapone is isolated prior to reaction with the polymeric portion of the conjugate.

[0184] In certain embodiments, the compounds are used to treat dopamine-responsive disorders. Representative dopamine-responsive disorders are described herein and include, but are 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. Loss of these neurons in the brain results in a deficiency of dopamine, a neurotransmitter essential for normal coordination and movement. Due to stable dopamine levels, striatal dopaminergic neurons fire in a random but continuous manner, allowing for precise coordination of movement. In patients with Parkinson's disease, presynaptic neurons degenerate. Administration of dopaminergic agents (e.g., dopamine agonists) to attempt to control symptoms results in discontinuous stimulation of postsynaptic neurons (e.g., caused by pulsatile stimulation of striatal dopamine receptors), promoting motor fluctuations (dyskinesias) that can worsen as the disease progresses. Early symptoms of dopamine deficiency in Parkinson's disease include tremors, stiffness, bradykinesia, and gait problems. Cognitive and behavioral problems, as well as dementia, occur in the late stages of Parkinson's disease.

[0185] Although Parkinson's disease is currently incurable, its symptoms can be treated with a variety of medications designed to maintain dopaminergic tone. Current medications used to treat Parkinson's disease include levodopa, dopamine agonists, adenosine A 2A antagonists, anticholinergic agents, monoamine oxidase-B inhibitors, and catechol-O-methyltransferase inhibitors, and other medications. There are challenges associated with these medications, including limited bioavailability, short in vivo half-lives, and high first-pass and / or peripheral metabolic rates. The short half-lives of these medications require frequent dosing multiple times a day, which results in pulsatile stimulation of striatal dopamine receptors, which may actually accelerate the death of dopaminergic neurons in the CNS.

[0186] Apomorphine is a compound containing a catechol group. The R-enantiomer of apomorphine is an agonist of both D1 and D2 dopamine receptors, with higher activity against D2. Members of the D2 subfamily, which consists of D2, D3, and D4 receptors, are inhibitory G protein-coupled receptors. In particular, D4 is an important target in the receptor signaling pathway and is associated with the pathogenesis of several neurological disorders. Apomorphine improves motor function by activating dopamine receptors in the nigrostriatal pathway, limbic system, hypothalamus, and pituitary. It also increases blood flow to the supplementary motor area and dorsolateral prefrontal cortex (stimulation of which has been found to reduce the tardive dyskinesia effect of levodopa (L-DOPA)). Subjects with Parkinson's disease have also been found to have excessive iron at the site of neurodegeneration; both the R- and S-enantiomers of apomorphine are potent iron chelators and free radical scavengers. Apomorphine also reduces the breakdown of dopamine in the brain and inhibits its synthesis.

[0187] Apomorphine is typically delivered to a patient via subcutaneous injection. A common side effect of administering apomorphine by subcutaneous injection is the formation of subcutaneous nodules at the injection site and a burning sensation at the injection site. Since apomorphine is delivered at least once a day and to different injection sites, patients often develop subcutaneous nodules in multiple locations on the body. These subcutaneous nodules can develop into open wounds or ulcers, which can become infected and require further treatment. In some cases, surgery may also be required. As a result, patients often require additional treatment to treat the side effects of apomorphine administration. The presence of subcutaneous nodules is painful, limits the available infusion sites, and over time interferes with drug absorption. By using the conjugates of the present invention, the side effects of apomorphine administration are eliminated or reduced, including but not limited to the formation of subcutaneous nodules.

[0188] In certain embodiments, the compound is represented by Formula IV, or a pharmaceutically acceptable salt thereof:

[0189]

[0190] where

[0191] R 15 and R 16 are as described for the compounds of Formula III; and

[0192] 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, nicotinoyl or 1-aryl tetrazolyl. In one embodiment, R 19 is a substituted or unsubstituted straight-chain alkyl of 1 to 5 carbons. In one embodiment, R 19 is selected from the group consisting of: -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3 and

[0193] In one embodiment, R 19 is CH3. When R 19 is CH3 and R 15 and R 16 are both H, the compound is apomorphine (sold under the trade names Apokyn, Ixense, Spontane and Uprima).

[0194] Thus, in certain embodiments, the present disclosure provides conjugates of Formula I, Formula II, Formula IIA, and Formula IIB, which comprise a water-soluble polymer and a compound of Formula IV. In certain preferred aspects, the water-soluble polymer is a polyoxazoline polymer. Such conjugates can be used to treat dopamine-responsive disorders such as, but not limited to, Parkinson's disease. In certain embodiments, the present disclosure provides a conjugate of Formula I, Formula II, Formula IIA, or Formula IIB, which comprises a water-soluble polymer and a compound of Formula IV, wherein R 19 is CH3. In certain preferred aspects, the water-soluble polymer is a polyoxazoline polymer. Such conjugates can be used to treat diseases or disorders as described herein, including but not limited to dopamine-responsive disorders such as, but not limited to, Parkinson's disease.

[0195] Representative polymer conjugate

[0196] The following are representative polymer conjugates according to the present disclosure.

[0197]

[0198] The conjugates of the examples. In any of the foregoing conjugates, o2 can be 0, and the polymer subunit of o1 can contain a mixture of the enantiomeric forms of the compound.

[0199] In the foregoing embodiments, any group can be used for R, R1, R6, R 16 and R 19 . In certain preferred embodiments, the variables are selected as described below.

[0200] R is selected from the group consisting of: hydrogen, unsubstituted and substituted alkyl, unsubstituted C1-C4 alkyl, and H.

[0201] R1 for each repeating unit is selected from the group consisting of: unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclic alkyl, unsubstituted C1-C4 alkyl, and substituted C1-C4.

[0202] R6 is selected from the group consisting of: substituted or unsubstituted alkyl, substituted or unsubstituted straight-chain C1-C4 alkyl, substituted or unsubstituted branched-chain C1-C4 alkyl, -(CH2) d -, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, and -CH2(CH3)-, where d is an integer from 1 to 10.

[0203] T is a thioalkyl carboxylic acid, a thioester, or a hydroxyl group.

[0204] Z is S, O, or N.

[0205] B is an optional linking group.

[0206] Q is a blocking nucleophile or a blocking moiety of a nucleophile.

[0207] Certain preferred combinations of Z, B, and Q are: Z is S, B is -(CH2) y -, and Q is -NH-tBoc, -COOH, -COOCH3, or -NH2, where y is an integer from 1 to 4.

[0208] In certain embodiments, R 16 is selected from the group consisting of 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 has 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 -C(O)-. In one embodiment, the blocking group has the structure CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 -. In certain embodiments, R 16 is selected from the group consisting of: (CH3)-C(O)-, CH3-(CH2)2-C(O)-, CH3-CH2-C(O)-, (CH3)2-CH-C(O)-, (CH3)3-C-C(O)-, CH3CH2-O-C(O)-CH2CH2-C(O)-, and

[0209] R 19 is selected from the group consisting of: –H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3, and

[0210] In certain embodiments, R is an unsubstituted C1 to C4 alkyl or H, R1 is an unsubstituted C1 to C4 alkyl, R6 is (CH2) d -, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, or -CH2(CH3)-, where d is an integer from 1 to 10, Z is S, B is -(CH2)2- and Q is -NH-tBoc, -COOH, -COOCH3, or -NH2, R 16is (CH3)-C(O)-, CH3-(CH2)2-C(O)-, CH3-CH2-C(O)-, (CH3)2-CH-C(O)-, CH3CH2-O-C(O)-CH2CH2-C(O)-, and and R 19 is -H, -CH3, -CH2-CH3.

[0211] Additional compound

[0212] The present disclosure also provides various compounds (i.e., intermediates) that can be used to prepare the polymer conjugates. Such compounds can also be used alone as active agents (i.e., not linked to a water-soluble polymer that is a component of the polymer conjugate).

[0213] In one embodiment, the present disclosure provides an intermediate of Formula V or a pharmaceutically acceptable salt thereof:

[0214]

[0215] wherein

[0216] R 11 、R 12 、R 13 and R 14 are independently selected from H, OH, halogen, alkoxy, NO2, unsubstituted alkyl, heteroalkyl, alkenyl or alkynyl, substituted alkyl, heteroalkyl, alkenyl or alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic group, substituted heterocyclic group, heteroaryl, substituted heteroaryl, heterocyclic group alkyl, substituted heterocyclic group alkyl, heteroaryl alkyl, substituted heteroaryl alkyl, or any two of R 11 、R 12 、R 13 and R 14 adjacent to each other may together with the carbon to which they are attached form an optionally substituted aryl, heteroaryl, heterocyclic ring; and

[0217] R 20 and R 21 one of is H or a blocking group and R 20 and R 21 the other of is H, a group containing an active functional group or a blocking group, provided that R 20 and R 21 are not both H.

[0218] In certain embodiments, "substituted alkyl" or "substituted heteroalkyl" means a C1-C substituted with up to 5 groups selected from the group consisting of 14Straight-chain or branched alkyl or heteroalkyl: -OH, -NH2, -NH-NH2, =O(OH), substituted aryl, and =O.

[0219] In one embodiment, R 20 and R 21 one of which is a blocking group and R 20 and R 21 the other of which is a group containing a reactive functional group. In one embodiment, R 20 and R 21 one of which is H and R 20 and R 21 the other of which is a group containing a reactive functional group. In one embodiment, R 20 and R 21 one of which is H and R 20 and R 21 the other of which is a blocking group. In one embodiment, R 20 and R 21 each of which is a blocking group.

[0220] When one of R 20 and R 21 is a blocking group and the other of R 20 and R 21 is a group containing a reactive functional group, the compound is suitable for use as an intermediate in the production of the disclosed polymer conjugates.

[0221] When one of R 20 and R 21 is a blocking group and the other of R 20 and R 21 is H, or when both of R 20 and R 21 are blocking groups, the compound is suitable for use as an active agent in the therapeutic methods disclosed herein. Without being bound by any particular theory, it is believed that administering a compound having a blocking group (i.e., R 20 and / or R 21 ) on one or both of the first phenolic hydroxyl or the second phenolic hydroxyl results in a compound that produces less skin irritation (compared to a compound having free hydroxyl groups on both the first phenolic hydroxyl and the second phenolic hydroxyl).

[0222] In those embodiments where both of R 20 and R 21 are blocking groups, the blocking groups on R 20 and R 21 can be the same or can be different. In R 20 and R 21In those embodiments where both are blocking groups, R 20 and R 21 may contain the same or different cleavable moieties on the blocking groups. In those embodiments where both R 20 and R 21 are blocking groups, the blocking groups on R 20 and R 21 contain the same cleavable moiety, and the cleavable moiety may be an ester linkage.

[0223] Exemplary cleavable moieties include, but are not limited to, ester linkages, carboxylate ester linkages (-C(O)-O-), carbonate ester linkages (-O-C(O)-O-), carbamate linkages (-O-C(O)-NH-), amide linkages (-C(O)-NH-), and disulfide linkages (S-S); other cleavable moieties are discussed herein. In certain embodiments, the first cleavable moiety is an ester linkage. In another certain embodiment, the cleavable moiety is a carboxylate ester linkage.

[0224] In one embodiment, the blocking group contains a second cleavable moiety, or forms a second cleavable moiety when the blocking group forms a bond with the O atom of R 20 and / or R 21 . In one embodiment, when the blocking group forms a bond with the O atom of R 20 and / or R 21 , the blocking group forms a second cleavable moiety. 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 naturally present or induced in a 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 foregoing.

[0225] In one embodiment, the blocking group of R 20 and / or R 21 is -R 22 -R 23 -, where R 22 is -C(O)-, -O-C(O)-, -C(O)-NH-cyclo-O-C(O)- (where cyclo represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic or cycloalkyl), -C(O)-NH-(C6H4)-O-C(O)- or -O-P(O)(OR9)(O)- (where R9 is H or a substituted or unsubstituted C1-C5 alkyl) and R 23is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl.

[0226] In one embodiment, R 22 forms a bond with the oxygen atom of R 20 and / or R 21 , and R 22 and the O attached thereto form a first cleavable moiety. In one embodiment, the cleavable moiety is -C(O)-O.

[0227] In one embodiment, R 23 is a substituted or unsubstituted alkyl. In one embodiment, R 23 is a 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-chain alkyl. In one embodiment, R 23 is a substituted or unsubstituted aralkyl. In one embodiment, R 23 is a substituted or unsubstituted aryl.

[0228] In one embodiment, the blocking group has the structure (CH3) y -(CH x )-(CH2) 0-6 -C(O)- O- compound, wherein 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) y -(CH x )-C(O)- O- compound, wherein 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 -C(O)- O- compound. In one embodiment, the blocking group has the structure CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 - O- compound. In the foregoing, the underlined portion represents a part of the compound containing the catechol moiety and is not considered part of the blocking group.

[0229] In one embodiment, the blocking group has the structure (CH3)-C(O)- O- compound. In one embodiment, the blocking group has the structure CH3-(CH2)2-C(O)-O- Compound. In one embodiment, the blocking group has the structure CH3-CH2-C(O)- O- Compound. In one embodiment, the blocking group has the structure (CH3)2-CH-C(O)- O- Compound. In one embodiment, the blocking group has the structure (CH3)3-C-C(O)- O- Compound. In one embodiment, the blocking group has the structure CH3CH2-O-C(O)-CH2CH2-C(O)- O - Compound. In one embodiment, the blocking group has the structure In one embodiment, the blocking group has the structure Previously, the underlined part represents a part of the compound containing a catechol moiety and is not considered part of the blocking group.

