Prodrugs, formulations and methods thereof

Abstract

In certain embodiments, the present invention relates to compounds of formula (I): wherein; x1 is selected from N or N + Y1; x2 is selected from NH or NY2; x3 is selected from NH or NY3; y1 is selected from the group consisting of-CH2OCO (OCH2CH2) n1OM1; or-CH2OCO (CH2CH2O) n < 1 > aZ1; or-CH2OCO (CH2) n < 1 > b COOH; y < 2 > is selected from-CH2OCO (OCH2CH2) n < 2 > O < 2 >; or-CH2OCO (CH2CH2O) n < 2 > aZ < 2 >; or-CH2OCO (CH2) n < 2 > b COOH; y < 3 > is selected from-CH2OCO (OCH2CH2) n3OM3; or-CH2OCO (CH2CH2O) n < 3 > aZ < 3 >; or-CH2OCO (CH2) n < 3 > b COOH; n1, n1a, n1b, n2, n2a, n2b, n3, n3a and n3b are independently 0 or an integer from 1 to 8; m1, M2, M3, Z1, Z2 and Z3 are independently selected from H, optionally substituted C1-6 alkyl groups and optionally substituted aryl groups; wherein at least one of X1, X2 and X3 is not N or NH; wherein at least one of Y1, Y2 or Y3 is the respective-CH2OCO (CH2CH2O) nZ; and pharmaceutically acceptable salts thereof. # imgabs0 # (I)

Description

Technical Field

[0001] The present application relates to prodrugs, pharmaceutical compositions comprising prodrugs, and corresponding treatment methods. Background Art

[0002] Tyrosine kinase inhibitors are developed as chemotherapeutic agents that inhibit receptor tyrosine kinase (RTK) signaling, which is a family of tyrosine protein kinases. RTK spans the cell membrane and has an intracellular (inside) and an extracellular (outside) part. After the ligand binds to the extracellular part, the receptor tyrosine kinase dimerizes and initiates an intracellular signaling cascade driven by autophosphorylation using the coenzyme messenger adenosine triphosphate (ATP). Many RTK ligands are growth factors, such as VEGF. VEGF involves a family of proteins that bind to VEGF receptor (VEGFR) types, namely VEGFR1-3 (all RTKs), thereby inducing angiogenesis. VEGF-A, which binds to VEGFR2, is the target of the above-mentioned anti-VEGF drugs. In addition to VEGFR1-3, several other RTKs are known to induce angiogenesis, such as platelet-derived growth factor receptor (PDGFR) activated by PDGF or stem cell growth factor receptor / type III receptor tyrosine kinase (c-Kit) activated by stem cell factor.

[0003] The TKI axitinib is used alone to treat advanced renal cell carcinoma (RCC, a cancer that starts in the cells of the kidney) in people who have not been successfully treated with other medicines. Axitinib is used in combination with either avelumab or pembrolizumab to treat advanced renal cell carcinoma.

[0004] Several TKIs have been evaluated for the treatment of age-related macular degeneration (AMD) by different routes of administration, including pazopanib (GlaxoSmithKline: NCT00463320), regorafenib (Bayer: NCT02348359), and PAN90806 (PanOptica: NCT02022540), all administered as eye drops, and X-82, an oral TKI (Tyrogenex; NCT01674569, NCT02348359). However, due to the low solution concentration of TKIs (their water solubility tends to be low) and the short residence time of TKIs on the ocular surface, topical application of eye drops results in poor penetration into the vitreous and limited distribution to the retina. In addition, drug concentrations are difficult to control when applied topically due to wash-off or user error. In addition, systemic administration of TKIs is not feasible because high doses are required to achieve effective concentrations of the drug in the eye, especially in the desired tissues. This can lead to unacceptable side effects due to high systemic exposure. In addition, drug concentrations are difficult to control. Alternatively, intravitreal injections of TKI suspensions have been performed. However, this mode of administration results in rapid clearance of the drug, so injections must be repeated frequently, for example on a daily or at least monthly basis. In addition, some TKIs are poorly soluble, resulting in the formation of aggregates upon intravitreal injection, which can migrate or deposit on the retina, leading to local contact toxicity and holes, such as macular holes or retinal holes.

[0005] Therefore, there is a need in the art for new compounds, pharmaceutical compositions and therapeutic methods, for example, to treat disease states such as renal cell carcinoma and ocular diseases such as AMD, diabetic macular edema (DME) and retinal vein occlusion (RVO) with TKI therapy.

[0006] All references cited herein are incorporated by reference in their entirety for all purposes.

[0007] Objectives and Summary of the Invention

[0008] It is an object of certain embodiments of the present invention to provide compounds useful for treating a disease or disorder.

[0009] It is an object of certain embodiments of the present invention to provide pharmaceutical compositions comprising the compounds disclosed herein.

[0010] It is an object of certain embodiments of the present invention to provide methods of treatment using the compounds and pharmaceutical compositions disclosed herein.

[0011] It is an object of certain embodiments of the present invention to provide methods of preparing the compounds and pharmaceutical compositions disclosed herein.

[0012] It is an object of certain embodiments of the invention to provide axitinib prodrugs that are more soluble than axitinib, for example, at least 2-fold, 10-fold, 25-fold, 50-fold, 75-fold, 100-fold, 150-fold, 200-fold, 250-fold, 500-fold, or 1000-fold more soluble than axitinib, or a range of any of these values, for example, 2 to 200-fold more soluble, 10 to 100-fold more soluble, or 50 to about 150-fold more soluble.

[0013] It is an object of certain embodiments of the present invention to provide methods for modulating the release of an active agent from a hydrogel or organogel comprising including a prodrug in the hydrogel or organogel dosage form.

[0014] It is an object of certain embodiments of the present invention to provide axitinib prodrugs for treating diseases or conditions with axitinib therapy.

[0015] It is an object of certain embodiments of the present invention to provide axitinib prodrugs in a hydrogel or xerogel (which is converted to a hydrogel in vivo) matrix to form an implant for sustained delivery of the prodrug to local tissues where it is then enzymatically converted to axitinib. The increased solubility of the prodrug acts to accelerate drug release from the hydrogel implant compared to the more hydrophobic active drug form of axitinib.

[0016] In certain embodiments, the present invention relates to compounds of formula I:

[0017]

[0018] I

[0019] in:

[0020] X 1 Select from N or N + Y 1 ;

[0021] X 2 Choose from NH or NY 2 ;

[0022] X 3 Choose from NH or NY 3 ;

[0023] Y 1 Selected from -CH2OCO(OCH2CH2)n 1 OM 1 ; or –CH2OCO(CH2CH2O)n 1a Z 1 ; or –CH2OCO(CH2)n 1b COOH;

[0024] Y 2Selected from -CH2OCO(OCH2CH2)n 2 OM 2 ; or –CH2OCO(CH2CH2O)n 2a Z 2 ; or –CH2OCO(CH2)n 2b COOH;

[0025] Y 3 Selected from -CH2OCO(OCH2CH2)n 3 OM 3 ; or – CH2OCO(CH2CH2O)n 3a Z 3 ; or –CH2OCO(CH2)n 3b COOH;

[0026] n 1 、n 1a 、n 1b 、n 2 n 2a 、n 2b 、n 3 、n 3a and n 3b are independently 0 or an integer from 1 to 8;

[0027] M 1 、M 2 、M 3 , Z 1 , Z 2 and Z 3 are independently selected from H, optionally substituted C 1-6 alkyl and optionally substituted aryl;

[0028] Where X 1 , X 2 and X 3 At least one of them is not N or NH;

[0029] where Y 1 , Y 2 or Y 3 At least one of them is –CH2OCO(CH2CH2O)nZ;

[0030] and pharmaceutically acceptable salts thereof.

[0031] In other embodiments, Y 1 , Y 2 and Y 3 Independently selected from each –(CH2)p 1 OCO(O(CH2)p 2 ) 1 OM; or –(CH2)p1a OCO((CH2)p 2 O)n 1 (CH2)Z; or –(CH2)p 1 OCO(CH2)q 1 COOH; where p 1 、p 1a and p 2 are independently selected from integers from 1 to 4, and q 1 are independently selected from integers from 0 to 4.

[0032] As used herein, the term "biodegradable drug delivery system of sustained release" refers to an object containing an activating agent and, for example, administered to a patient's body as an implant, which retains a certain period of time in the patient's body while releasing the activating agent into the surrounding environment. The drug delivery system can be any predetermined shape (for example, rod-shaped, spherical, oblate, elliptical, disc-shaped, tubular, hemispherical or irregularly shaped) before insertion or application, and when the system enters the desired position, the shape can be maintained to a certain extent, but after application, the size (for example, length and / or diameter) of the system may change due to hydration and / or biodegradation, as further disclosed herein. The drug delivery system can be designed to be biodegradable over time (as disclosed below), therefore it can soften, change its shape and / or reduce size, and can eventually be eliminated by dissolving or disintegrating.

[0033] The term "biodegradable" refers to a material or object (e.g., a drug delivery system according to the present invention) that degrades in vivo (i.e., when placed in a human or animal body) or in vitro when immersed in an aqueous solution under physiological conditions (e.g., 37°C, pH 7.2-7.4). In the context of the present invention, a drug delivery system comprising an organogel containing an active agent, as disclosed in detail below, once applied or deposited in a human or animal body, slowly biodegrades over time. In certain embodiments, biodegradation occurs at least in part by ester hydrolysis in an aqueous environment in vivo. Biodegradation can occur by covalent crosslinking and / or hydrolysis or enzymatic cleavage within polymer units. The drug delivery system slowly softens and decomposes, thereby being cleared by physiological pathways. In certain embodiments, the organogel of the present invention maintains its shape over an extended period of time (e.g., about 1 month, 3 months, or 6 months). In certain embodiments, the shape is maintained due to covalent crosslinking of the polymer components that form the organogel, for example, until the active agent or at least a major amount thereof (e.g., at least 50%, at least 75%, or at least 90%) has been released.

[0034] "Organogel" in the present invention is a solid or semi-solid system that forms a covalently cross-linked three-dimensional network of one or more hydrophilic or hydrophobic natural or synthetic polymers (as disclosed herein), wherein the one or more hydrophilic or hydrophobic natural or synthetic polymers include a hydrophobic organic liquid disclosed herein. Therefore, in the present invention, "organogel" is limited to so-called chemical organogels, in which the intermolecular interactions between the molecules of the organogelator are chemical bonds (e.g., covalent bonds) formed during gelation by chemical reactions that induce cross-linking. "Organogel" as used herein refers to a three-dimensional polymer network of at least two precursors / gelling agents / precursors that are covalently cross-linked to each other in the presence of a hydrophobic organic liquid and an optional organic solvent, and includes a hydrophobic organic liquid contained in the covalently cross-linked polymer network.

[0035] The term "polymer network" describes a structure formed by polymer chains (having the same or different molecular structures and the same or different molecular weights) that are covalently cross-linked to each other. Types of polymers suitable for the purposes of the present invention are disclosed below. The term "polymer network" is used interchangeably with the term "matrix".

[0036] For the purposes of this disclosure, the term "alkyl" when used by itself or as part of another group refers to a group containing 1 to 12 carbon atoms (i.e., C 1-12 alkyl) or a straight or branched aliphatic hydrocarbon having a specified number of carbon atoms (i.e., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is selected from a straight chain C 1-10 In another embodiment, the alkyl group is selected from branched C 1-10 In another embodiment, the alkyl group is selected from a linear C 1-6 In another embodiment, the alkyl group is selected from branched C 1-6 In another embodiment, the alkyl group is selected from a linear C 1-4 In another embodiment, the alkyl group is selected from branched C 1-4 In another embodiment, the alkyl group is selected from branched C 2-4 Non-limiting exemplary C 1-10 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. Non-limiting exemplary C 1-4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl.

[0037] For the purposes of this disclosure, the term "optionally substituted alkyl" when used by itself or as part of another group refers to an alkyl group as defined above that is unsubstituted or substituted with one, two or three substituents independently selected from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxylalkyl, cycloalkyl, and the like. In one embodiment, the optionally substituted alkyl group has two substituents. In another embodiment, the optionally substituted alkyl group has one substituent. Non-limiting exemplary optionally substituted alkyl groups include -CH2CH2NO2, -CH2CH2CO2H, -CH2CH2SO2CH3, -CH2CH2COPh, -CH2C6H 11 wait.

[0038] For the purposes of this disclosure, the term "aryl" as used by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system (i.e., C 6-14 Aryl). Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl. In one embodiment, the aryl group is selected from phenyl or naphthyl.

[0039] For the purpose of this disclosure, the term "optionally substituted aryl" itself or as part of another group refers to that the aryl as defined above is unsubstituted or is substituted by 1 to 5 substituents independently selected from halogen, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, formamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, alkoxyalkyl, (amino) alkyl, hydroxyalkylamino, (alkylamino) alkyl, (dialkylamino) alkyl, (cyano) alkyl, (formamido) alkyl, mercaptoalkyl, (heterocycle) alkyl or (heteroaryl) alkyl. In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. Non-limiting exemplary substituted aryl includes 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl and 3-chloro-4-fluorophenyl. The term optionally substituted aryl means including a group having a fused optionally substituted cycloalkyl and a fused optionally substituted heterocycle. Examples include:

[0040] .

[0041] The term "pharmaceutically acceptable salt" used herein may include, but is not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formates, acetates, trifluoroacetates, maleates, tartrates, etc.; sulfonates such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.; and metal salts such as sodium salts, potassium salts, cesium salts, etc.; alkaline earth metals such as calcium salts, magnesium salts, etc.; organic amine salts such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc. In certain embodiments, the therapeutically effective agent is a free base. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1Synthetic schemes for the prodrugs of Example 1 and Example 2 are depicted.

[0043] Figure 2 The 1H-NMR of Compound 6 (Int-1) of Example 1 is depicted.

[0044] Figure 3 1H-NMR of Example 1 is depicted.

[0045] Figure 4 and 5 The LCMS of Example 1 is depicted.

[0046] Figure 6 The HPLC of Example 1 is depicted.

[0047] Figure 7 Stability data for Example 8 is depicted. DETAILED DESCRIPTION

[0048] In certain embodiments, the invention relates to compounds that are more hydrophilic than the compound of formula II and that can be converted in vivo to the compound of formula II.

[0049] In certain embodiments, the compound of Formula I is converted in vivo to the compound of Formula II (Axitinib)

[0050]

[0051] II

[0052] In certain embodiments, the present invention relates to compounds of formula I:

[0053]

[0054] I

[0055] in:

[0056] X 1 Select from N or N + Y 1 ;

[0057] X 2 Choose from NH or NY 2 ;

[0058] X 3 Choose from NH or NY 3 ;

[0059] Y 1 Selected from -CH2OCO(OCH2CH2)n 1 OM 1 ; or –CH2OCO(CH2CH2O)n 1a Z 1; or –CH2OCO(CH2)n 1b COOH;

[0060] Y 2 Selected from -CH2OCO(OCH2CH2)n 2 OM 2 ; or –CH2OCO(CH2CH2O)n 2a Z 2 ; or –CH2OCO(CH2)n 2b COOH;

[0061] Y 3 Selected from -CH2OCO(OCH2CH2)n 3 OM 3 ; or – CH2OCO(CH2CH2O)n 3a Z 3 ; or –CH2OCO(CH2)n 3b COOH;

[0062] n 1 、n 1a 、n 1b 、n 2 n 2a 、n 2b 、n 3 、n 3a and n 3b are independently 0 or an integer from 1 to 8;

[0063] M 1 、M 2 、M 3 , Z 1 , Z 2 and Z 3 are independently selected from H, optionally substituted C 1-6 alkyl and optionally substituted aryl;

[0064] Where X 1 , X 2 and X 3 At least one of them is not N or NH;

[0065] where Y 1 , Y 2 or Y 3 At least one of them is –CH2OCO(CH2CH2O)nZ;

[0066] and pharmaceutically acceptable salts thereof.

[0067] In certain embodiments, the present invention relates to compounds of formula I, wherein:

[0068] X 1YesN + Y 1 ;

[0069] X 2 is NH; and

[0070] X 3 NH; and

[0071] Y 1 Yes –CH2OCO(CH2CH2O)n 1 Z 1 ;

[0072] In certain embodiments, the present invention relates to compounds of formula I, wherein:

[0073] X 1 is N;

[0074] X 2 It's NY 2 ;

[0075] X 3 is NH; and

[0076] Y 2 Yes –CH2OCO(CH2CH2O)n 2 Z 2 .