[0230] In one embodiment, the group containing the active functional group is R 24 -R 25 -R 26 where R 24 is -C(O)-, -O-C(O)-, -C(O)-NH-cyclo-O-C(O)-(where cyclo represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic or cycloalkyl), -C(O)-NH-(C6H4)-O-C(O)- or -O-P(O)(OR9)(O)-(where R9 is H or a 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, and R 26 is an active functional group or a part containing an active functional group, and the active functional group is capable of forming a linkage with a group on the polymer (including a group at the side-bonding position 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-hydroxysuccinimide (NHS) and 1-benzotriazinyl active ester), active carbonate, chloroformate, alcohol, azide, vinyl sulfone and o-pyridyl disulfide (OPSS). In one embodiment, R 26 is an azide group (N3) or an alkynyl 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 connected thereto form a first cleavable moiety. In one embodiment, the first cleavable moiety is –C(O)-O.

[0231] In one embodiment, R25 is a substituted or unsubstituted alkyl group. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 alkyl group. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 straight-chain alkyl group. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 branched-chain alkyl group.

[0232] In one embodiment, R 26 is N3. When R 26 is N3, the compound of formula V can be linked to a polymer containing an alkynyl group (such as but not limited to acetylene) via copper(I)-catalyzed azide-alkyne click chemistry. In such a reaction, the compound of formula V is linked to the azide group as described herein and undergoes a copper(I)-catalyzed click reaction with the alkynyl group on the polymer. In one of the foregoing embodiments, the alkynyl group is at a pendant position on the polymer. In one of the foregoing embodiments, the polymer is a polyoxazoline polymer and the alkynyl group is at a pendant position on the polyoxazoline polymer.

[0233] In one embodiment, R 26 is an alkyne. When R 26 is an alkyne (such as but not limited to acetylene), the compound of formula V can be linked to a polymer containing an N3 group via copper(I)-catalyzed azide-alkyne click chemistry. In such a reaction, the compound of formula V is linked to the alkynyl group as described herein and undergoes a copper(I)-catalyzed click reaction with the azide group on the polymer. In one of the foregoing embodiments, the azide group is at a pendant position on the polymer. In one of the foregoing embodiments, the polymer is a polyoxazoline polymer and the azide group is at a pendant position on the polyoxazoline polymer.

[0234] In one embodiment, the group containing the reactive functional group has the structure N 3- (CH2) 1-6 -C(O) -O- compound. In one embodiment, the group containing the reactive functional group has the structure C ＝ C-(CH2) 1-6 -C(O)- O -compound. In one embodiment, the group containing the reactive functional group has the structure N 3- (CH2)3-C(O) -O- compound. In one embodiment, the group containing the reactive functional group has the structure C ＝ C-(CH2)3-C(O)- O -compound. In the foregoing, the underlined portion represents a part of the compound containing the catechol moiety and is not considered to be a part of the group containing the reactive functional group.

[0235] In one embodiment, R 20 and R 21 one of which is a blocking group and R 20 and R 21 the other of which is H. In another embodiment, each of R 20 and R 21 is a blocking group, and the blocking groups on R 20 and R 21 are the same. In another embodiment, each of R 20 and R 21 is a blocking group, and the blocking groups on R 20 and R 21 are different. In those embodiments where both R 20 and R 21 are blocking groups, the blocking groups on R 20 and R 21 contain the same cleavable moiety. In those embodiments where both R 20 and R 21 are blocking groups, the blocking groups on R 20 and R 21 contain different cleavable moieties. In those embodiments where both R 20 and R 21 are blocking groups, the blocking groups on R 20 and R 21 contain an ester linkage as the cleavable moiety. One or both of R 20 and R 21 being a blocking group in those embodiments can be used as an active agent in the therapeutic methods described herein without being attached to a water-soluble polymer (i.e., not being a component of a polymer conjugate as described above).

[0236] In one embodiment, the present disclosure provides an intermediate of Formula VI or a pharmaceutically acceptable salt thereof:

[0237]

[0238] wherein

[0239] 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, nicotinoyl or 1-aryl-1H-tetrazolyl; and

[0240] R 20 and R 21 one of which is H or a blocking group and R 20 and R21 Another one of them is H, a group containing a reactive functional group, or a blocking group, provided that R 20 and R 21 are not both H.

[0241] In one embodiment, R 19 is a substituted or unsubstituted straight-chain alkyl group having 1 to 5 carbons. In one embodiment, R 19 is selected from the group consisting of: -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3, and In one embodiment, R 19 is CH3.

[0242] In one embodiment, one of R 20 and R 21 is a blocking group and R 20 and R 21 the other one of them is a group containing a reactive functional group. In one embodiment, one of R 20 and R 21 is H and R 20 and R 21 the other one of them is a group containing a reactive functional group. In one embodiment, one of R 20 and R 21 is H and R 20 and R 21 the other one of them is a blocking group. In one embodiment, each of R 20 and R 21 is a blocking group.

[0243] In those embodiments where both R 20 and R 21 are blocking groups, the blocking groups on R 20 and R 21 can be the same or can be different. In those embodiments where both R 20 and R 21 are blocking groups, the blocking groups on R 20 and R 21 can contain the same cleavable moiety or different cleavable moieties. In those embodiments where both R 20 and R 21 are blocking groups, the blocking groups on R 20 and R 21 contain the same cleavable moiety, and the cleavable moiety can be an ester linkage.

[0244] Exemplary cleavable moieties include, but are not limited to, ester linkages, carboxylic ester linkages (-C(O)-O-), carbonate linkages (-O-C(O)-O-), carbamate linkages (-O-C(O)-NH-), amide linkages (-C(O)-NH-), and disulfide linkages (S-S); other cleavable moieties are discussed herein. In certain embodiments, the first cleavable moiety is an ester linkage. In another certain embodiment, the cleavable moiety is a carboxylic ester linkage.

[0245] In one embodiment, the blocking group contains a second cleavable moiety, or forms a second cleavable moiety when the blocking group forms a bond with the O atom of R 20 and / or R 21 In one embodiment, when the blocking group forms a bond with the O atom of R 20 and / or R 21 the blocking group forms a second cleavable moiety. 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 in a 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 foregoing.

[0246] In one embodiment, the blocking group is –R 22 -R 23 -, where R 22 is -C(O)-, -O-C(O)-, -C(O)-NH-cyclo-O-C(O)-(where cyclo represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic or cycloalkyl), -C(O)-NH-(C6H4)-O-C(O)- or -O-P(O)(OR9)(O)-(where R9 is H or a substituted or unsubstituted C1-C5 alkyl) and R 23 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl

[0247] In one embodiment, R 22 forms a bond with the oxygen atom of the second phenolic hydroxyl group, and R 22 and the O attached thereto form a second cleavable moiety. In one embodiment, the second cleavable moiety is –C(O)-O.

[0248] In one embodiment, R 23 is a substituted or unsubstituted alkyl. In one embodiment, R 23is a substituted or unsubstituted C1-C6 alkyl group. In one embodiment, R 23 is a substituted or unsubstituted C1-C6 straight-chain alkyl group. In one embodiment, R 23 is a substituted or unsubstituted C1-C6 branched-chain alkyl group. In one embodiment, R 23 is a substituted or unsubstituted aralkyl group. In one embodiment, R 23 is a substituted or unsubstituted aryl group.

[0249] In one embodiment, the blocking group has the structure (CH3) y -(CH x )-(CH2) 0-6 -C(O)- O- compound, wherein 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) y -(CH x )-C(O)- O- compound, wherein 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 -C(O)- O- compound. In one embodiment, the blocking group has the structure CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 - O- compound. In the foregoing, the underlined portion represents a part of the compound containing the catechol moiety and is not considered part of the blocking group.

[0250] In one embodiment, the blocking group has the structure (CH3)-C(O)- O- compound. In one embodiment, the blocking group has the structure CH3-(CH2)2-C(O)- O- compound. In one embodiment, the blocking group has the structure CH3-CH2-C(O)- O- compound. In one embodiment, the blocking group has the structure (CH3)2-CH-C(O)- O- compound. In one embodiment, the blocking group has the structure (CH3)3-C-C(O)- O- compound. In one embodiment, the blocking group has the structure CH3CH2-O-C(O)-CH2CH2-C(O)- O - compound. In one embodiment, the blocking group has the structure In one embodiment, the blocking group has the structure In the foregoing, the underlined portion represents a part of a compound containing a catechol moiety. In the foregoing, the underlined portion represents a part of a compound containing a catechol moiety and is not considered part of a closed group.

[0251] In one embodiment, the group containing the reactive functional group is R 24 -R 25 -R 26 , where R 24 is -C(O)-, -O-C(O)-, -C(O)-NH-cyclo-O-C(O)- (where cyclo represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic or cycloalkyl group), -C(O)-NH-(C6H4)-O-C(O)- or -O-P(O)(OR9)(O)- (where R9 is H or a substituted or unsubstituted C1-C5 alkyl group), R 25 is an unsubstituted or substituted alkyl group, an unsubstituted or substituted alkenyl group, an unsubstituted or substituted aralkyl group or an unsubstituted or substituted aryl group, and R 26 is a moiety containing a reactive group that is capable of forming a linkage with a group on the polymer (including a group at a pendant position 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-hydroxysuccinimide (NHS) and 1-benzotriazinyl active ester), active carbonate, chloroformate, alcohol, azide, vinyl sulfone and o-pyridyl disulfide (OPSS). In one embodiment, R 26 is an azide group (N3) or an alkynyl 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 connected thereto form a first cleavable moiety. In one embodiment, the second cleavable moiety is –C(O)-O.

[0252] In one embodiment, R 25 is a substituted or unsubstituted alkyl group. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 alkyl group. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 straight-chain alkyl group. In one embodiment, R 25 is a substituted or unsubstituted C1-C6 branched-chain alkyl group.

[0253] In one embodiment, R 26 is N3. When R 26When N is N3, the compound of formula V can be linked to a polymer containing an alkynyl group (such as but not limited to acetylene) via copper(I)-catalyzed azide-alkyne click chemistry. In such a reaction, the compound of formula V is linked to an azide group as described herein and undergoes a copper(I)-catalyzed click reaction with the alkynyl group on the polymer. In one of the foregoing embodiments, the alkynyl group is at a pendant position on the polymer. In one of the foregoing embodiments, the polymer is a polyoxazoline polymer and the alkynyl group is at a pendant position on the polyoxazoline polymer.

[0254] In one embodiment, R 26 is an alkyne. When R 26 is an alkyne (such as but not limited to acetylene), the compound of formula V can be linked to a polymer containing an N3 group via copper(I)-catalyzed azide-alkyne click chemistry. In such a reaction, the compound of formula V is linked to an alkynyl group as described herein and undergoes a copper(I)-catalyzed click reaction with the azide group on the polymer. In one of the foregoing embodiments, the azide group is at a pendant position on the polymer. In one of the foregoing embodiments, the polymer is a polyoxazoline polymer and the azide group is at a pendant position on the polyoxazoline polymer.

[0255] In one embodiment, the group containing the reactive functional group has the structure N 3- (CH2) 1-6 -C(O) -O- compound. In one embodiment, the blocking group has the structure C ＝ C-(CH2) 1-6 -C(O)- O -compound. In one embodiment, the group containing the reactive functional group has the structure N 3- (CH2)3-C(O) -O- compound. In one embodiment, the blocking group has the structure C ＝ C-(CH2)3-C(O)- O -compound. In the foregoing, the underlined portion represents a part of the compound containing the catechol moiety and is not considered to be a part of the group containing the reactive functional group.

[0256] Certain preferred compounds according to the present disclosure that are used as intermediates are provided below.

[0257]

[0258]

[0259] and the compounds of the examples.

[0260] In the foregoing preferred compounds according to the present disclosure, R19 and R 23 and R 25 may be as described herein.

[0261] In one embodiment, R 19 is selected from the group consisting of: –H, CH3, -CH2-CH3, -CH2-CH2-CH3, and R 23 (when present) is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl, and R 25 (when present) is -(CH2) 1-6 - or -(CH2)3-.

[0262] In one embodiment, R 19 is selected from the group consisting of: –H, CH3, -CH2-CH3, -CH2-CH2-CH3, and R 23 (when present) is (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), (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), CH3-(CH2) 0-6 -C(O)- or CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 -, and R 25 (when present) is -(CH2) 1-6 - or -(CH2)3-.

[0263] In one embodiment, R 19 is selected from the group consisting of: –H, CH3, -CH2-CH3, -CH2-CH2-CH3, and R 23 (when present) is CH3-, CH3-(CH2)2-, CH3-CH2-, (CH3)2-CH-, (CH3)3-C-, or and R 25 (when present) is -(CH2) 1-6 - or -(CH2)3-.

[0264] In any of the foregoing compounds, R 19 is CH3.

[0265] Certain preferred compounds according to the present disclosure are provided below for use as active agents.

[0266]

[0267] Among the aforementioned preferred compounds according to the present disclosure, R 19 and R 23 may be as described herein. Without being bound by any particular theory, it is believed that administering a compound having a blocking group on at least one of the first phenolic hydroxyl or the second phenolic hydroxyl results in a compound that causes less skin irritation (compared to a compound having free hydroxyl groups on both the first phenolic hydroxyl and the second phenolic hydroxyl).