[0077] In certain embodiments, the present invention relates to compounds of formula I, wherein:

[0078] X 1 is N;

[0079] X 2 It is NH;

[0080] X 3 It's NY 3 ;and

[0081] Y 3 Yes –CH2OCO(CH2CH2O)n 3 Z 3 .

[0082] In certain embodiments, the present invention relates to compounds of formula I, wherein n 1 Is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0083] In certain embodiments, the present invention relates to compounds of formula I, wherein n 2 Is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0084] In certain embodiments, the present invention relates to compounds of formula I, wherein n 3 Is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0085] In certain embodiments, the present invention relates to compounds of formula I, wherein n 1a Is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0086] In certain embodiments, the present invention relates to compounds of formula I, wherein n 2a Is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0087] In certain embodiments, the present invention relates to compounds of formula I, wherein n 3a Is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0088] In certain embodiments, the present invention relates to compounds of formula I, wherein n 1b Is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0089] In certain embodiments, the present invention relates to compounds of formula I, wherein n 2b Is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0090] In certain embodiments, the present invention relates to compounds of formula I, wherein n 3b Is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0091] In certain embodiments, M 1 It is methyl, ethyl, propyl or phenyl.

[0092] In certain embodiments, M 2 It is methyl, ethyl, propyl or phenyl.

[0093] In certain embodiments, M 3 It is methyl, ethyl, propyl or phenyl.

[0094] In certain embodiments, Z 1 It is methyl, ethyl, propyl or phenyl.

[0095] In certain embodiments, Z 2 It is methyl, ethyl, propyl or phenyl.

[0096] In certain embodiments, Z 3It is methyl, ethyl, propyl or phenyl.

[0097] In certain embodiments, the compound of Formula 1 is axitinib-N-mPEG-succinyloxymethyl; or a pharmaceutically acceptable salt thereof.

[0098] In certain embodiments, the present invention is directed to a pharmaceutical composition comprising a compound of Formula I disclosed herein and a pharmaceutically acceptable excipient.

[0099] In certain embodiments, the pharmaceutical composition is in the form of an oral solid dosage form, such as a tablet, capsule, or powder.

[0100] In certain embodiments, the pharmaceutical composition is in the form of an ophthalmic preparation, such as an implant, an injection, a solution, a suspension or an ointment. The preparation can be administered intravitreally, topically or in any anterior or posterior part of the eye of a mammal (e.g., a human).

[0101] In certain embodiments, the prodrug is contained in a hydrogel (eg, the polyethylene glycol-based systems disclosed herein) or an organogel, eg, for ocular administration.

[0102] The prodrug contained in the hydrogel or organogel can be a prodrug of axitinib disclosed herein or any other prodrug of axitinib or a prodrug of a different active agent known in the art. In certain embodiments, the hydrogel or organogel and the prodrug can be selected to manipulate the release of the active agent from the dosage form. In such embodiments, the prodrug can increase or decrease the solubility of the base drug.

[0103] In certain embodiments, the prodrugs contained in the hydrogel or organogel may be as described in US2021 / 0078970, which is incorporated herein by reference. These prodrugs include the following compounds of formula I, or pharmaceutically acceptable salts, esters, solvates or polymorphs thereof:

[0104]

[0105] Among them, R 1 and R 2 are independently hydrogen (H) or a protecting group (P); R 3 is a protecting group, which may be present or absent, and when R 3 When present, the nitrogen atom is positively charged and a counterion is also present; provided that the compound of Formula I is not axitinib. 1 and R 2 In the embodiment where both are protecting groups (P), the protecting groups may be the same or different.

[0106] In one embodiment, the compound of Formula I is a compound of Formula II below, or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof:

[0107]

[0108] Where R 1 and R 2 are independently hydrogen (H) or a protecting group (P), when R 1 and R 2 When they are all protecting groups, the protecting groups may be the same or different.

[0109] In another embodiment, the compound of Formula I is a compound of Formula III below, or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof:

[0110]

[0111] Where R 3 is a protecting group (P), and is a counter ion.

[0112] In one embodiment, the protecting group is selected from acyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, arylthiocarbonyl, alkylcarbamoyl, arylcarbamoyl, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted α-aminoalkanoyl, acyl derived from natural or unnatural amino acids (with or without substituents), acyl of a peptide residue, phosphonyl, phosphinyl, aminophosphinyl, alkylaminophosphinyl, sulfonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, heteroaryloxycarbonyl and O-substituted hydroxymethyl with or without substituents.

[0113] In another embodiment, the protecting group is selected from R 4 W(R 5 R 6 C) m —, wherein: m is an integer selected from 0 to 6; W is oxygen (—O—), sulfur (—S—), nitrogen (—NH—) or absent; R 5 and R 6 are independently hydrogen or lower alkyl; and R 4 for

[0114]

[0115] Where X is oxygen (-O-), sulfur (-S-), nitrogen (-NH-) or methylene (-CH2-) group, R 6 and R 7 are independently hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted aryl or heteroaryl, a PEG moiety (such as R 10 -(OCH2CH2) n -, where n = 1 to 10 and R 10is hydrogen or lower alkyl), an ester forming group such as lower alkyl or aryl; or when X is oxygen or sulfur, a salt forming moiety (such as sodium, potassium, tetraethylammonium or tetrabutylammonium); or, R 6 and X is, in combination, alkyl or aryl, with or without further substitution; provided that the compound of Formula I, II or III is not axitinib.

[0116] In some embodiments, the counter ion is selected from, but not limited to, a halogen ion (F − , Cl − Br − and I − ), sulfate ion, methanesulfonate ion, toluenesulfonate ion, oxalate ion and other pharmaceutically acceptable anion moieties.

[0117] In other embodiments, the prodrugs contained in the hydrogel or organogel may be as described in US20180022734, which is incorporated herein by reference. These prodrugs include sunitinib compounds of the following formula I.

[0118]

[0119] in:

[0120] R 12 , R 13 Selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 the group consisting of aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl;

[0121] R 14 is selected from the group consisting of R′, OR′, SR′ and N(R′)2; and

[0122] R′ is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 The group consisting of aryl, 4-15 membered heterocyclic group, 5-15 membered heteroaryl, hydroxy C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkylamide and phosphate.

[0123] In some embodiments, R 12 , R 13 is H, and R 14Selected from the group consisting of N,N-dimethylaminomethyl, tert-butyl, phenyl, p-fluorophenyl, biphenyl, dimethylamino, cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclobutyl, pentyl, isopentyl, neopentyl, cyclopentyl, 1-methylcyclobutyl, N-methylamino, N-ethylamino, N,N-methylethylamino, n-hexyl, cyclohexyl, methylthio, ethylthio, propylthio, isopropylthio, cyclopropylthio, butylthio, isobutylthio, cyclobutylthio, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclobutyloxy, pentylamino, pentylthio, pentyloxy, isopentylamino, neopentylamino, tert-butylamino, cyclopentylamino, cyclopentylthio, cyclopentyloxy, cyclohexylamino, cyclohexylthio, cyclohexyloxy, p-methoxyphenyl, p-chlorophenyl and o-fluorophenyl.

[0124] In certain embodiments, the increase in the solubility of the axitinib prodrug allows for the regulation of the release of the active substance from the hydrogel compared to the base drug (i.e., axitinib). For example, the release rate may be at least 1.1 times, at least 1.2 times, at least 1.5 times, at least 2 times, at least 5 times, at least 10 times, at least 20 times, at least 50 times, at least 100 times, at least 250 times, at least 500 times, or at least 1000 times, including all ranges between any previous values. In certain embodiments, the present invention relates to a method for treating a disease or disorder comprising administering a compound of formula I or a pharmaceutical composition disclosed herein.

[0125] In certain embodiments, the disease or condition is cancer, such as advanced renal cell carcinoma.

[0126] In certain embodiments, the disease or disorder is an ocular disease or disorder such as AMD, DME, or RVO.

[0127] In certain embodiments, after administration to a patient or subject, the compound of Formula I is converted in vivo to the compound of Formula II

[0128]

[0129] II

[0130] In certain embodiments, the invention relates to methods of treating a disease or condition by therapy comprising administering an axitinib comprising a compound of Formula I or a pharmaceutical composition disclosed herein.

[0131] In certain embodiments, the invention relates to hydrogels comprising a compound disclosed herein.

[0132] In certain embodiments, the invention relates to xerogels comprising a compound disclosed herein.

[0133] In certain embodiments, hydrogels or xerogels can be formed from precursors having functional groups that form crosslinks to produce a polymer network. These crosslinks between polymer chains or arms can be chemical (i.e., covalent bonds) and / or physical (e.g., ionic bonds, hydrophobic associations, hydrogen bridges, etc.) in nature.

[0134] The polymer network can be prepared by a precursor, or by a type of precursor or by two or more types of precursors that allow reaction. Precursors are selected in view of the properties required for the resulting hydrogel. There are a variety of suitable precursors for preparing hydrogels and xerogels. Generally speaking, any pharmaceutically acceptable and cross-linkable polymers that form hydrogels can be used for purposes of the present invention. Hydrogels and components incorporated therein (including polymers for making polymer networks) should be physiologically safe so that they do not induce, for example, immune responses or other adverse effects. Hydrogels and xerogels can be formed by natural, synthetic or biosynthetic polymers. Natural polymers can include glycosaminoglycans, polysaccharides (such as dextran), polyamino acids and proteins or their mixtures or combinations.

[0135] Synthetic polymers can generally be any polymer produced synthetically from a variety of starting materials by different types of polymerization including free radical polymerization, anionic or cationic polymerization, chain growth or addition polymerization, condensation polymerization, ring opening polymerization, etc. Polymerization can be initiated by certain initiators, by light and / or heat, and can be mediated by catalysts.

[0136] In general, for the purposes of the present invention, one or more synthetic polymers from the group comprising one or more polyalkylene glycol units, such as polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinyl pyrrolidone), polylactic acid, polylactic-glycolic acid copolymers, random or block copolymers or combinations / mixtures of any of these may be used, but this list is not intended to be limiting.

[0137] To form a covalently crosslinked polymer network, the precursors can be covalently crosslinked with each other. In certain embodiments, a precursor having at least two reactive centers (eg, in free radical polymerization) can act as a crosslinker because each reactive group can participate in the formation of a different growing polymer chain.

[0138] Precursors can have biologically inert and hydrophilic parts, such as a core. In the case of branched polymers, a core refers to a continuous portion of a molecule connected to an arm extending from the core, wherein the arm carries a functional group that is typically located at the end of the arm or branch. Multi-arm PEG precursors are examples of such precursors and are further disclosed below.

[0139] Therefore, the hydrogel for the present invention can be for example made by a multi-arm precursor with a first (group) functional group and another multi-arm precursor with a second (group) functional group. For example, the multi-arm precursor can have a hydrophilic arm, for example, with a polyethylene glycol unit terminated by a primary amine (nucleophile), or can have an activated ester end group (electrophile). Polymer network according to the present invention can comprise identical or different polymer units cross-linked to each other.

[0140] Certain functional groups can be made more reactive by using activating groups. Such activating groups include, but are not limited to, carbonyldiimidazole, sulfonyl chloride, aryl halide, sulfosuccinimide ester, N-hydroxysuccinimide ester, succinimide ester, epoxide, aldehyde, maleimide, imidoester, acrylate, and the like. N-hydroxysuccinimide ester (NHS) is a useful group for crosslinking nucleophilic polymers such as primary amine-terminated or thiol-terminated polyethylene glycol. The NHS-amine crosslinking reaction can be carried out in aqueous solution and in the presence of a buffer such as phosphate buffer (pH 5.0-7.5), triethanolamine buffer (pH 7.5-9.0), borate buffer (pH 9.0-12), or sodium bicarbonate buffer (pH 9.0-10.0).

[0141] In certain embodiments, each precursor may contain only nucleophilic functional groups or only electrophilic functional groups, as long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if the crosslinking agent has only nucleophilic functional groups such as amines, the precursor polymer may have electrophilic functional groups such as N-hydroxysuccinimide. On the other hand, if the crosslinking agent has electrophilic functional groups such as sulfosuccinimide, the functional polymer may have nucleophilic functional groups such as amines or thiols. Therefore, functional polymers such as proteins, poly (allylamine) or amine-terminated difunctional or multifunctional poly (ethylene glycol) can also be used to prepare the polymer network of the present invention.

[0142] In one embodiment, the first reactive precursors each have from about 2 to about 16 nucleophilic functional groups (referred to as functionality), and the second reactive precursors that are allowed to react with the first reactive precursors to form a polymer network each have from about 2 to about 16 electrophilic functional groups. Reactive precursors with a number of reactive (nucleophilic or electrophilic) groups that are multiples of 4 (thus, for example, 4, 8, and 16 reactive groups) are particularly suitable for the present invention. For the precursors to be used according to the present invention, any number of functional groups can be used, for example, including any one of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups, while ensuring functionality sufficient to form a fully cross-linked network.

[0143] In certain embodiments of the invention, the polymer network forming the hydrogel contains polyethylene glycol (PEG) units. It is known in the art that PEG forms hydrogels when cross-linked, and these PEG hydrogels are suitable for pharmaceutical applications, for example as a matrix for drugs intended to be administered to all parts of the human or animal body.

[0144] The polymer network of the hydrogel implant of the present invention can comprise one or more multi-arm PEG units with 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7 or 8 arms. The PEG units can have different or the same number of arms. In certain embodiments, the PEG units used in the hydrogel of the present invention have 4 and / or 8 arms. In certain specific embodiments, a combination of 4-arm and 8-arm PEG units is used.

[0145] The number of arms of the PEG used helps control the flexibility or softness of the resulting hydrogel. For example, a hydrogel formed by cross-linking a 4-arm PEG is generally softer and more flexible than a hydrogel formed by an 8-arm PEG of the same molecular weight. Specifically, as disclosed herein below in the section relating to the manufacture of the implant, if it is necessary to stretch the hydrogel before or after drying, a more flexible hydrogel, such as a 4-arm PEG, can be used, optionally in combination with another multi-arm PEG, such as an 8-arm PEG disclosed above.

[0146] In certain embodiments of the present invention, the mean molecular weight of the polyethylene glycol unit used as a precursor is in the range of about 2,000 to about 100,000 daltons, or in the range of about 10,000 to about 60,000 daltons, or in the range of about 15,000 to about 50,000 daltons. In certain specific embodiments, the mean molecular weight of the polyethylene glycol unit is about 10,000 to about 40,000 daltons, or about 20,000 daltons. The PEG precursor of the same mean molecular weight can be used, or the PEG precursors of different mean molecular weights can be combined with each other. The mean molecular weight of the PEG precursor used in the present invention is given with a number average molecular weight (Mn), and in certain embodiments, it can be measured by MALDI.

[0147] In 4-arm PEG, each arm may have an average arm length (or molecular weight) of the total molecular weight of PEG divided by 4. The 4a20kPEG precursor, which is a precursor that can be used in the present invention, therefore has 4 arms, and the average molecular weight of each arm is about 5,000 Daltons. In addition to the 4a20kPEG precursor, the 8a20k PEG precursor that can be used in the present invention therefore has 8 arms, and each arm has an average molecular weight of 2,500 Daltons. Compared with shorter arms, longer arms can provide increased flexibility. Compared with PEG with shorter arms, PEG with longer arms can expand more. Compared with PEG with more arms, PEG with fewer arms can also expand more and can be more flexible. In certain specific embodiments, a combination of PEG precursors with different arm numbers, such as a combination of a 4-arm PEG precursor and an 8-arm precursor, can be used in the present invention. In addition, longer PEG arms have a higher melting temperature when dried, which can provide higher dimensional stability during storage. For example, an 8-arm PEG of molecular weight 15,000 Daltons cross-linked to trilysine may not be able to maintain a stretched configuration at room temperature, whereas a 4-arm 20,000 Dalton PEG cross-linked to an 8-arm 20,000 Dalton PEG may be dimensionally stable in a stretched configuration at room temperature.