[0268] In one embodiment, R 19 is selected from the group consisting of: –H, CH3, -CH2-CH3, -CH2-CH2-CH3, and and R 23 is (or when there are two R 23 groups, independently selected from) unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted aryl.

[0269] In one embodiment, R 19 is selected from the group consisting of: –H, CH3, -CH2-CH3, -CH2-CH2-CH3, and and R 23 is (or when there are two R 23 groups, independently selected from) (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), (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), CH3-(CH2) 0-6 -C(O)- or CH3-(CH2) 0-6 -C(O)-(CH2) 0-6 -.

[0270] In one embodiment, R 19 is selected from the group consisting of: –H, CH3, -CH2-CH3, -CH2-CH2-CH3, and and R 23 is (or when there are two R 23When the group is independently selected from) CH3-, CH3-(CH2) 2-, CH3-CH2-, (CH3) 2-CH-, (CH3) 3-C- or

[0271] In any of the foregoing compounds, R 19 is CH3.

[0272] Therapeutic method

[0273] The present disclosure also provides polymer conjugates of Formula I, Formula II, Formula IIA and Formula IIB for use as active agents in the treatment methods described herein. Such conjugates comprise a polymer moiety linked via a first cleavable linkage to a compound comprising a catechol moiety, wherein the cleavable linkage is formed between the polymer and the first phenolic hydroxyl group of the catechol moiety, and the second phenolic hydroxyl group of the catechol moiety is linked to a blocking group, wherein the cleavage (i.e., release rate) of the compound comprising the catechol moiety is at least partially controlled by the structure and / or design of the blocking group. The present disclosure further shows that the release of the compound from the polymer conjugate can be controlled. In one aspect, the compound is delivered with a pharmacokinetic / release profile that does not have the peaks and valleys seen in prior art treatments. In one aspect, over a period of time (e.g., 12 hours to 168 hours), a near-steady-state release of the compound from the polymer conjugate is achieved.

[0274] In one embodiment, the conjugate provides delivery of a therapeutically effective amount of the compound to a subject over the following time periods: 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 controlled delivery or sustained controlled delivery. In any of the foregoing embodiments, the compound is delivered with a pharmacokinetic / release profile that does not have peaks and valleys.

[0275] In one embodiment, the conjugate provides delivery of a therapeutically effective amount of the compound to a subject over a period of one week or longer. In one embodiment, the conjugate provides delivery of a therapeutically effective amount of the compound to a subject over the following time periods: one to two weeks; one to three weeks; or one to four weeks. In any of the foregoing embodiments, the delivery is controlled delivery or sustained controlled delivery. In any of the foregoing embodiments, the compound is delivered with a pharmacokinetic / release profile that does not have peaks and valleys.

[0276] In one embodiment, the delivery provides a release profile that provides a therapeutically effective amount of the compound over such time periods. Accordingly, the polymer conjugates of the present disclosure can be used to treat human diseases by appropriate selection of the compound and / or the capping group. In addition, the polymer conjugates of the present disclosure allow for less frequent administration compared to the art to achieve a therapeutically effective amount of the compound in a subject. In one embodiment, the polymer conjugates of the present disclosure are administered once daily, once every other day, once a week, once every two weeks, once every three weeks, once a month, or at other desired intervals.

[0277] The present disclosure also provides compounds of Formula V or Formula VI for use as active agents in the therapeutic methods described herein. The generation of one or two free hydroxyl groups on the compound of Formula V or Formula IV is at least partially controlled by the structure of the capping group on the first hydroxyl and / or the second hydroxyl.

[0278] The present disclosure provides various therapeutic methods using the conjugates and compounds of the present disclosure. The present disclosure provides methods of treating a disease or disorder, the method comprising the step of 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 Formula VI), wherein the disease or disorder is selected based on the compound that is part of the polymer conjugate. For example, when the compound is a dopamine agonist, the disease or disorder to be treated can be a disease or disorder associated with dopamine deficiency in the peripheral or central nervous system. In another example, when the compound is a dopamine agonist, the disease or disorder to be treated can be a hypodopaminergic disorder, pituitary tumor (prolactinoma), Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, hypodopaminergic disorder, SSRI-induced sexual dysfunction, depression, obesity, and type II diabetes. Other diseases and disorders that can be treated are described in Rubi et al. (Endocrinology, 151(12), 5570-5581, 2010, which reference is incorporated by reference for such teachings).

[0279] Compounds containing a catechol moiety have been reported to treat a variety of diseases and disorders, as described in Yang et al. (Molecules, 2007, 12, 878-884), which document is incorporated by reference for such teachings.

[0280] The present disclosure provides methods for treating dopamine-responsive diseases or disorders, the methods comprising the step of 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 Formula VI), wherein the agent is a dopamine agonist. In one embodiment, the dopamine-responsive disease or disorder is a hypodopaminergic disorder, pituitary tumor (prolactinoma), Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, hypodopaminergic disorder, SSRI-induced sexual dysfunction, depression, obesity, and type II diabetes. In another embodiment, such disease or disorder is Parkinson's disease. In another embodiment, such disease or disorder is restless legs syndrome 。

[0281] The present disclosure provides methods for treating Parkinson's disease, the methods comprising the step of 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 Formula VI), wherein the agent is a dopamine agonist.

[0282] The present disclosure provides methods for treating dopamine deficiency in the peripheral or central nervous system, the methods comprising the step of 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 Formula VI), wherein the agent is a dopamine agonist.

[0283] In any of the foregoing treatment methods, one or more of the following may apply to each of the treatment methods.

[0284] In any of the foregoing embodiments, any of the polymer conjugates described herein may be used, and the compound may be selected based on the disease or disorder to be treated.

[0285] 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 as shown for Formulas II-IIB.

[0286] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer.

[0287] In any of the foregoing embodiments, the compound is a compound of Formula III or Formula IV or a compound of Yang et al. (Molecules, 2007, 12, 878-884) Figure 1 or a compound in Table 1S. In one embodiment, the compound comprising a catechol moiety is a compound described by Yang et al. (specifically including Figure 1 and Table S1) that can be used to treat dopamine-responsive disorders (such as but not limited to Parkinson's disease). In one embodiment, the compound comprising a catechol moiety is apomorphine, fenoldopam, entacapone, or tolcapone.

[0288] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is a compound of formula III or formula IV or a compound of Yang et al. (Molecules, 2007, 12, 878 - 884) Figure 1 or a compound in Table 1S. In any of the foregoing embodiments, the polymer is a polyoxazoline polymer, and the compound is a compound of formula III or formula IV or a compound described by Yang et al. (specifically including Figure 1 and Table S1) that can be used to treat dopamine-responsive disorders such as, but not limited to, Parkinson's disease. In one embodiment, the compound is apomorphine, abuterol, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoproterenol, isoprenaline, levodopa, levonordefrin, maprotolol, methyldopa, methyldopa ethyl ester, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam. In another embodiment, the compound is apomorphine, fenoldopam, entacapone, tolcapone, chf-1303, dopamantane, dopamine, droxidopa, etilevodopa, idebenone, or levodopa. In another embodiment, the compound is apomorphine, fenoldopam, entacapone, tolcapone, or levodopa. In the foregoing list of exemplary compounds, it should be understood that the first phenolic hydroxyl group of the catechol moiety is modified by R 15 to give OR 15 , and the second phenolic hydroxyl group of the catechol moiety is modified by R 16 to give OR 16 . In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is a compound of formula III or formula IV or is apomorphine, fenoldopam, entacapone, or tolcapone.

[0289] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer.

[0290] In any of the foregoing embodiments, the compound is a dopamine agonist such as, but not limited to, apomorphine.

[0291] In any of the foregoing embodiments, the compound is fenoldopam, entacapone, or tolcapone.

[0292] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is a dopamine agonist such as, but not limited to, apomorphine.

[0293] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is fenoldopam, entacapone, or tolcapone.

[0294] In any of the foregoing embodiments, the compound is apomorphine.

[0295] In any of the foregoing embodiments, the polymer is a polyoxazoline polymer and the compound is apomorphine.

[0296] In any of the foregoing embodiments, the polymer conjugate or compound (e.g., a compound of Formula V and / or Formula VI) can be administered alone or as part of a pharmaceutical composition as described herein. In any of the foregoing embodiments, it can be determined that a subject is 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 Formula VI) is administered in a therapeutically effective amount. In any of the foregoing embodiments, the subject can be a mammal. In the foregoing embodiment, the subject can be a human.

[0297] In any of the foregoing embodiments, a method of treatment can be achieved by subcutaneously administering (e.g., by subcutaneous injection) the polymer conjugate or compound (e.g., a compound of Formula V and / or Formula VI) of the present disclosure or a pharmaceutical composition containing such polymer conjugate or compound.

[0298] In any of the foregoing embodiments, a method of treatment can be achieved by subcutaneously administering a compound (e.g., a compound of Formula V and / or Formula VI) of the present disclosure or a pharmaceutical composition containing such compound. Suitable routes of subcutaneous administration include but are not limited to subcutaneous injection or subcutaneous infusion. In a particular embodiment, the compound of Formula V and / or Formula VI is a compound comprising a blocking group on one or both (preferably both) of the first phenolic hydroxyl group and the second phenolic hydroxyl group, wherein the cleavable moiety on one or more of the blocking groups is an ester linkage. In another particular embodiment, the compound of Formula V and / or Formula VI is apomorphine comprising a blocking group on one or both (preferably both) of the first phenolic hydroxyl group and the second phenolic hydroxyl group, wherein the cleavable moiety on one or more of the blocking groups is an ester linkage. Without being bound by any particular theory, the compounds of Formula V and VI comprising a blocking group on one or both (preferably both) of the first phenolic hydroxyl group and the second phenolic hydroxyl group (wherein the cleavable moiety on one or more of the blocking groups is an ester linkage) are advantageously administered to a subject via subcutaneous infusion without the side effects (such as but not limited to skin irritation) seen with the administration of prior art compounds. Since the enzymes required to cleave the ester linkage are not present in the blood of a human subject, the cleavable moiety on one or more of the blocking groups is not cleaved upon subcutaneous administration (including subcutaneous injection or subcutaneous infusion). Thus, the hydroxyl groups of the catechol moiety are not exposed on the compound until the compound leaves the subcutaneous space, thereby reducing the administration side effects seen in the prior art (especially when the compound is apomorphine).

[0299] Preferred apomorphine compounds for administration by subcutaneous injection or subcutaneous infusion include but are not limited to the following compounds:

[0300]

[0301] In any of the foregoing embodiments, the polymer conjugate is administered once daily, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered once every other day, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered every three days, every four days, every five days, or every six days, 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 also be used, based on the nature of the selected polymer conjugate and the release kinetics of the compound.

[0302] In any of the foregoing embodiments, the polymer conjugate is administered subcutaneously once daily, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is administered subcutaneously once 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 three days, every four days, every five days, or every six days, 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 also be used, based on the nature of the selected polymer conjugate and the release kinetics of the compound.

[0303] In any of the foregoing embodiments, the polymer conjugate is a polyoxazoline polymer and the compound is apomorphine, and the polymer conjugate is administered once daily by subcutaneous administration, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is a polyoxazoline polymer and the compound is apomorphine, and the polymer conjugate is administered once every other day by subcutaneous administration, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is a polyoxazoline polymer and the compound is apomorphine, and the polymer conjugate is administered every three days, every four days, every five days or every six days by subcutaneous administration, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is a polyoxazoline polymer and the compound is apomorphine, and the polymer conjugate is administered once weekly by subcutaneous administration, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is a polyoxazoline polymer and the compound is apomorphine, and the polymer conjugate is administered once every two weeks by subcutaneous administration, either alone or as part of a pharmaceutical composition. In any of the foregoing embodiments, the polymer conjugate is a polyoxazoline polymer and the compound is apomorphine, and the polymer conjugate is administered once every four weeks by subcutaneous administration, either alone or as part of a pharmaceutical composition. Other dosing frequencies may also be used, depending on the nature of the selected polymer conjugate and the release kinetics of the compound.

[0304] In any of the foregoing embodiments, the polymer conjugates described herein may also be administered in combination with other therapeutic agents, such as other agents useful for treating dopamine-responsive disorders (such as but not limited to Parkinson's disease or any other disorder described herein). When administered with other therapeutic agents, the polymer conjugates of the present disclosure may be administered before, after, or simultaneously with the additional therapeutic agent. Accordingly, in one embodiment, the present disclosure also provides a composition comprising a polymer conjugate described herein, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier.

[0305] Kit

[0306] The present disclosure provides a kit comprising, consisting essentially of, or consisting of: a water-soluble polymer, including but not limited to a polyoxazoline polymer, and a compound of formula V or formula VI, and one or more of the following: a reagent for coupling an intermediate to the polymer, a packaging material, and instructions for coupling the intermediate to the polymer.

[0307] The present disclosure provides a kit that comprises, consists essentially of, or consists of: a compound comprising a catechol moiety, a reagent for forming a protecting group on one of the phenolic hydroxyls of the catechol moiety and / or a functional group on the other phenolic hydroxyl of the catechol moiety, and one or more of the following: a water-soluble polymer (including but not limited to a polyoxazoline polymer), a packaging material, and instructions for forming a protecting group on one of the phenolic hydroxyls of the catechol moiety and / or a functional group on the other phenolic hydroxyl of the catechol moiety.

[0308] The present disclosure provides a kit that comprises, consists essentially of, or consists of: a polymer conjugate of the present disclosure and one or more of the following: a packaging material and instructions for administering the polymer conjugate to a subject for treating a disease or disorder, wherein the disease or disorder is selected based on the compound that is part of the polymer conjugate. For example, when the compound is a dopamine agonist, the disease or disorder to be treated can be Parkinson's disease. Compounds comprising a catechol moiety have been reported to treat a variety of diseases and disorders, as described in Yang et al. (Molecules, 2007, 12, 878 - 884), which is incorporated by reference for such teachings.

[0309] The present disclosure provides a kit that comprises, consists essentially of, or consists of: a polymer conjugate of the present disclosure and one or more of the following: a packaging material and instructions for administering the polymer conjugate to a subject for treating a dopamine-responsive disease or disorder. In one embodiment, the dopamine-responsive disease or disorder is a hypodopaminergic disorder, Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, pituitary tumor (prolactinoma), hypodopaminergic disorder, SSRI-induced sexual dysfunction, depression, obesity, and type II diabetes. In one embodiment, such disease or disorder is Parkinson's disease. In one embodiment, such disease or disorder is restless legs syndrome.

[0310] The present disclosure provides a kit that comprises, consists essentially of, or consists of: a polymer conjugate of the present disclosure and one or more of the following: a packaging material and instructions for administering the polymer conjugate to a subject for treating a hypodopaminergic disorder.

[0311] The present disclosure provides a kit that comprises, consists essentially of, or consists of: a polymer conjugate of the present disclosure and one or more of the following: a packaging material and instructions for administering the polymer conjugate to a subject for treating Parkinson's disease.

[0312] The present disclosure provides a medicament cartridge comprising, consisting essentially of, or consisting of: a polymer conjugate of the present disclosure and one or more of the following: a packaging material and instructions for administering the polymer conjugate to a subject for treating restless legs syndrome.

[0313] In any of the above medicament cartridges, one or more of the following may also apply: i) the medicament cartridge further comprises an additional active agent; ii) the medicament cartridge further comprises an additional active agent and the instructions specify administering the additional active agent in relation to the administration of the polymer conjugate; iii) the instructions specify that the polymer conjugate will be administered subcutaneously; iv) the instructions specify that the polymer conjugate will be administered subcutaneously once a day, once every other day, once every three days, once every four days, once every five days, or once every six days, once a week, once every two weeks, or once every four weeks; v) the medicament cartridge further comprises a delivery system or a part thereof for administering the polymer conjugate; vi) in one embodiment of the general formula as shown in Formula II or Formula III, the polymer conjugate is a poly(oxazoline) polymer conjugate; vii) the compound is a compound of Formula II or Formula III or a compound of Yang et al. (Molecules, 2007, 12, 878 - 884) Figure 1 or a compound in Table 1S; viii) the polymer is a polyoxazoline polymer and the compound is a compound of Formula II or Formula III or a compound of Yang et al. (Molecules, 2007, 12, 878 - 884) Figure 1 or a compound in Table 1S; ix) the compound is fenoldopam, entacapone, or tolcapone; x) the compound is fenoldopam, entacapone, or tolcapone and the polymer is a polyoxazolidine polymer; xi) the compound is apomorphine; xii) the compound is apomorphine and the polymer is a polyoxazole polymer; xiii) the compound is a dopamine agonist; xiv) the compound is a dopamine agonist and the polymer is a polyoxazole polymer;

[0314] In certain embodiments, all of i) to xiv) apply. In certain embodiments, one, two, three, or four or more of i) to xiv) apply. In certain embodiments, at least one of iii), iv), and vi) to xiv) applies. In certain embodiments, two of iii), iv), and vi) to xii) apply.

[0315] Pharmaceutical composition and route of administration

[0316] There is provided a pharmaceutical composition comprising an amount of a polymer conjugate or compound of the present disclosure (e.g., a compound of Formula V and / or Formula VI). In one embodiment, such a pharmaceutical composition contains a therapeutically effective amount of a conjugate or compound of the present disclosure (e.g., a compound of Formula V and / or Formula VI). In certain embodiments, the conjugate of the present disclosure is a conjugate of Formula I, Formula II, Formula IIA or Formula IIB. In certain embodiments, the conjugate of the present disclosure is a conjugate of Formula I, Formula II, Formula IIA or Formula IIB and the polymer is a polyoxazoline polymer. Additionally, other active agents may be included in such pharmaceutical compositions. The additional active agent to be included may be selected based on the disease or disorder to be treated.

[0317] The disclosed pharmaceutical compositions may comprise one or more conjugates or compounds of the present disclosure (e.g., a compound of Formula V and / or Formula VI), said conjugate or compound alone or in combination with an additional active agent, in combination with a pharmaceutically acceptable carrier. Examples of such carriers and methods of formulation can be found in Remington: The Science and Practice of Pharmacy (20th Edition, Lippincott, Williams & Wilkins, edited by Daniel Limmer). Such conjugates and pharmaceutical compositions can be used to manufacture a medicament for use in the treatment methods described herein. The conjugate or compound of the present disclosure (e.g., a compound of Formula V and / or Formula VI) is available both in free form and in the form of pharmaceutically acceptable salts.

[0318] The pharmaceutically 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 excipient will be determined in part by one or more particular conjugates and the particular method for administering the formulation. Accordingly, there are numerous suitable pharmaceutical composition formulations. The following methods and excipients are merely exemplary and in no way limiting. Suitable carriers and excipients include solvents (such as water, alcohols and propylene glycol), solid absorbents and diluents, surfactants, suspending agents, tablet binders, lubricants, flavoring agents and coloring agents. Pharmaceutically acceptable carriers may include polymers and polymer matrices. Examples of acceptable pharmaceutical carriers include carboxymethylcellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others. Generally, a pharmaceutically acceptable carrier is chemically inert to the active agent in the composition and has no adverse side effects or toxicity under the conditions of use. In some embodiments, the term "pharmaceutically acceptable" means approved by a federal regulatory agency or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in animals and more particularly for use in humans.

[0319] In one embodiment, such pharmaceutical compositions contain a therapeutically effective amount of a conjugate or compound of the present disclosure (e.g., a compound of Formula V and / or Formula VI). In certain embodiments, the conjugate is a conjugate of Formula I, Formula II, Formula IIA, or Formula IIB. Additionally, other active agents may be included in such pharmaceutical compositions. The additional active agent to be included may be selected based on the disease or disorder to be treated.

[0320] The disclosed pharmaceutical compositions may contain one or more conjugates or compounds of the present disclosure (e.g., a compound of Formula V and / or Formula VI), which conjugates or compounds, alone or in combination with additional active agents, are combined with a pharmaceutically acceptable carrier.

[0321] The conjugates of the present disclosure and pharmaceutical compositions containing such conjugates or compounds (e.g., a compound of Formula V and / or Formula VI) may be administered by any conventional method useful for use in conjunction with a medicament, the medicament being used as a single therapeutic agent or in combination with additional therapeutic agents. Those skilled in the art will understand that suitable methods for administering the conjugates of the present disclosure to a patient, either alone or in the form of a pharmaceutical formulation, are available, and although more than one route may be used, a particular route may provide a more direct and more effective response than another route.

[0322] In one embodiment, whether alone or as part of a pharmaceutical composition, the conjugate or compound of the present disclosure (e.g., a compound of Formula V and / or Formula VI) is administered in a therapeutically effective amount. Of course, the therapeutically effective amount and the dosage administered will vary depending on known factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health, and weight of the recipient; the severity and stage of the disease state or condition; the type of concurrent treatment; the frequency of treatment; and the desired effect.

[0323] The total amount of the conjugate or compound (e.g., a compound of Formula V and / or Formula VI) administered, whether alone or as part of a pharmaceutical composition, will also be determined by the route, timing, and frequency of administration and the presence, 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 understand that various disease states or disorders, particularly chronic disease states or disorders, may require extended treatment involving multiple administrations.

[0324] In one embodiment of the pharmaceutical composition, the conjugate or compound of the present disclosure (e.g., a compound of Formula V and / or Formula VI) will generally be present in an amount of about 0.5 - 95% by weight based on the total weight of the composition. A variety of dosage forms may be administered as part of a single treatment.

[0325] 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 in liquid dosage forms such as emulsions, 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 a sterile liquid dosage form, intranasally (drops), or by inhalation through the pulmonary system (such as by a propellant-based metered-dose inhaler or a dry powder inhalation device). Other dosage forms include topical administration, such as transdermal administration, via a patch mechanism or an ointment.

[0326] Preparations suitable for enteral or oral administration can be liquid solutions, such as a therapeutically effective amount of a conjugate or compound (e.g., a compound of Formula V and / or Formula VI) dissolved in a diluent such as milk, water, saline, a buffer solution, infant formula, other suitable carriers, or combinations thereof. The conjugate or compound can then be mixed with the diluent immediately prior to administration. In alternative embodiments, preparations suitable for enteral or oral administration can be capsules, sachets, tablets, lozenges, and troches. In each embodiment, the preparation can contain a predetermined amount of a conjugate or compound of the present disclosure, the conjugate or compound being in solid or particulate, powder, suspension, and suitable emulsion form. Liquid preparations can contain diluents such as water and alcohols, such as ethanol, benzyl alcohol, propylene glycol, glycerol, and polyvinyl alcohol, with or without pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Capsule forms can be of the ordinary hard or soft gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can 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, and other excipients, coloring agents, diluents, buffers, disintegrants, wetting agents, preservatives, flavoring agents, and pharmaceutically compatible carriers.

[0327] Troche forms can contain a conjugate in a flavoring agent (usually sucrose and acacia or tragacanth), and soft pastilles, emulsions, and gels containing the active ingredient in an inert matrix such as gelatin and glycerol or sucrose and acacia, containing such carriers known in the art in addition to the active ingredient.

[0328] Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the preparation isotonic with the blood of the patient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The conjugate or compound, alone or as part of a pharmaceutical composition, can be administered in a physiologically acceptable diluent in a pharmaceutically acceptable carrier such as a sterile liquid or liquid mixture including water, saline, dextrose aqueous solution and related sugar solutions, alcohols such as ethanol, isopropanol or cetyl alcohol, diols such as propylene glycol or polyethylene glycols such as poly(ethylene glycol) 400, glycerol ketals such as 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 pharmaceutically acceptable surfactant such as a soap or detergent, suspending agents such as pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0329] Oils which can be used in parenteral preparations include petroleum, animal, vegetable or synthetic oils. Specific examples of oils include peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Fatty acids suitable for parenteral preparations include oleic acid, stearic acid and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for parenteral preparations include alkali metal salts of fatty acids, ammonium salts and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium halides and alkylpyridinium halides, (b) anionic detergents such as, for example, sulfonates of alkyls, aryls and olefins, sulfates and sulfosuccinates of alkyls, olefins, ethers and glycerol monoesters, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl β-aminopropionates and 2-alkylimidazoline quaternary ammonium salts, and (e) mixtures thereof.

[0330] Parenteral preparations generally contain from about 0.5% to about 50% by weight of the conjugate or compound in solution. Suitable preservatives and buffers can be used in such preparations. To minimize or eliminate irritation at the injection site, such compositions may contain one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such preparations is from about 5% to about 15% by weight. Suitable surfactants include polyethylene glycol sorbitan fatty acid esters such as sorbitan monooleate, and high molecular weight addition products of ethylene oxide with a hydrophobic matrix formed by the condensation of propylene oxide with propylene glycol.

[0331] Examples

[0332] The following examples provide a description of 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. As a result of certain methods for synthesizing compounds with the desired linkages and capping groups, the polymer conjugates are shown to contain two different linkages of the compound to the polymer moiety (i.e., for apomorphine, the compound is shown to be linked to the polymer moiety via linkages between both the hydroxyl groups at positions 10 and 11). For example, in Example 4, apomorphine-10,11-[(4'-azidobutyrate)(isobutyrate)] hydrochloride containing a linking group and an isobutyrate capping group was synthesized, where the linking group was at position 10 of the apomorphine molecule in Compound 3a and the capping group was at position 11 (and inverted in Compound 3b). Linking Compounds 3a and 3b to the polymer moiety (see Example 7) resulted in apomorphine being linked to the polymer moiety via the hydroxyl groups at both positions 10 and 11. However, if a particular form of the compound (e.g., one of 3a or 3b) is desired, the compounds can be separated using conventional techniques (e.g., chromatography). The following examples also provide methods for analyzing these conjugates, as well as measurements of the hydrolysis rates of these conjugates in human plasma.

[0333] Materials

[0334] Apomorphine hydrochloride was obtained from Johnson Matthey. POZ 10p-acid 20K and 4-azidobutyryl chloride were synthesized by Serina Therapeutics. Butyryl chloride, isobutyryl chloride, benzoyl chloride, 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. Sodium L(+)-ascorbate, 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. The SNAPUltra C18 30g column and the Isolera system for column purification were from Biotage.