[0148] When referring to a PEG precursor having a certain average molecular weight, such as a 15kPEG- or 20kPEG-precursor, the average molecular weight indicated (i.e., an Mn of 15,000 or 20,000, respectively) refers to the PEG portion of the precursor prior to the addition of the end groups ("20k" herein means 20,000 Daltons, "15k" means 15,000 Daltons - the same abbreviations are used herein for other average molecular weights of PEG precursors). In certain embodiments, the Mn of the PEG portion of the precursor is determined by MALDI. The degree of end group substitution disclosed herein can be determined after the end groups are functionalized by 1 H-NMR determination.

[0149] In certain embodiments, the electrophilic end groups used with the PEG precursors to prepare the hydrogels of the present invention are N-hydroxysuccinimidyl (NHS) esters, including but not limited to: "SAZ" refers to a succinimidyl azelate end group, "SAP" refers to a succinimidyl adipate end group, "SG" refers to a succinimidyl glutarate end group, and "SS" refers to a succinimidyl succinate end group.

[0150] In certain embodiments, the nucleophilic end groups used with the PEG precursors to prepare the hydrogels of the present invention are amine (denoted as "NH2") end groups. Thiol (-SH) end groups or other nucleophilic end groups are also possible.

[0151] In certain preferred embodiments, 4-arm PEG and 8-arm PEG, which have an average molecular weight of about 20,000 Daltons and an electrophilic end group as described above, are cross-linked to form a polymer network, thereby forming a hydrogel according to the present invention, wherein the 4-arm PEG has an average molecular weight of about 20,000 Daltons and has an electrophilic end group as described above, and the 8-arm PEG also has an average molecular weight of about 20,000 Daltons and has a nucleophilic end group as described above.

[0152] The reaction of a PEG unit containing a nucleophilic group and a PEG unit containing an electrophilic group (e.g., a PEG unit containing an amine terminal group and a PEG unit containing an activated ester group) results in the cross-linking of multiple PEG units through a hydrolyzable linker having the formula: wherein m is an integer from 0 to 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In a particular embodiment, m is 6, for example in the case of using PEG containing SAZ end groups. For SAP end groups, m will be 3, for SG end groups, m will be 2, and for SS end groups, m will be 1. All crosslinks within the polymer network may be the same or different.

[0153] In certain preferred embodiments, SAZ end groups are used in the present invention. This end group can increase the duration in the eye, and the implants of certain embodiments of the present invention comprising a hydrogel containing PEG-SAZ units are only biodegraded in the eye (e.g., in the vitreous humor of the human eye) after an extended period of time (e.g., 9 to 12 months as further disclosed below), and can even last longer in some cases. SAZ groups are more hydrophobic than, for example, SAP-, SG-, or SS-end groups because the number of carbon atoms in the chain is higher (m is 6, and the total number of carbon atoms between the amide group and the ester group is 7).

[0154] In certain preferred embodiments, a 4-arm 20,000 Dalton PEG precursor is combined with an 8-arm 20,000 Dalton PEG precursor, such as a 4-arm 20,000 Dalton PEG precursor with a SAZ group (as defined above) and an 8-arm 20,000 Dalton PEG precursor with an amine group (as defined above). These precursors are also abbreviated herein as 4a20kPEG-SAZ and 8a20kPEG-NH2, respectively. The chemical structure of 4a20kPEG-SAZ is:

[0155]

[0156] Where R represents the pentaerythritol core structure. The chemical structure of 8a20kPEG-NH2 (with hexaglycerol core) is:

[0157]

[0158] In the above formula, n is determined by the molecular weight of each PEG arm.

[0159] In certain embodiments, the molar ratio of the nucleophilic end groups and electrophilic end groups that react with each other is about 1: 1, i.e., each SAZ group provides an amine group. In the case of 4a20kPEG-SAZ and 8a20kPEG-NH2, this results in a weight ratio of about 2: 1, because the amount of end groups contained in 8-arm PEG is twice that of 4-arm PEG. However, an excess of electrophilic (e.g., NHS end groups, such as SAZ) end groups or nucleophilic (e.g., amine) end groups can be used. In particular, an excess of nucleophilic precursors, such as precursors containing amine end groups, i.e., the weight ratio of 4a20kPEG-SAZ and 8a20kPEG-NH2 can also be less than 2: 1.

[0160] Each and any combination of the PEG precursor containing electrophilic group and nucleophilic group disclosed herein can be used for preparing implant according to the present invention.For example, any 4-arm or 8-arm PEG-NHS precursor (for example, with SAZ, SAP, SG or SS end group) can be combined with any 4-arm or 8-arm PEG-NH2 precursor (or any other PEG precursor with nucleophilic group).In addition, the PEG unit containing electrophilic group and the precursor containing nucleophilic group can have the same or different mean molecular weight.

[0161] Another cross-linking agent containing a nucleophilic group can be used instead of a PEG-based cross-linking agent. For example, a low molecular weight amine linker such as trilysine (or a trilysine salt or derivative, such as trilysine acetate) or other low molecular weight multi-arm amines can be used.

[0162] In certain embodiments, the cross-linking agent containing nucleophilic groups can be combined or conjugated with a visualization agent. A visualization agent is an agent comprising a fluorophore or other group that can be visualized. Fluorophores such as fluorescein, rhodamine, coumarin and cyanine can be used as visualization agents, for example. Visualization agents can be conjugated with cross-linking agents, for example, by some nucleophilic groups of cross-linking agents. Since cross-linking requires a sufficient amount of nucleophilic groups, "conjugated / conjugation" generally includes partial conjugation, meaning that only a portion of nucleophilic groups are used to conjugate with visualization agents, for example, about 1% to about 20% of the cross-linking agent, or about 5% to about 10%, or about 8% of the nucleophilic groups can be conjugated with visualization agents. In other embodiments, visualization agents can also be conjugated with polymer precursors, for example, by some reactive (e.g., electrophilic) groups of polymer precursors.

[0163] The hydrogels disclosed herein may also be suitable for use as xerogels.

[0164] Extrusion dosage form

[0165] The materials disclosed herein for use in hydrogels can also be extruded together with the prodrugs.

[0166] In certain embodiments, a method of preparing a sustained release biodegradable ocular insert is contemplated, the method comprising extruding a polymer composition and a prodrug to form an insert suitable for ocular administration.

[0167] In other embodiments, the method includes feeding the polymer composition and the prodrug to an extruder; mixing the components in the extruder; extruding a strand; and cutting the strand into unit dose inserts or implants.

[0168] In certain embodiments, the polymer composition and the prodrug are fed separately into the extruder. In other embodiments, the polymer composition and the prodrug are fed simultaneously into the extruder. In certain embodiments, the polymer composition is premixed before being introduced into the extruder, such as melt blending.

[0169] In certain embodiments, the method further includes cooling the wire, for example, prior to cutting the wire.

[0170] In certain embodiments, the method further comprises stretching the wire, for example, prior to cutting the wire.

[0171] In certain embodiments, stretching is performed under wet conditions, heated conditions, or a combination thereof. In certain embodiments, stretching is performed under dry conditions, heated conditions, or a combination thereof.

[0172] In certain embodiments, the extruded composition undergoes a curing step, such as exposure to moisture. In certain embodiments, curing crosslinks the polymer composition.

[0173] In certain embodiments, the method further comprises drying the wire after stretching the wire.

[0174] In other embodiments, any method steps disclosed herein can be performed simultaneously or sequentially in any order.

[0175] In certain embodiments, the method further comprises melting the polymer in an extruder at a temperature below the melting point of the prodrug. The temperature can be, for example, less than about 100°, less than about 90°, less than about 80°, less than about 70°, less than about 60°, less than about 50°. In some embodiments, the temperature is from about 50°C to about 80°C. In certain embodiments, extrusion is performed above the melting point of the polymer and the prodrug.

[0176] In certain embodiments, when the extruded composition is in a linear or unit dose, it is dried. In certain embodiments, drying is performed after the wire is stretched. Drying can be, for example, evaporative drying at ambient temperature or can include heating, vacuum, or a combination thereof.

[0177] In certain embodiments, the hydrogel strand is stretched by a stretch factor ranging from about 0.25 to about 10, from 0.5 to about 6, or from about 1 to about 4.