[0335] Example 1 - Synthesis of apomorphine mono-(4'-azidobutyrate) hydrochloride

[0336]

[0337] Apomorphine hydrochloride (4.00 g, 12.72 mmol, 1 eq.) was weighed into a 500 mL RB flask with 385 mL of DCM. Under argon, triethylamine (3.546 mL, 25.44 mmol, 2 eq.) was added, and then a solution of 4-azidobutyryl chloride (1.877 g, 12.72 mmol, 1 eq.) in 15 mL of DCM was added to the reaction mixture. The solution was stirred for 30 minutes at room temperature under argon, after which the solution was washed with 0.1 N HCl (1271 mL). After phase separation, NaCl (147 g) 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 g). After filtration to remove sodium sulfate, the filtrate was evaporated to dryness. The residue was further dried in vacuo to give 2.90 g of an off-white crude product. Reverse-phase HPLC analysis of the crude product showed 97.8% of 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 in 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 × 200 mL). The DCM phase was dried over anhydrous sodium sulfate (150 g). After filtration, the filtrate was concentrated to dryness by rotary evaporation and further dried in vacuo overnight to give 2.65 g of a light gray solid (1a + 1b, 50% yield). HPLC purity > 99.9%.

[0338] Example 2 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(butyrate)] hydrochloride

[0339]

[0340] Apomorphine-(4'-azidobutyrate) hydrochloride (1a + 1b, 0.40 g, 0.964 mmol) was weighed into a 100 mL round-bottom flask with 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 eq.). The solution was stirred overnight at room temperature under argon. Reverse-phase HPLC analysis of the reaction mixture indicated that the reaction was complete. The solution was evaporated to dryness, and the remaining syrup was dissolved in DCM (100 mL), washed with deionized water (200 mL), and then washed with 0.1 N HCl (200 mL). The DCM phase was dried over anhydrous sodium sulfate (40 g) and then filtered. The filtrate was evaporated to dryness. The residue was further dried in vacuo to give 0.58 g of an amber waxy solid (2a + 2b).

[0341] Example 3 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(isobutyrate)] hydrochloride

[0342]

[0343] Apomorphine-(4'-azidobutyrate) hydrochloride (1a + 1b, 0.10 g, 0.241 mmol) was weighed into a 25 mL round-bottom flask with anhydrous DCM (10 mL). Under argon, trifluoroacetic acid (1 mL) was added, followed by isobutyryl chloride (0.25 mL, 2.41 mmol, 10 eq.). 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 g) and filtered. The filtrate was evaporated to dryness and further dried under vacuum to give 0.12 g of an amber residue (3a + 3b). HPLC analysis of the product showed a purity of 100%.

[0344] Example 4 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(isobutyrate)] hydrochloride

[0345]

[0346] Apomorphine-(4'-azidobutyrate) hydrochloride (1a + 1b, 0.50 g, 1.205 mmol) was weighed into a 100 mL round-bottom flask with anhydrous DCM (50 mL). Under argon, triethylamine (0.34 mL, 2.410 mmol, 2 eq.) was added, followed by isobutyryl chloride (0.155 mL, 1.446 mmol, 1.2 eq.). The solution was stirred overnight at room temperature under an argon atmosphere. Subsequently, the solution was washed twice with 0.1 N HCl (145 mL). The DCM phase was dried over anhydrous sodium sulfate (25 g), then filtered. The filtrate was evaporated to dryness. It was further dried under vacuum to give 0.49 g of an amber residue (3a + 3b). HPLC analysis of the product showed a purity of 99.4%.

[0347] Example 5 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(benzoate)] hydrochloride

[0348]

[0349] Apomorphine-(4'-azidobutyrate) hydrochloride (1a + 1b, 0.50 g, 1.205 mmol) was weighed into a 100 mL round-bottom flask with anhydrous DCM (50 mL). Under argon, triethylamine (0.34 mL, 2.410 mmol, 2 eq.) was added, followed by benzoyl chloride (0.168 mL, 1.446 mmol, 1.2 eq.). 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 g) and then filtered. The filtrate was evaporated to dryness. Further drying under vacuum gave 0.55 g of an amber residue (4a + 4b). HPLC analysis of the product showed a purity of 97.7%.

[0350] Example 6 - Synthesis of POZ10p20k [Apo(4-butyrate)(4-triazole butyrate)] by click reaction 10 (5)

[0351] Apomorphine-10,11-[(4’-azidobutyrate)(butyrate)] hydrochloride (2a + 2b, 0.10 g, 0.21 mmol, 11.6 eq.) and POZ 10p-acid 20K (0.37 g, 0.018 mmol, 1 eq.) were dissolved in DMSO (10 mL) and deionized water (5 mL) in a 50 mL round-bottom flask. Then, under argon, sodium ascorbate (0.017 g, 0.085 mmol, 4.64 eq.) was added to the flask, followed immediately by CuSO4·5H2O (0.021 g, 0.085 mmol, 4.64 eq.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl (150 mL) with 10 wt% NaCl 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 the aqueous solution through Ambersep M4195 medium packed in a glass column. The column was eluted with 2 mM HCl (50 mL). NaCl (9 g) was added to the collected eluate (60 mL) and the turbid solution was extracted with DCM (2 × 50 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (30 g). After filtration to remove sodium sulfate, the filtrate was concentrated to near dryness by rotary evaporation. The residue was dissolved in DCM (4 mL), followed by precipitation in ether (60 mL). After filtration, the precipitate was collected and dried in vacuo to give 0.39 g of a white powder (POZ10p20k 10 , 5; POZ-Apomorphine A).

[0352]

[0353] Example 7 - Synthesis of POZ10p20k [Apo(2-methyl propionate)(4-triazole butyrate)] via click reaction 10 (6)

[0354] In a 50 mL round-bottom flask, apomorphine-10,11-[(4’-azidobutyrate)(isobutyrate)] hydrochloride (3a + 3b, 0.086 g, 0.178 mmol, 11.6 eq.) and POZ 10p-acid 20K (0.31 g, 0.015 mmol, 1 eq.) were dissolved in DMSO (8 mL) and deionized water (4 mL). Then, under argon, sodium ascorbate (0.014 g, 0.071 mmol, 4.64 eq.) was added to the flask, followed immediately by CuSO4·5H2O (0.018 g, 0.071 mmol, 4.64 eq.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl (150 mL) containing 10 wt% NaCl 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 the aqueous solution through Ambersep M4195 medium packed in a glass column. The column was eluted with 2 mM HCl (40 mL). NaCl (7.5 g) was added to the collected eluate (50 mL) and the turbid solution was extracted with DCM (2 × 50 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (30 g). 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 then precipitated in ether (50 mL). After filtration, the precipitate was collected and dried in vacuo to give 0.36 g of a white powder (POZ10p20k[Apo(2-methylpropionate)(4-triazolebutyrate)] 10 , 6; POZ-apomorphine B).

[0355]

[0356] Example 8 - Synthesis of POZ10p20k [Apo(4-benzoate)(4-triazolebutyrate)] via click reaction 10 (7)

[0357] In a 50 mL round-bottom flask, apomorphine-10,11-[(4’-azidobutyrate)(benzoate)] hydrochloride (4a + 4b, 0.129 g, 0.238 mmol, 11.6 eq.) and POZ 10p-acid 20K (0.42 g, 0.021 mmol, 1 eq.) were dissolved in DMSO (10 mL) and deionized water (5 mL). Then, under argon, sodium ascorbate (0.019 g, 0.095 mmol, 4.64 eq.) was added to the flask, and immediately thereafter CuSO4·5H2O (0.024 g, 0.095 mmol, 4.64 eq.) was added. The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl (150 mL) containing 10 wt% NaCl 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 copper in the aqueous solution was removed by passing the aqueous solution through Ambersep M4195 medium packed in a glass column. The column was eluted with 2 mM HCl. NaCl (11.3 g) was added to the collected eluate (75 mL), and the turbid solution was extracted with DCM (2 × 50 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (50 g). 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 then precipitated in ether (50 mL). After filtration, the precipitate was collected and dried in vacuo to give 0.5 g of a white powder (POZ10p20k[Apo(4-benzoate)(4-triazolebutyrate)] 10 , 7; POZ-apomorphine C).

[0358]

[0359] Example 9 - Synthesis of POZ10p20k [Apo(4 - triazole - 4 - butyrate)] by click reaction 10 (8)

[0360] In a 50 mL round-bottom flask, apomorphine-(4’-azidobutyrate) hydrochloride (1a + 1b, 0.069 g, 0.166 mmol, 11.3 eq.) and POZ 10p-acid 20K (0.30 g, 0.0146 mmol, 1 eq.) were dissolved in deionized water (10 mL). Then, under an argon atmosphere, sodium ascorbate (0.013 g, 0.066 mmol, 4.54 eq.) was added to the flask, and immediately thereafter, CuSO4·5H2O (0.017 g, 0.066 mmol, 4.54 eq.) was added. The solution was then stirred overnight at room temperature under an argon atmosphere. The copper in the aqueous solution was removed by passing the aqueous solution through Ambersep M4195 medium packed in a glass column. The column was eluted with 2 mM HCl. NaCl (7.5 g) was added to the collected eluate (75 mL), and the turbid solution was extracted with DCM (4 × 20 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (30 g). 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 then precipitated in ether (60 mL). After filtration, the precipitate was collected and dried in vacuo to give 0.3 g of a white powder (POZ10p20k 10 , 8; POZ-apomorphine F).

[0361]

[0362] Example 10 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(acetate)] hydrochloride

[0363]

[0364] Apomorphine-(4'-azidobutyrate) hydrochloride (1a + 1b, 0.18 g, 0.434 mmol) was weighed into a 50 mL round-bottom flask with anhydrous DCM (20 mL). Under argon, triethylamine (0.12 mL, 0.868 mmol, 2 eq.) was added, and then acetyl chloride (0.035 mL, 0.477 mmol, 1.1 eq.) was added. The solution was stirred at room temperature under an argon atmosphere for 30 minutes. Subsequently, the solution was washed twice with 0.1 N HCl (87 mL). The DCM phase was dried over anhydrous sodium sulfate (10 g) and then filtered. The filtrate was evaporated to dryness. Further drying under vacuum gave 0.13 g of an off-white residue (9a + 9b). HPLC analysis of the product showed a purity of 99.8%.

[0365] Example 11 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(propionate)] hydrochloride

[0366]

[0367] Apomorphine-(4'-azidobutyrate) hydrochloride (1a + 1b, 0.20 g, 0.482 mmol) was weighed into a 50 mL round-bottom flask with anhydrous DCM (20 mL). Under argon, triethylamine (0.13 mL, 0.964 mmol, 2 eq.) was added, followed by propionyl chloride (0.047 mL, 0.530 mmol, 1.1 eq.). The solution was stirred for 30 minutes at room temperature under an argon atmosphere. Subsequently, the solution was washed twice with 0.1 N HCl (96 mL). The DCM phase was dried over anhydrous sodium sulfate (10 g) and then filtered. The filtrate was evaporated to dryness. It was further dried under vacuum to give 0.19 g of an off-white residue (6a + 6b). HPLC analysis of the product showed a purity of 98.8%.

[0368] Example 12 - Synthesis of POZ10p20k [Apo(acetate)(4-triazole butyrate)] via click reaction 10 (11)

[0369] Apomorphine-10,11-[(4’-azidobutyrate)(acetate)] hydrochloride (9a + 9b, 0.13 g, 0.27 mmol, 11.6 eq.) and POZ 10p-acid 20K (0.48 g, 0.024 mmol, 1 eq.) were dissolved in DMSO (8 mL) and deionized water (4 mL) in a 50 mL round-bottom flask. Then, under argon, sodium ascorbate (0.022 g, 0.110 mmol, 4.66 eq.) was added to the flask, followed immediately by CuSO4·5H2O (0.027 g, 0.110 mmol, 4.66 eq.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl (84 mL) with 10 wt% NaCl 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). Copper in the aqueous solution was removed by passing the aqueous solution through Ambersep M4195 medium packed in a glass column. The column was eluted with 2 mM HCl (90 mL). NaCl (10 g) was added to the collected eluate (100 mL) and the turbid solution was extracted with DCM (2 × 40 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (40 g). 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 then precipitated in diethyl ether (55 mL). After filtration, the precipitate was collected and dried in vacuo to give 0.44 g of a white powder (POZ10p20k[Apo(acetate)(4-triazolebutyrate)] 10 , 11; POZ-apomorphine D).

[0370]

[0371] Example 13 - Synthesis of POZ10p20k [Apo(propionate)(4 - triazole butyrate)] via click reaction 10 (12)

[0372] In a 50 mL round-bottom flask, apomorphine-10,11-[(4’-azidobutyrate)(propionate)] hydrochloride (10a + 10b, 0.19 g, 0.39 mmol, 11.7 eq.) and POZ 10p-acid 20K (0.68 g, 0.033 mmol, 1 eq.) were dissolved in DMSO (11 mL) and deionized water (5.5 mL). Then, under argon, sodium ascorbate (0.031 g, 0.156 mmol, 4.66 eq.) was added to the flask, followed immediately by CuSO4·5H2O (0.039 g, 0.156 mmol, 4.66 eq.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl (120 mL) containing 10 wt% NaCl 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). Copper in the aqueous solution was removed by passing the aqueous solution through Ambersep M4195 medium packed in a glass column. The column was eluted with 2 mM HCl. NaCl (11 g) was added to the collected eluate (110 mL) and the turbid solution was extracted with DCM (2 × 40 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (40 g). 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 then precipitated in ether (76 mL). The precipitate was collected after filtration and dried in vacuo to give 0.70 g of a white powder (POZ10p20k[Apo(propionate)(4-triazolebutyrate)] 10 , 12; POZ-apomorphine E).