[0178] In certain embodiments, the wire is cut into segments having an average length equal to or less than about 20 mm, 17 mm, 15 mm, 12 mm, 10 mm, 8 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, or 0.5 mm.

[0179] In certain embodiments, the prodrug is suspended in the polymer composition.

[0180] In certain embodiments, the prodrug is uniformly dispersed in the polymer composition.

[0181] In certain embodiments, the extrusion process is performed in the absence of a solvent (eg, water), and in certain embodiments, the amount of solvent used is less than about 10% w / w, less than about 5% w / w, or less than about 1% w / w.

[0182] In certain embodiments, the content uniformity of the unit dose insert is within 10%, within 5%, or within 1%.

[0183] In certain embodiments, the duration of the dosage form following ocular administration is from about 7 days to about 6 months.

[0184] In certain embodiments, the polymorphic form of the prodrug does not change or does not substantially change. In certain embodiments, the purity of the prodrug after solidification is greater than 99%, greater than 99.5%, or greater than 99.9% compared to the prodrug before extrusion.

[0185] In certain embodiments, the prodrug has an average particle size of less than about 100 μm, less than about 50 μm, less than about 25 μm, or less than about 10 μm.

[0186] In certain embodiments, the prodrug has a D50 particle size of less than about 10 μm and / or a D99 particle size of less than about 50 μm, or a D90 particle size of about 5 μm or less and / or a D98 particle size of about 10 μm or less.

[0187] Organic gel

[0188] In certain embodiments, the prodrugs herein may be used in organogels.

[0189] In certain embodiments, the present invention provides a sustained release, biodegradable drug delivery system comprising an organogel and a prodrug, the organogel comprising a hydrophobic organic liquid and a biodegradable covalently cross-linked polymer network, wherein the hydrophobic organic liquid and the prodrug are contained in the biodegradable covalently cross-linked polymer network. In certain embodiments, a sustained release, biodegradable drug delivery system comprising an organogel and a prodrug is provided, the organogel comprising a hydrophobic organic liquid and a biodegradable covalently cross-linked polymer network, wherein the hydrophobic organic liquid and the prodrug are fixed in the biodegradable covalently cross-linked polymer network.

[0190] In certain embodiments, the sustained release, biodegradable drug delivery system comprises at least three components: a biodegradable covalently cross-linked polymer network, a hydrophobic organic liquid, and a prodrug.

[0191] In certain embodiments, the organogel is formed by polymerization of nonlinear, multifunctional monomers or polymeric precursor components disclosed below, and forms a covalently cross-linked polymeric network that includes a hydrophobic organic liquid and fixes it within the polymeric network, for example until it is released from the network in vivo. Therefore, the organogel of the present invention is similar to a hydrophobic analog of a hydrogel that contains water instead of a hydrophobic organic phase. The organogel is similar to the hydrogel in that its matrix is ​​composed of a polymer component (gel factor) that forms a network and a non-reactive component. In a hydrogel, the non-reactive component is water, while in the organogel of the present invention, it is a hydrophobic organic compound, such as an oil, having a glass transition (Tg) and a melting (Tm) transition temperature below body temperature.

[0192] In certain embodiments, the covalent crosslinking of the precursors forming the polymer network provides limited mobility for the hydrophobic organic liquid (e.g., oil) component. This can provide continuous control of drug release by limiting the diffusion of drug transport through the organogel and / or eliminating the generation of defects, which provide a fast escape path for the generation of the drug. In certain embodiments, the drug delivery system of the present invention is a delivery system that is fully or partially diffusion-controlled, i.e., the release of oil and / or prodrug is mainly controlled by the diffusion process. The degradation of the polymer matrix may also occur in the organogel of the present invention, but does not mainly control the release of the prodrug. In non-crosslinked gels such as extruded linear polymers, the release of the prodrug is mainly controlled by the degradation of the polymer matrix, which mainly releases the prodrug in the degradation control system. The precursors forming the network should be miscible in the hydrophobic organic liquid component so that when crosslinked, it "keeps" the component to form a solid or semi-solid, thereby forming an organogel. In certain embodiments, the compatibility of the hydrophobic organic liquid with the polymer network has an impact on the rate at which the hydrophobic organic liquid escapes into the surrounding tissue fluid in vivo and may be gradually replaced by the aqueous liquid, thus providing an additional means of controlling drug release kinetics on prodrug solubility and network degradation.

[0193] In certain embodiments, the use of organogel in the sustained release, biodegradable drug delivery system of the present invention therefore allows the release of prodrugs from the drug delivery system to be changed by adjusting or appropriately selecting the precursor components forming the cross-linked polymer network according to their hydrophilicity and / or hydrophobicity. In addition, in certain embodiments, the release of prodrugs from the drug delivery system can be changed or controlled by appropriately selecting a hydrophobic organic liquid according to the properties of the hydrophobic organic liquid (e.g., hydrophobicity, viscosity, compatibility with the prodrug, solubility or insolubility of the prodrug in the hydrophobic organic phase, etc.).

[0194] The organogel-based drug delivery system of certain embodiments of the present invention provides several advantages over hydrogels. For example, certain organogels are anhydrous and can thus stabilize water-degradable (hydrolyzable) components such as water-sensitive prodrugs and allow them to be stored stably for a long period of time and do not require hydration when implanted.

[0195] Water-soluble compounds have low or no solubility in organogels, allowing the drug to be incorporated as a particulate solid embedded in the organogels matrix. The low solubility of the drug in the organogels matrix provides a mechanism to control the rate of drug release. This property greatly increases the range of compounds that can be included in implants.

[0196] Controlling the lipophilicity / hydrophilicity of organogels can be used to tune the release rate of drugs and influence diffusion rates. Pure hydrogels cannot be tuned in this way because they are water-based, so in these systems the drug itself must be modified to a prodrug form to adjust drug / matrix solubility. In organogels, this can be avoided. Furthermore, varying the lipophilicity / hydrophilicity of organogels can also be used to influence the degradation rate of the polymer matrix, which also has an additional effect on the release rate of the drug.

[0197] Organogels can be designed to slowly release hydrophobic organic liquids (such as oils) from the matrix in vivo, allowing for a slow conversion to a hydrogel followed by degradation. This provides a new mode of controlled drug release and increased biocompatibility.

[0198] The optional addition of solvents to the organogel can be used during the manufacturing process to overcome compatibility issues of the components, and the solvent can be removed to produce an organogel with fixed oil. Removal of the solvent can be accomplished by thermal treatment, which is not possible for materials that undergo melting or glass transitions at high temperatures. Solvent removal can also be accomplished by methods commonly used for non-crosslinked polymers such as water extraction, vacuum drying, freeze drying, evaporation, etc. The lack of the need for careful removal of the solvent greatly simplifies the manufacturing process.

[0199] In certain embodiments, the organogel has the physical qualities of low modulus, dimensional stability, and favorable drug release kinetics. In certain embodiments, the organogel can be dimensionally stable to heat and will not melt. Therefore, implant manufacturing processes such as hot melt extrusion can be used to form certain organogels of the present invention.

[0200] The drug delivery system of the present invention comprising an organogel can be used to deliver a variety of drugs, including steroids, non-steroidal anti-inflammatory drugs (NSAIDS), ocular hypotensive drugs, antibiotics, peptides or other drugs. The organogel can be used to deliver drugs and therapeutic agents, such as anti-inflammatory agents (such as diclofenac), analgesics (such as bupivacaine), calcium channel blockers (such as nifedipine), antibiotics (such as ciprofloxacin), cell cycle inhibitors (such as simvastatin), proteins or peptides (such as insulin), enzymes, anti-tumor agents, local anesthetics, hormones, angiogenic agents, anti-angiogenic agents, growth factors, antibodies, neurotransmitters, psychotropic drugs, anticancer drugs, chemotherapeutic drugs, drugs that affect reproductive organs, genes and oligonucleotides or other configurations, and viruses such as AAV for gene delivery. The release rate from the organogel may depend on the properties of one or more of the prodrug, hydrophobic organic liquid and polymer network, as well as other possible factors, including one or more of the drug size, relative hydrophobicity, organogel density, organogel solid content, etc.