[0373]

[0374] Example 14 - Synthesis of apomorphine-10,11-[(4'-azidobutyrate)(monoethyl succinate)] hydrochloride

[0375]

[0376] Apomorphine-(4'-azidobutyrate) hydrochloride (1a + 1b, 0.60 g, 1.446 mmol) was weighed into a 100 mL round-bottom flask with anhydrous DCM (60 mL). Under argon, triethylamine (0.40 mL, 2.892 mmol, 2 eq.) was added, followed by ethyl 4-chloro-4-oxobutyrate (0.31 g, 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 g) and filtered. The filtrate was evaporated to dryness and dried in vacuo to give 0.72 g of a solid (11a + 11b). HPLC analysis of the product showed a purity of 99.8%.

[0377] Example 15 - Synthesis of POZ10p20k [Apo(4'-triazolylbutyrate)(monoethyl succinate)] by click reaction 10 (13)

[0378] Apomorphine-10,11-[(4’-azidobutyrate)(monoethyl succinate)] hydrochloride (5a + 5b, 0.34 g, 0.631 mmol, 11.7 eq.) and POZ 10p-acid 20K (1.1 g, 0.054 mmol, 1 eq.) were dissolved in DMSO (18 mL) and deionized water (9 mL) in a 50 mL round-bottom flask. Then, under argon, sodium ascorbate (0.05 g, 0.253 mmol, 4.66 eq.) was added to the flask, followed immediately by CuSO4·5H2O (0.063 g, 0.253 mmol, 4.66 eq.). The solution was then stirred overnight at room temperature under argon. The reaction mixture was diluted with 5 mM HCl (195 mL) with 10 wt% NaCl 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 copper in the aqueous solution was removed by passing the aqueous solution through Ambersep M4195 medium packed in a glass column. The column was eluted with 2 mM HCl (160 mL). NaCl (18 g) was added to the collected eluate (182 mL), and the turbid solution was extracted with DCM (2 × 100 mL). After phase separation, the DCM phase was dried over anhydrous sodium sulfate (30 g). After filtration to remove sodium sulfate, the filtrate was concentrated to near dryness by rotary evaporation. The residue was dissolved in DCM (12 mL), followed by precipitation in diethyl ether (124 mL). After filtration, the precipitate was collected and dried in vacuo to give 1.16 g of a white powder (POZ10p20k[Apo(4’-triazolebutyrate)(monoethyl succinate] 10 ,13, POZ-apomorphine G).

[0379]

[0380] Example 16 - Random H-[(Ptyn) 10 (EOZ) 190 -T-CO2H(POZ10p20k) Exemplary Synthesis

[0381]

[0382] The synthesis of POZ polymers with various side 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 teachings. In a specific embodiment, the synthesis of H-[(Ptyn) 10 (EOZ) 190 -T-CO2H is provided, although other POZ polymers with different molecular weights, different starting groups and end groups, and different groups at the pendant positions can be prepared by the same method. Additionally, block copolymers can be produced in addition to the random copolymers described in this example. The methods for producing random copolymers 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 teachings.

[0383] For the synthesis of H-[(Ptyn) 10 (EOZ) 190 -T-CO2H, trifluoromethanesulfonic 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 eq) and 2-ethyl-2-oxazoline (EOZ, 46.61 g, 470.2 mmol, 240 eq) in chlorobenzene (124 mL). After stirring at room temperature for 5 minutes, the mixture was heated to 80 °C for 10 hours and then cooled to room temperature. In a separate flask, the capping reagent was prepared by dropwise adding methyl 3-mercaptopropionate (1.23 mL, 0.0114 mol) to a suspension of sodium hydride (60% in mineral oil, 0.272 g, 0.0068 mol) in chlorobenzene (34 mL). The mixture was stirred for 7 hours and then H-(Ptyn) 10 (EOZ) 200 +An active polymer solution. 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 vacuo to give 22.8 g of the desired product as a white powder (50% yield).

[0384] 1 1H NMR (Varian, 500 MHz, 10 mg / mL CDCl3) showed common 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 appeared at 2.63 ppm (m, 2H, -SCH2CH2CO2H), 2.74 ppm (m, 2H, -CH2SCH2CH2CO2H), and 2.85 ppm (m, 2H, -SCH2CH2CO2H). The pendant pentynyl peaks appeared at 1.85 ppm (m, 2H, -CH2CH2C≡CH) and 2.03 ppm (br s, 1H, -CH2CH2C≡CH). By comparing the integrals of the terminal acetylene protons and the polymer backbone protons, the number of pendant Ptyn groups was determined to be 8.5. GPC gave Mn = 19,500 Da and Mp = 20,800 Da, and the PDI was 1.07.

[0385] Example 17 - Hydrolysis of POZ20K10p monoester and diester of apomorphine in human plasma at 37 °C

[0386] Female plasma was aliquoted into cryotubes (BioIVT), thawed in a 37 °C water bath, and gently mixed by inverting several times. The tubes were then placed in an ice bath until ready for use. The following POZ-apomorphine conjugates were tested in this example: POZ-apomorphine A (Example 6; drug payload 10.1 wt%), POZ-apomorphine B (Example 7; drug payload 10.3 wt%), POZ-apomorphine C (Example 8; drug payload 12.0 wt%), POZ-apomorphine D (Example 12, drug payload 10.2%), POZ-apomorphine E (Example 13, drug payload 10.2%), POZ-apomorphine F (Example 9; drug payload 14.2 wt%), and POZ-apomorphine G (Example 15; drug payload 10.7 wt%).

[0387] 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 the solution was added to 3 mL of refrigerated female plasma. This was done in triplicate. After mixing the contents of the tube by gently inverting the tube several times, (200 μL) of the plasma solution was aliquoted into separate microcentrifuge tubes with screw caps using an Eppendorf pipette, and the samples were placed in a horizontal shaking water bath and incubated at 37 °C.

[0388] At each time point, one tube of the plasma solution was quenched with 1000 μL of 0.1% trifluoroacetic acid (TFA) in acetonitrile (ACN). The solution was vortexed to extract the POZ-apomorphine conjugate from the precipitated protein. After centrifuging at 14000 RPM for 5 min, 500 μL of the supernatant was removed and added to 500 μL of 0.1% TFA in pure water (H2O), and then the mixture was transferred to an HPLC vial.

[0389] The mixture was analyzed by the following HPLC method: Agilent 1260 diode array HPLC with a Zorbax 300SB C-8 column (5 mm × 4.6 × 150 mm). Mobile phase A: 0.1% TFA in H2O; Mobile phase B: 0.1% TFA in ACN; Gradient: 32% B from 0.0 - 7.5 min, 75% B from 7.5 - 10.5 min; Run time: 12 min; Posttime: 3 min; Flow rate: 1.8 mL / min; Injection volume: 100 μL; UV λmax: 274 nm.

[0390] A calibration curve (concentration vs. peak area) of POZ20K10p-apomorphine in 5% dextrose was established. The conjugate concentration at each time point was calculated by integrating the peak area of the conjugate at a retention time of 10.8 minutes.

[0391] The hydrolysis rate of apomorphine from each POZ-apomorphine conjugate was calculated using the disappearance rate of the conjugate and is shown in Figure 1 The values were normalized to the % released using the drug load % of each compound. As Figure 1As shown, the half-life of POZ-apomorphine F (lacking a blocking group on the second phenolic hydroxyl group) was calculated to be approximately 6 minutes. Adding a blocking group to the second phenolic hydroxyl group increased the half-life 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 h (POZ-apomorphine D); 6 h (POZ-apomorphine E); 8 h (POZ-apomorphine G); 9 h (POZ-apomorphine A); 20 h (POZ-apomorphine B); and 66 h (POZ-apomorphine C). The in vitro release half-life durations were as follows: benzoate > methyl propionate > butyrate > ethyl succinate > propionate > acetate > unblocked monoester. Figure 1 It clearly shows that the release rate of apomorphine from the POZ conjugate depends on the structure of the blocking group on the second phenolic hydroxyl group, allowing the release rate (release curve) to be selected based on the choice of the blocking group (structure of the blocking group) on the second phenolic hydroxyl group of the catechol moiety of apomorphine. Such a result is surprising and unexpected.

[0392] Example 18 - Pharmacokinetic study of POZ-apomorphine conjugate and unconjugated free apomorphine

[0393] In vivo pharmacokinetic studies of apomorphine HCl (hemihydrate) and the POZ-apomorphine conjugates of the present disclosure were conducted in primates to determine the free plasma apomorphine levels (for all test articles) and total (for POZ-apomorphine conjugates) plasma apomorphine levels, as well as the skin response to each test article, after a single subcutaneous (SC) infusion (apomorphine HCl) and a single SC injection (POZ-apomorphine conjugate).

[0394] POZ-apomorphine conjugate

[0395] The POZ-apomorphine conjugates used in this study were those described in Example 6 (POZ-apomorphine A) and Example 7 (POZ-apomorphine B).

[0396] Administration

[0397] Non-naive female cynomolgus monkeys were used in the study. The animals had been at least 4 weeks since drug treatment in the previous study. One animal (C3503) had a washout period of 18 days. They were assigned to 3 groups of 3 animals each. The animals in Group 1 received a 12-h single SC infusion of apomorphine HCl at a dose of 1.5 mg / kg. The animals in Groups 2 and 3 received a single SC injection of the POZ-apomorphine A and POZ-apomorphine B conjugates at a dose of 1.5 mg / kg (based on apomorphine equivalent). The dosing schedule is shown in Table 1.

[0398]

[0399] 1 For all groups, n = 3

[0400] 2 Based on the active drug

[0401] 3 12 - hour slow infusion

[0402] 4 Single injection

[0403] The test article (as described in Table 1) was administered subcutaneously at the right shoulder of each monkey. Observe the signs of poor health, general adverse reactions, inflammation at the injection site, and mortality to the treatment of the animals as described herein.

[0404] Blood sampling and plasma preparation

[0405] All animals were dosed at 0 h. Blood samples from Group 1 were collected at 1, 2, 4, 8, 12, 18, 24, and 48 hours after dosing. Blood samples from Group 2 and Group 3 were collected at 1, 3, 6, 12, 24, 48, 72, 120, 168, and 240 hours after dosing.

[0406] Approximately 1.0 mL of blood was collected from each animal via the cephalic vein into a tube containing the 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 wet ice, and processed to provide plasma. The tube was mixed by gentle wrist rotation and placed in an ice bath. The samples were centrifuged within 20 minutes of collection (centrifuged at 3,000 RPM for 15 minutes at 2 - 8 °C). For all groups, at least 500 μL of plasma was obtained at each time point. Two aliquots of at least 250 μL were obtained and processed as follows:

[0407] Aliquot 1 (for free drug analysis, Groups 1, 2, and 3). The plasma was transferred to a sample tube and gently mixed. After mixing, the sample was frozen and stored at - 70 to - 80 °C, then transferred to a bioanalytical laboratory to determine the free drug concentration.

[0408] Aliquot 2 (for total drug analysis, Groups 2 and 3 only). The plasma was transferred to a sample tube and gently mixed. After mixing, the sample was frozen and stored at - 70 to - 80 °C, then transferred to a bioanalytical laboratory to determine the total drug concentration.

[0409] Sample analysis

[0410] Free apomorphine in all plasma samples was analyzed (for groups 2 and 3, this analysis measured the amount of apomorphine released from the polymer), and total apomorphine in groups 2 and 3 was analyzed (released drug plus drug still conjugated to the polymer). The analysis was performed by liquid chromatography triple quadrupole mass spectrometry (LC-MS / MS). Using 30.0 μL plasma aliquots, the lower limit of quantification (LLOQ) for free apomorphine determination in plasma of animals in group 1 was 0.1 ng / mL, and for animals in groups 2 and 3 was 0.2 ng / mL. The LLOQ for total apomorphine determination in plasma of groups 2 and 3 was 0.5 ng / mL. The upper limit of quantification for free apomorphine in plasma of all groups was 300 ng / mL and for total apomorphine was 1000 ng / mL.

[0411] The formulated dose solutions were also tested for test article concentration and dose accuracy.

[0412] Observation results

[0413] All animals were weighed on the day prior to dosing to determine the dose volume to be administered. During the study, cage-side observations of general health status and appearance were made twice daily (at approximately 9:30 a.m. and 4:00 p.m.). Prior to the start of the study, a physical examination of the animals was performed to confirm the health status of the animals. Additionally, the animals were observed before and after the initial dosing and at each sample collection time point. General condition, behavior, activity, excretion, respiration, or other abnormal observations were recorded throughout the study. Clinical observations were evaluated for each animal by a staff veterinarian or veterinary technician.

[0414] The body weights of each non-naïve female monkey at the start of the study are shown in Table 2.

[0415]

[0416] Example 19 - The POZ-apomorphine conjugate provides enhanced pharmacokinetics compared to unconjugated free apomorphine Kinetic properties

[0417] Pharmacokinetic analysis

[0418] Using a non-compartmental model by validated procedures (Pharsight, version 6.3), the plasma concentration-time curves of free apomorphine and total apomorphine were analyzed. The maximum plasma concentration (C max ) and the time to reach C max (T max ) were obtained from the curve of plasma concentration versus time. To understand how the drug load (% w / w) would affect the pharmacokinetic characteristics, the area under the plasma concentration-time curve (AUC) from zero to 168 hours after dosing (AUC0-168 ) was determined as the treatment period, and the AUC from zero time to the last observation time was also 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). 0-最后 ) (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).