[0201] The drug delivery system of the present invention can be in the form of an implant, a medical implant or a pharmaceutically acceptable implant, an implant coating or an oral dosage form.

[0202] Treatment

[0203] In certain embodiments, the prodrugs disclosed herein are used to treat ocular diseases involving angiogenesis.

[0204] In other embodiments, the ocular disease may be mediated by one or more receptor tyrosine kinases (RTKs), such as VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α / β, and / or c-Kit.

[0205] In some embodiments, the eye disease is a retinal disease, including choroidal neovascularization, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, acute macular neuroretinopathy, central serous chorioretinopathy, and cystoid macular edema; wherein the eye disease is acute multifocal squamous pigment epitheliopathy, Behcet's disease, avian elastic choroidopathy, infectious (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple vanishing white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpentine choroiditis wherein the ocular disease is a vascular disease or an exudative disease, including Coat's disease, juxtafoveal telangiectasia, papillary phlebitis, frost-branch vasculitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, and familial exudative vitreoretinopathy; or wherein the ocular disease is caused by trauma or surgery, including sympathetic ophthalmia, uveoretinal disease, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, perioperative hypoperfusion, radiation retinopathy, or bone marrow transplant retinopathy.

[0206] In alternative embodiments, prodrugs used herein can be used to treat eye disorders associated with tumors. Such disorders include, for example, retinal diseases, solid tumors, tumor metastases, benign tumors associated with tumors, such as hemangiomas, neurofibromas, trachoma and purulent granulomas, congenital RPE hypertrophy, posterior uveal melanoma, choroidal hemangiomas, choroidal osteomas, choroidal metastases, retinal and retinal pigment epithelial complex hamartomas, retinoblastomas, fundus angiogenic tumors, retinal astrocytomas, or intraocular lymphomas.

[0207] In other embodiments, the prodrugs of the present invention may be used to treat any ocular disease involving vascular leakage.

[0208] In certain embodiments, the ocular disease is selected from neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). In specific embodiments, the ocular disease is neovascular age-related macular degeneration. In other embodiments, the ocular disorder is dry eye.

[0209] Compounds and pharmaceutical compositions disclosed herein can be administered by any route, such as oral, parenteral, ocular, transdermal, nasal, pulmonary or rectal administration. In certain embodiments, it can be administered to the vitreous or other locations. Another example of a space is a lacrimal point (tubule, upper / lower tubule), a fornix, an upper / lower fornix, a space below the fascia of the eye, a choroid, a choroidal suprafascia, a fascia, a cornea, a cancerous tissue, an organ, a prostate, a breast, a space or injury produced by surgery, a void space, a potential space. In certain embodiments, the dosage form is a lacrimal plug, an insert in the canaliculus, an insert in the anterior chamber or an insert in the vitreous body.

[0210] In certain embodiments, the prodrugs and formulations herein are used by intravitreal, suprachoroidal, subretinal, subconjunctival, or subfascial administration (eg, for oncology treatment).

[0211] In certain embodiments, the present invention relates to a prodrug (e.g., an axitinib prodrug disclosed herein) administered in combination with a base drug (e.g., axitinib) in the same formulation (e.g., an ocular formulation) or in a different formulation to provide a faster-releasing loading dose when there is a lag time in the release or therapeutic effect of the base drug. In embodiments where the prodrug has a slower release than the base drug, the combination can provide a longer duration of action than the base drug administered alone.

[0212] In certain embodiments, axitinib prodrugs may be formulated and / or administered according to US Patent No. 11,439,592 B2.

[0213] Example

[0214] Example 1

[0215] Axitinib-N-mPEG-succinyloxymethyl prodrug

[0216] The compound of Example 2 was prepared according to the following scheme:

[0217] Scheme 2A: Preparation of Intermediate-1

[0218]

[0219] Scheme 2B: Preparation of axitinib-N-mPEG-succinyloxymethyl prodrug

[0220]

[0221] Listed below are the sample quantities, batch sizes, conditions, yields, and discussion for each step of the process:

[0222]

[0223]

[0224]

[0225]

[0226] Scheme 1b (Alternative Route): Preparation of Axitinib-N-mPEG-Succinyloxymethyl Prodrug

[0227]

[0228]

[0229] Example 2 Solubility Experiment

[0230] The solubility test was carried out under the following test items and conditions:

[0231] Test items: Axitinib (HPLC purity 99.99%);

[0232] Axitinib-N-mPEG-succinyloxymethyl prodrug (HPLC purity 93.6%)

[0233] Test medium: Phosphate buffered saline, pH 7.4

[0234] Incubation conditions: 24 hours at 22°C, constant shaking

[0235] Test concentration: 1 mg / mL

[0236] Data analysis: Solubility of test items determined by HPLC analysis and calibration curve

[0237] HPLC conditions were as follows:

[0238]

[0239] The results are as follows:

[0240]

[0241] The literature reports that the solubility of axitinib is about 0.2 mcg / mL. The results show that the prodrug solubility of N-mPEG succinyloxymethyl prodrug is improved by about 500 times.

[0242] Example 3 (prediction)

[0243] The conversion of the axitinib-N-mPEG-succinyloxymethyl prodrug to axitinib is described as follows.

[0244] method

[0245] Each prodrug was incubated at one concentration (1 μM in the final incubation) with hrCES (combination of hrCES-1 and hrCES-2, 0.1 mg protein / mL per hrCES) in phosphate buffer (100 mM, pH 7.4) containing MgCl2 (5 mM). The incubation mixture was equilibrated in a shaking water bath at 37°C for 5 minutes. The reaction was initiated by the addition of the prodrug and then incubated at 37°C. Aliquots of the incubation solution were sampled at 0, 15, 30, 60, and 120 minutes. The reaction was terminated by the addition of 50% ice-cold acetonitrile (ACN) / 0.1% formic acid containing an internal standard (IS, 0.2 μM metoprolol, or 0.2 μM tolbutamide, for positive or negative ionization mode in mass spectrometry, respectively).

[0246] After protein removal by centrifugation at 1,640 g (3,000 rpm) for 10 min at 4°C, the supernatant was transferred to an HPLC autosampler plate and stored at −20°C until analysis. The remaining prodrug (expressed as the peak area ratio of prodrug to IS) and the acid product formed by each prodrug (the final hydrolysis product of each prodrug) were determined by LC-MS / MS (Appendix 1). The CES activity of the hrCES used in this study was verified in parallel by determining the time-dependent formation of PNP (0, 3, 5, and 10 min) based on the absorbance at 410 nm using 1 mM of the nonspecific esterase probe substrate PNPB. The experimental conditions for CES reaction phenotyping and sample analysis are summarized below.

[0247] Conditions and sample analysis for CES reactions using hrCES

[0248]

[0249] Data analysis

[0250] Calculate the remaining percentage of prodrug using the following formula:

[0251] Prodrug remaining % = 100 × At / A0

[0252] Wherein, At is the peak area ratio (prodrug to IS) at time t, and A0 is the peak area ratio (prodrug to IS) at time 0.

[0253] The elimination rate constant of the prodrug was estimated by first-order reaction kinetics: Ct = C0 • e -kt

[0254] where C0 and Ct are the concentrations of the prodrug at time 0 and incubation time t (min) (expressed as the peak area ratio of the prodrug to the IS), and k is the elimination rate constant (min-1).

[0255] Before the curve begins to level off, calculate the elimination half-life of the prodrug (if applicable) using the following formula:

[0256] t1 / 2 = 0.693 / k

[0257] Where t1 / 2 is the half-life (min) and k is the elimination rate constant (min-1).

[0258] Calculate the in vitro intrinsic clearance of the prodrug (if applicable) using the following formula:

[0259] CLint = k / P

[0260] where CLint is the in vitro intrinsic clearance, k is the elimination rate constant (min-1), and P is the enzyme concentration in the incubation medium (mg protein / mL).

[0261] All intrinsic clearance parameters were estimated using GraphPad® Prism (GraphPad Software, San Diego, CA, USA) and Microsoft Office Excel (Microsoft Corporation, Redmond, WA, USA).