[0419] Report the T max and C max values for each plasma concentration-time curve. Using at least 3 points, calculate and report the elimination half-life t 1 / 2 z value with the correlation coefficient of the elimination phase.

[0420] The percentage of apomorphine released (PR) was calculated using the following formula to understand the exposure difference of the released drug to the total drug between Group 2 and Group 3:

[0421] PR% = [AUC 0-最后 (free) ÷ AUC 0-最后 (total)] × 100.

[0422] Nominal sampling times were used to calculate all parameters as there was no sampling time bias in any case.

[0423] Pharmacokinetics of free apomorphine

[0424] The pharmacokinetics of free apomorphine were studied in female monkeys after a single SC infusion of apomorphine HCl (1.5 mg / kg) and a single SC injection of 1.5 mg / kg (based on apomorphine equivalent) doses of POZ-apomorphine A and POZ-apomorphine B conjugates. The mean plasma concentrations of free apomorphine for each test article are shown in Figure 2 .

[0425] The calculated pharmacokinetic parameters of free apomorphine in plasma are presented in Table 3 (mean, SD, n = 3). These parameters include C max values, T max values, t 1 / 2 z Vz / F value, CL / F value, and the AUC at infinity (AUC 0-inf ) value, the AUC at 1 week (AUC 0-168) values and the AUC (AUC 0-最后 ) values up to the last measurable time point.

[0426]

[0427]

[0428] Review of the concentration-time profiles ( Figure 2 ) and the calculated pharmacokinetic results (Table 3) showed distinct differences between apomorphine HCl and the POZ-apomorphine A and POZ-apomorphine B conjugates. The concentration (ng / mL) of free apomorphine after a single 12-h SC infusion of 1.5 mg / kg apomorphine HCl provided T max at 4 h and an average C max of approximately 10.6 ng / mL. The AUC 0-最后 value was calculated to be 89.8 h*ng / ml. After the infusion, the drug was completely cleared by 24 h post-infusion and was below the limit of quantification (BLQ). The terminal half-life of apomorphine HCl was calculated to be 1.7 h.

[0429] On the other hand, the free apomorphine levels after SC injection of the POZ-apomorphine A and POZ-apomorphine B conjugates showed differences in the concentration-time curves for each conjugate. The concentration (ng / ml) of free apomorphine after a single SC injection of 1.5 mg / kg (apomorphine equivalent) of the POZ-apomorphine A conjugate gradually increased during the first 3 days, with average T max and C max of 88 h and 6.6 ng / mL, respectively. The AUC 0-最后 value was calculated to be 656 h*ng / ml. The drug was completely cleared by 240 h post-injection and was BLQ. The concentration (ng / ml) of free apomorphine after a single SC injection of 1.5 mg / kg (apomorphine equivalent) of the POZ-apomorphine B conjugate gradually increased during the first 5 days, with average T max and C max of 104 h and 3.5 ng / mL, respectively. The AUC 0-最后 value was calculated to be 640 h*ng / ml. The drug had not been cleared by 240 h post-injection. The terminal half-lives of apomorphine released from the POZ-apomorphine A and B conjugates were 22.5 h and 143.4 h, respectively.

[0430] The t 1 / 2 z values determined in vivo for the POZ-apomorphine A and B conjugates showed a correlation with the t 1 / 2For trends with the same value, the half-life of the POZ-apomorphine A conjugate in each assay was shorter than that of the POZ-apomorphine B conjugate. This comparison shows that in vitro plasma assays can reliably predict the half-life in in vivo studies.

[0431] Pharmacokinetics of total apomorphine

[0432] The pharmacokinetics of total apomorphine were studied in female monkeys after a single SC injection of a dose of 1.5 mg / kg (based on apomorphine equivalent) of the POZ-apomorphine A and POZ-apomorphine B conjugates. The mean plasma concentration of free apomorphine for each condition is shown in Figure 3 .

[0433] The calculated pharmacokinetic parameters of total apomorphine in plasma are presented in Table 4. These parameters include C max value, T max value, t 1 / 2 z Vz / F value, CL / F value, and the AUC at infinity (AUC 0-inf ), the AUC at 1 week (AUC 0-168 ), and the AUC up to the last measurable time point (AUC 0-最后 ) values.

[0434]

[0435] Review of the concentration-time profiles ( Figure 3 ) and the calculated pharmacokinetic results (Table 4) for the POZ-apomorphine A and B conjugates at a dose of 1.5 mg / kg (apomorphine equivalent) shows that their concentration-time curves are different. The total drug level of the POZ-apomorphine A conjugate gradually increased within the first 3 days, with mean T max and C max being 88 h and 151.3 ng / mL, respectively. The AUC 0-最后 value was calculated as 13835 h*ng / ml. The drug was cleared by 240 h and was BLQ. The total drug level of the POZ-apomorphine B conjugate gradually increased within the first 5 days, with mean T max and C max being 107 h and 72.6 ng / mL, respectively. The AUC 0-最后 value was calculated as 11610 h*ng / ml. The drug had not been cleared by 240 h. The terminal half-lives of apomorphine released from the POZ-apomorphine A and B conjugates were 20.9 h and 106.9 h, respectively.

[0436] The ratio of released apomorphine to total apomorphine is reported as the % of released apomorphine (PR; calculated as described herein). The PR values of the POZ-apomorphine A and B conjugates are 4.8 and 5.5, respectively. The apomorphine release values and total values for Group 1 are the same (as shown in Table 3).

[0437] Summary of pharmacokinetic data

[0438] Following a single SC infusion of apomorphine HCl and a single SC injection of the POZ-apomorphine A and POZ-apomorphine B conjugates, the pharmacokinetic characteristics of released apomorphine and total apomorphine were as follows.

[0439] The linkage of apomorphine to the POZ polymer allows for the sustained delivery of apomorphine over 5 - 10 days. Compared to apomorphine HCl, the T max values of the POZ-apomorphine A and POZ-apomorphine B conjugates increased by 22-fold and 26-fold, respectively. Compared to apomorphine HCl, the t 1 / 2 z values of the POZ-apomorphine A and POZ-apomorphine B conjugates increased by 13.2-fold and 84.3-fold, respectively.

[0440] In addition, compared to apomorphine HCl, the linkage of apomorphine to the POZ polymer caused the C max of POZ-apomorphine A and POZ-apomorphine B to decay from 10.6 ng / mL to 6.6 ng / mL and 3.5 ng / mL, respectively. Additionally, when apomorphine is released from the POZ-apomorphine A and B conjugates, the drug exposure measured by AUC 0-最后 increased by more than 7-fold. These data show that when apomorphine is released from the POZ-apomorphine A and B conjugates, the total drug exposure of apomorphine is significantly increased.

[0441] The data show a surprising effect that the nature of the blocking group on the second phenolic hydroxyl of the catechol moiety of apomorphine affects the release rate of apomorphine from the POZ conjugate. The POZ-apomorphine A conjugate provides a sustained release of apomorphine over a 5-day period, while the POZ-apomorphine B conjugate provides a steady-state release of apomorphine over a 10-day period. This result clearly confirms that based on the selection of the blocking group on the second phenolic hydroxyl of the catechol moiety of apomorphine, the release rate of apomorphine from the POZ conjugate can be controlled to provide a release rate (release profile).

[0442] The total apomorphine plasma level reflects the level of apomorphine released in the concentration-time curve. The ratio of released apomorphine to total apomorphine (PR) was shown to be 4.8 - 5.5%. After administration of the POZ-apomorphine A and B conjugates, there was no sign of dose dumping (burst effect).

[0443] Example 20 - When administered by the subcutaneous route, the POZ-apomorphine conjugate does not cause skin irritation

[0444] It has been reported in the literature that apomorphine (Apo-Go, 10 mg / mL formulation) will produce redness and irritating lumps (nodules) upon subcutaneous injection. These skin reactions were monitored daily in all animals. Photographs were taken to study the severity of the reactions and the observations were recorded. Based on the presence of erythema and swelling, the skin reactions were recorded as none, mild, well-defined, moderate, and severe.

[0445] Observation results of skin reaction

[0446] The visual observations of each test animal were summarized in Table 5.

[0447]

[0448]

[0449]

[0450] Figures 4A to 4C Differences between the animals of Group 1 (1502), Group 2 (2502), and Group 3 (3502) on Day 5 after infusion were shown. As Figure 4A shown, animal 1502 showed scarring with yellow discharge at the infusion site as well as redness and swelling, while animals 2502 and 3502 had no scarring, discharge, swelling, or redness (see Figure 4B and Figure 4C respectively).

[0451] In summary, the animals of Group 1 had significant redness, swelling, and yellow exudate at and around the infusion site from Day 1 to Day 7, while the animals of Group 2 and Group 3 had no skin reactions throughout the study.

[0452] These results indicate that the POZ-apomorphine A and B conjugates are well tolerated by primates after SC injection.

[0453] Example 21 - When administered by the subcutaneous route, after multiple doses, the POZ-apomorphine conjugate does not cause Skin irritation

[0454] In primates, an in vivo pharmacokinetic study of the POZ-apomorphine conjugates of the present disclosure was conducted to determine free plasma apomorphine levels (for all test articles) and total (for the POZ-apomorphine conjugates) plasma apomorphine levels, as well as skin reactions to each test article, following a single subcutaneous (SC) infusion (apomorphine HCl) and a single SC injection (POZ-apomorphine conjugate).

[0455] POZ-apomorphine conjugate

[0456] 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).

[0457] Administration

[0458] Non-naïve female cynomolgus monkeys were used in the study. The animals were at least 4 weeks since drug treatment in the previous study. They were assigned to 3 groups of 3 animals each. The animals in Group 1, Group 2, and Group 3 received four weekly doses of SC injection of the POZ-apomorphine A, POZ-apomorphine B, and POZ-apomorphine G conjugates at a dose of 3.0 mg / kg (based on apomorphine equivalent). The dosing schedule is shown in Table 6.

[0459]

[0460] 1 For all groups, n = 3

[0461] 2 Based on the active drug

[0462] 4 Single injections were performed on Day 0, Day 7, Day 14, and Day 21

[0463] Each monkey was given the test article subcutaneously (as described in Table 6) on the right shoulder on Day 0 and Day 14 and on the left shoulder on Day 7 and Day 21. Adverse health signs, general adverse reactions, inflammation at the injection site, and mortality to the treatment were observed as described herein and in Example 18. Photographs were taken to study the severity of the reaction and the recorded observations.

[0464] Blood sampling and plasma preparation

[0465] All animals were dosed at 0 h. Blood samples from Groups 1 to 3 were collected 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 h after dosing. Blood samples were collected and processed as described in Example 18.

[0466] Sample analysis

[0467] All plasma samples were analyzed for free apomorphine (this analysis measures the amount of apomorphine released from the polymer) and total apomorphine (the released drug plus the drug still conjugated to the polymer). The analysis was performed as described in Example 18.

[0468] Pharmacokinetic analysis

[0469] As described in Example 18, the plasma concentration-time curves of free apomorphine and total apomorphine were analyzed using a validated non-compartmental model by the program (Pharsight, version 6.3).

[0470] Observation results

[0471] All animals were weighed one day before dosing to determine the dose volume to be administered, and this was done / will be done as described in Example 18.

[0472] Observation results of skin reaction

[0473] As described in Example 20, it has been reported that apomorphine (Apo-Go, 10 mg / mL formulation) causes severe skin irritation after administration in humans. To determine whether the Apo-A, Apo-B, and Apo-G conjugates induce skin reactions at a concentration of 3.0 mg / kg (compared to the 1.5 mg / kg dose described in Examples 18 and 20), these skin reactions of all animals were monitored / will be monitored daily. Photos were taken / will be taken to study the skin reactions, and the observations were recorded / will be recorded. Based on the presence of erythema and swelling, the skin reactions were recorded / will be recorded as none, mild, well-defined, moderate, and severe.

[0474] After the third dose (day 14) of the Apo-A, Apo-B, and Apo-G conjugates, photos were taken 12 h after administration. The skin at the injection site (referred to as the lump site) of each animal in Groups 1 to 3 appeared normal, without signs of erythema and swelling. Figures 5A to 5CShow skin sites without scars, secretions, swelling, or redness 12 hours after the third dose for one animal from each group.

[0475] These results indicate that the conjugates of POZ - apomorphine A, B, and G are well tolerated in primates after SC injection at a dose of 3.0 mg / kg (based on apomorphine equivalents).

[0476] Additional aspects

[0477] Additional exemplary claims supported by the specification include, but are not limited to, the following.

[0478] Aspect 1: A compound of formula V or a pharmaceutically acceptable salt thereof,

[0479]

[0480] Wherein:

[0481] R 11 、R 12 、R 13 and R 14 are independently selected from H, OH, halogen, alkoxy, NO2, unsubstituted alkyl, heteroalkyl, alkenyl or alkynyl, substituted alkyl, heteroalkyl, alkenyl or alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic group, substituted heterocyclic group, heteroaryl, substituted heteroaryl, heterocyclic alkyl, substituted heterocyclic alkyl, heteroaryl alkyl, substituted heteroaryl alkyl, or any two of R 11 、R 12 、R 13 and R 14 adjacent to each other may together with the carbon to which they are attached form an optionally substituted aryl, heteroaryl, heterocyclic ring; and

[0482] R 20 and R 21 one of which is H or a blocking group and R 20 and R 21 the other of which is H, a group containing an active functional group or a blocking group, provided that R 20 and R 21 are not both H, wherein the group containing the active functional group contains a first cleavable moiety and the blocking group contains a second cleavable moiety.