[0262] Example 4 (prediction)

[0263] The test substance was prepared as a suspension in a mixture of DMSO (5%) and 0.5%-CMC-Na (95%, v / v), and for the prodrug of the present invention, the concentration was 3 mg / mL axitinib molar equivalent. Male ICR mice (64, weight range 18-22 g) were randomly divided into 4 groups (16 animals per group). After the animals were fasted for 12 hours, the test substance was administered to the animals by oral gavage at a dose of 30 mg / kg axitinib molar equivalent. Blood samples were collected from the orbits into heparinized EP tubes at 0.25, 0.5, 1, 2, 4, 6 and 8 hours after administration of the dosing solution. The blood samples were centrifuged at 5,000 rpm and 4°C for 10 min, and plasma samples were collected and stored at -80°C. Sample analysis: Plasma samples (10 μL) were thoroughly mixed with acetonitrile (110 μL). The samples were then centrifuged at 12,000 rpm and 4°C. The supernatant was analyzed using LC-MS / MS instrumentation, with the target analytes being axitinib and its corresponding prodrug molecules.

[0264] Example 5 (prediction)

[0265] Male ICR mice (weight: 18 to 22 g) were randomly divided into 6 groups of 6 animals in each group, and blood samples from 6 animals were collected at each time point for a total of 6 time points. The dosing solution of the test substance was prepared by dissolving or suspending the compound in a solvent system. For all compounds, the dosing solution concentration was 3 mg / mL axitinib molar equivalent and the dose was 30 mg / kg axitinib molar equivalent. The animals were fasted for 12 hours and then the test substance was administered in the dosing vehicle at a dosing volume calculated based on the above information. After dosing, blood samples were collected at preset time points of 0.5, 1, 2, 4, 6 and 8 hours. The blood samples were centrifuged at 5,000 rpm and 4°C for 10 min, and plasma samples were collected and stored at -80°C. Sample analysis: The plasma samples (20 μL) were thoroughly mixed with acetonitrile (220 μL). The samples were then centrifuged at 12,000 rpm and 4°C. The supernatant and target analytes were analyzed using an LC-MS / MS instrument.

[0266] Example 6

[0267] Axitinib-N-mPEG2-oxymethyl prodrug

[0268] The compound of Example 6 was prepared according to the following scheme:

[0269]

[0270]

[0271] Listed below are the sample quantities, batch sizes, conditions, yields, and discussion for each step of the process:

[0272] Step 1

[0273]

[0274]

[0275] Steps 2-5

[0276]

[0277] Step 2

[0278]

[0279] Step 3

[0280]

[0281] Step 4

[0282]

[0283] Step 5

[0284]

[0285] Axitinib-Nm(PEG) obtained in Example 6 2- The micronization of the oxymethyl prodrug in dry dispersion was D90 = 12.4 μm; D50 = 3.6 μm and D10 = 0.6 μm, and in water dispersion was D90 = 12.2 μm; D50 = 5.2 μm and D10 = 1.1 μm.

[0286] Example 7

[0287] The solubility of the axitinib prodrug of the present invention in phosphate buffered saline (PBS, pH-7.40) was tested. The results are shown in the following table:

[0288]

[0289] Example 8

[0290] The stability of the axitinib prodrug of the present invention was tested in phosphate buffered saline (PBS, pH-7.40). The results are shown in the following table and Figure 7 As shown:

[0291]

[0292] Example 9

[0293] The HPLC purity of the axitinib prodrug of the present invention is as follows:

[0294]

Claims

1. A compound of formula I: ， I in: X 1 Select from N or N + Y 1 ; X 2 Choose from NH or NY 2 ; X 3 Choose from NH or NY 3 ; Y 1 Selected from -CH2OCO(OCH2CH2)n 1 OM 1 ; or –CH2OCO(CH2CH2O)n 1a Z 1 ; or –CH2OCO(CH2)n 1b COOH; Y 2 Selected from -CH2OCO(OCH2CH2)n 2 OM 2 ; or –CH2OCO(CH2CH2O)n 2a Z 2 ; or –CH2OCO(CH2)n 2b COOH; Y 3 Selected from -CH2OCO(OCH2CH2)n 3 OM 3 ; or – CH2OCO(CH2CH2O)n 3a Z 3 ; or –CH2OCO(CH2)n 3b COOH; n 1 、n 1a 、n 1b 、n 2 n 2a 、n 2b 、n 3 、n 3a and n 3b are independently 0 or an integer from 1 to 8; M 1 、M 2 、M 3 , Z 1 , Z 2 and Z 3 are independently selected from H, optionally substituted C 1-6 alkyl and optionally substituted aryl; Where X 1 , X 2 and X 3 At least one of them is not N or NH; where Y 1 , Y 2 or Y 3 At least one of them is –CH2OCO(CH2CH2O)nZ; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein: X 1 YesN + Y 1 ; X 2 is NH; and X 3 NH; and Y 1 Here – CH2OCO(CH2CH2O)n 1 Z 1 .

3. The compound of claim 1, wherein: X 1 is N; X 2 It is NY. 2 ; X 3 is NH; and Y 2 Here – CH2OCO(CH2CH2O)n 2 Z 2 .

4. The compound of claim 1, wherein: X 1 is N; X 2 It is NH; X 3 It's NY 3 ;and Y 3 Here – CH2OCO(CH2CH2O)n 3 Z 3 .

5. A compound as claimed in any one of the preceding claims, wherein n 1 、n 2 or 3 Serves 2.

6. A compound as claimed in any one of the preceding claims, wherein n 1a 、n 2a or 3a Serves 2.

7. A compound as claimed in any one of the preceding claims, wherein n 1b 、n 2b or 3b Serves 2.

8. A pharmaceutical composition as claimed in any one of the preceding claims, comprising a compound of formula I and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition according to claim 8, which is in the form of an oral solid dosage form.

10. The pharmaceutical composition according to claim 9, which is in the form of a tablet.

11. The pharmaceutical composition according to claim 8, which is in the form of an ophthalmic preparation.

12. The pharmaceutical composition according to claim 11, which is in the form of an implant, an injection, a solution, a suspension or an ointment.

13. A method of treating a disease or condition comprising administering a compound or pharmaceutical composition according to any one of the preceding claims.

14. The method of claim 13, wherein the disease or condition is advanced renal cell carcinoma.

15. The method of claim 13, wherein the disease or condition is an ocular disease or condition.

16. The method of claim 15, wherein the ocular disease or disorder is AMD, DME, or RVO.

17. A method as claimed in any one of the preceding claims, wherein the compound of formula I is converted in vivo into a compound of formula II II。 18. A method of treating a disease or condition by axitinib therapy comprising administering a compound or pharmaceutical composition according to any one of the preceding claims.

19. A hydrogel comprising the compound of any one of claims 1 to 8.

20. A xerogel comprising the compound of any one of claims 1 to 8.

21. A compound which is more hydrophilic than the compound of formula II and which can be converted into the compound of formula II in vivo.

22. The hydrogel of claim 19, further comprising a polyethylene glycol compound.

23. The xerogel of claim 20, further comprising a polyethylene glycol compound.

24. The compound of claim 1, which is axitinib-N-mPEG-succinyloxymethyl.

25. The pharmaceutical composition of claim 8, comprising axitinib-N-mPEG-succinyloxymethyl.

26. The method of claim 13, wherein the compound is axitinib-N-mPEG-succinyloxymethyl.

27. A compound or pharmaceutical composition as claimed in any preceding claim for use in a method of treatment.

28. Use of a compound or pharmaceutical composition as claimed in any one of the preceding claims for the manufacture of a medicament for use in a method of treatment.

29. The compound or pharmaceutical composition of claim 27, wherein the use is advanced renal cell carcinoma.

30. The compound or pharmaceutical composition of claim 27, wherein the use is an ocular disease or disorder.

31. The compound or pharmaceutical composition of claim 27, wherein the ocular disease or disorder is diabetic retinopathy, AMD, DME, or RVO.

32. The method of claim 28, wherein the method of treatment is for advanced renal cell carcinoma.

33. The use of claim 28, wherein the method of treatment is for an ocular disease or disorder.

34. The use of claim 28, wherein the ocular disease or disorder is AMD, DME or RVO.

35. The hydrogel of claim 19, comprising the following compounds ， wherein the variables are as disclosed herein.

36. The xerogel of claim 20, comprising the following compounds ， wherein the variables are as disclosed herein.

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