[0483] Aspect 2: The compound according to aspect 1, wherein one of R 20 and R 21 is the blocking group and the other of R 20 and R 21 is the group containing the active functional group.

[0484] Aspect 3: The compound according to Aspect 1, wherein the group containing the active functional group is R 24 -R 25 -R 26 , wherein:

[0485] R 24 is -C(O)-, -O-C(O)-, -C(O)-NH-cyclo-O-C(O)-, -C(O)-NH-(C6H4)-O-C(O)- or -O-P(O)(OR9)(O)-;

[0486] cyclo represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic or cycloalkyl;

[0487] R9 is H or a substituted or unsubstituted C1-C5 alkyl;

[0488] R 25 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl; and

[0489] R 26 is an active functional group or a moiety containing an active functional group, and the active functional group is capable of forming a linkage with a group on the polymer.

[0490] Aspect 4: The compound according to Aspect 3, wherein the active functional group is an azide or an alkyne group.

[0491] Aspect 5: The compound according to Aspect 3, wherein R 24 -R 25 -R 26 is N3-(CH2) 1-6 -C(O)-, C ＝ C-(CH2) 1-6 -C(O)-, N3-(CH2)3-C(O) or C ＝ C-(CH2)3-C(O).

[0492] Aspect 6: The compound according to Aspect 3, wherein R 24 forms a bond with the oxygen of R 20 or R 21 , and R 24 and the O connected thereto form the first cleavable moiety.

[0493] Aspect 7: The compound according to Aspect 2, wherein the compound is a compound of formula VI or a pharmaceutically acceptable salt thereof

[0494]

[0495] wherein:

[0496] R 19 is H, an unsubstituted alkyl, alkenyl or alkynyl, a substituted alkyl, alkenyl or alkynyl, benzyl, a substituted benzyl, cycloalkyl, a substituted cycloalkyl, aryl, a substituted aryl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinoyl or 1-aryl tetrazolyl.

[0497] Aspect 8: The compound according to aspect 7, wherein R 19 is -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3 or

[0498] Aspect 9: The compound according to aspect 7, wherein the group containing the active functional group is R 24 -R 25 -R 26 , wherein:

[0499] R 24 is -C(O)-, -O-C(O)-, -C(O)-NH-cyclo-O-C(O)-, -C(O)-NH-(C6H4)-O-C(O)- or -O-P(O)(OR9)(O)-;

[0500] cyclo represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic or cycloalkyl;

[0501] R9 is H or a substituted or unsubstituted C1-C5 alkyl;

[0502] R 25 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl; and

[0503] R 26 is an active functional group or a moiety containing an active functional group, and the active functional group is capable of forming a linkage with a group on the polymer.

[0504] Aspect 10: The compound according to aspect 9, wherein the active functional group is an azide or an alkynyl.

[0505] Aspect 11: The compound according to aspect 9, wherein R 24 -R 25 -R 26 is N3-(CH2) 1-6 -C(O)-, C ＝ C-(CH2) 1-6 -C(O)-, N3-(CH2)3-C(O) or C ＝ C-(CH2)3-C(O).

[0506] Aspect 12: The compound according to aspect 9, wherein R 24 forms a bond with the oxygen of one of R 20 or R 21 , and R 24 and the O attached thereto form the first cleavable moiety.

[0507] Aspect 13: The compound according to any one of aspects 1 to 12, wherein the blocking group is –R 22 -R 23 ;

[0508] R 22 is -C(O)-, -C(O)-O-, -C(O)-NH-, cyclo-O-C(O)-, -C(O)-NH-(C6H4)-O-C(O)-, CH3(CH2) 1-4 -O-C(O)-(CH2) 1-4 -C(O)- or -O-P(O)(OR9)-;

[0509] cyclo represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic or cycloalkyl;

[0510] R9 is H or a substituted or unsubstituted C1-C5 alkyl; and

[0511] R 23 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl.

[0512] Aspect 14: The compound according to any one of aspects 1 to 13, wherein R 22 forms a bond with the oxygen of one of R 20 or R 21 , and R 22 and the O attached thereto form the second cleavable moiety.

[0513] Aspect 15: The compound according to any one of aspects 1 to 13, wherein 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 -, where when y is 1, x is 2, when y is 2, x is 1, or when y is 3, x is 0.

[0514] Aspect 16: A compound according to any one of Aspects 1 to 15, wherein 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-C-C(O)-, CH3CH2-O-C(O)-CH2CH2-C(O)-,

[0515] Aspect 17: A compound according to Aspect 1, wherein R 20 and R 21 each is the blocking group, or one of R 20 and R 21 is the blocking group and the other of R 20 and R 21 is H.

[0516] Aspect 18: A compound according to Aspect 17, wherein the blocking group is -R 22 -R 23 ;

[0517] R 22 is -C(O)-, -C(O)-O-, -C(O)-NH-cyclo-O-C(O)-, -C(O)-NH-(C6H4)-O-C(O)-, CH3(CH2) 1-4 -O-C(O)-(CH2) 1-4 -C(O)- or -O-P(O)(OR9)-;

[0518] cyclo represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic or cycloalkyl;

[0519] R9 is H or a substituted or unsubstituted C1-C5 alkyl; and

[0520] R 23 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl.

[0521] Aspect 19: A compound according to Aspect 17 or 18, wherein R 22 forms a bond with the oxygen of one or both of R 20 or R 21 , and R 22 and the O to which it is attached form the second cleavable moiety.

[0522] Aspect 20: A compound according to any one of Aspects 17 to 19, wherein 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 -, where when y is 1, x is 2; when y is 2, x is 1; or when y is 3, x is 0.

[0523] Aspect 21: The compound according to any one of aspects 17 to 19, the compound according to aspect 81, wherein 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-C-C(O)-, CH3CH2-O-C(O)-CH2CH2-C(O)-,

[0524] Aspect 22: The compound according to aspect 17, wherein the compound is a compound of formula VI or a pharmaceutically acceptable salt thereof

[0525]

[0526] Wherein:

[0527] 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, nicotinoyl or 1-aryl tetrazolyl.

[0528] Aspect 23: The compound according to aspect 22, wherein R 19 is -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3 or

[0529] Aspect 24: The compound according to aspect 22 or 23, wherein the blocking group is -R 22 -R 23 ;

[0530] R 22 is -C(O)-, -C(O)-O-, -C(O)-NH-cyclo-O-C(O)-, -C(O)-NH-(C6H4)-O-C(O)-, CH3(CH2) 1-4 -O-C(O)-(CH2) 1-4-C(O)- or -O-P(O)(OR9)-;

[0531] The ring represents a substituted or unsubstituted aryl, heterocycloalkyl, heteroaryl, heterocyclic group or cycloalkyl;

[0532] R9 is H or a substituted or unsubstituted C1-C5 alkyl; and

[0533] R 23 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted aryl.

[0534] Aspect 25: A compound according to any one of aspects 22 to 24, wherein R 22 forms a bond with the oxygen of one or both of R 20 or R 21 , and R 22 and the O to which it is attached form the second cleavable moiety.

[0535] Aspect 26: A compound according to any one of aspects 22 to 25, wherein 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 -, where when y is 1, x is 2, when y is 2, x is 1, or when y is 3, x is 0.

[0536] Aspect 27: A compound according to any one of aspects 22 to 25, wherein 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-C-C(O)-, CH3CH2-O-C(O)-CH2CH2-C(O)-,

[0537] Aspect 28: A method of treating a dopamine-responsive disease or disorder in a subject, the method comprising the step of administering to the subject an amount of a compound according to any one of aspects 1 to 27, wherein the agent is a dopamine agonist.

[0538] Aspect 29: The method according to aspect 28, wherein the dopamine-responsive disease or disorder is a hypodopaminergic disorder, pituitary tumor (prolactinoma), Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, hypodopaminergic disorder, SSRI-induced sexual dysfunction, depression, obesity or type II diabetes.

[0539] Aspect 30: The method according to aspect 28, wherein the dopamine-responsive disease or disorder is Parkinson's disease.

[0540] Aspect 31: The method according to any one of aspects 28 to 30, wherein the dopamine agonist is apomorphine, abuterol, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoproterenol, isoprenaline, levodopa, levonordefrin, maprotolol, methyldopa, methyldopa ethyl ester, norepinephrine, protokylol, tolcapone or (r)-(+)-fenoldopam.

Claims

1. A conjugate of formula I or a pharmaceutically acceptable salt thereof POL n –(L–A–B) b I Wherein: POL is a water-soluble polymer; n is the degree of polymerization and is from 1 to 1000; L is a linking bond containing a first cleavable moiety that connects A and POL; A is a compound containing a first phenolic hydroxyl group linked to L and a second phenolic hydroxyl group linked to B, and has formula IV or a pharmaceutically acceptable salt thereof wherein R 15 or R 16 One of them is L; R 15 or R 16 and another one in 16 is B; and R 19 is H, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted benzyl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinoyl or 1-aryl tetrazolyl; B is a blocking group containing a second cleavable moiety; wherein B comprises CH3-C(O)-, CH3-(CH2)2-C(O)-, CH3-CH2-C(O)-, (CH3)2-CH-C(O)-, (CH3)3-C-C(O)-, CH3CH2-O-C(O)-CH2CH2-C(O)-, and b is from 1 to 50, provided that n is always greater than or equal to b; and wherein the first cleavable moiety and the second cleavable moiety are different.

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

3. The conjugate according to claim 1, wherein the water-soluble polymer is a copolymer comprising 50% to 99.5% of a poly(oxazoline) polymer.

4. The conjugate according to claim 1, wherein L is a direct bond or a linking group.

5. The conjugate according to claim 1, wherein the first cleavable moiety comprises an ester, a carboxylic ester 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).

6. The conjugate according to claim 5, wherein the first cleavable moiety is an ester bond.

7. The conjugate according to claim 1, wherein R 15 is L and R 16 is B.

8. The conjugate according to claim 1, wherein R 19 is selected from the group consisting of: -H, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2-CH2-CH2-CH2-CH3 and 9. The conjugate according to claim 8, wherein R 19 is -CH3.

10. The conjugate according to claim 1, having the formula IIB or a pharmaceutically acceptable salt thereof R-{[N(COX)CH2CH2] o1 -[N(COY)CH2CH2] o2 -[N(COR1)CH2CH2] n} a -T (IIB) wherein R is a starting group; X is independently selected from -L-A-B for each repeating unit; Y is independently selected from -L-A-B, a non-reactive pendant moiety, or a pendant moiety containing a reactive functional group for each repeating unit, and wherein X and Y may be the same or different; R1 is independently selected from unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclic alkyl for each repeating unit; a is ran indicating a random copolymer or a block indicating a block copolymer o1 is an integer from 1 to 50; 02 is from 0 to 49, provided that the sum of o1 and o2 is less than or equal to 50; and T is a capping group.

11. The conjugate according to claim 10, wherein L is a linking group having the following structure wherein R3 links the triazole moiety to POL; and R4 links the triazole moiety to A, and wherein R4 forms a bond with the first phenolic hydroxyl group of A.

12. The conjugate according to claim 11, wherein: R3 is -C(O)-R5- R5 is absent or is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted heterocyclic alkyl; R4 is -R6-R7-R8- R6 is a substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl or oligo(ethylene oxide); R7 is a group containing a first cleavable moiety or a part thereof; and R8 is absent or is O.

13. The conjugate according to claim 12, wherein R7 and R8 combine to form the first cleavable moiety.

14. The conjugate according to claim 12, wherein R6 is a substituted or unsubstituted straight-chain C1-C4 alkyl or a substituted or unsubstituted branched-chain C1-C4 alkyl, wherein R7 is -C(O)-O- and wherein R8 is absent.

15. The conjugate according to claim 12, wherein R6 is a substituted or unsubstituted straight-chain C1-C4 alkyl or a substituted or unsubstituted branched C1-C4 alkyl, wherein R7 is -C(O)- and wherein R8 is -O- or absent.

16. The conjugate according to claim 11, wherein 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-, wherein d is an integer from 1 to 10.

17. The conjugate according to claim 11, wherein 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)-, wherein d is an integer from 1 to 10.

18. The conjugate according to claim 10, wherein T is Z-B1-Q, Z is S, O or N, B1 is an optional linking group, and Q is a capping nucleophile.

19. The conjugate according to claim 18, wherein B1 is -(CH2) 1-16 -, Z is S, and Q is -COOH, -COOCH3, -NH2 or NH-tBoc.

20. The conjugate according to claim 10, wherein the conjugate has the following structure wherein R1 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl or unsubstituted or substituted heterocyclic alkyl; R6 is a substituted or unsubstituted alkyl or aryl; R 16 is B; R 19 is H, an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted benzyl, acyl, tetrahydrofuranyl, tetrahydropyranyl, nicotinoyl or 1-aryl tetrazolyl.

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