Prodrugs, formulations, and methods thereof

Abstract

In certain embodiments, the present invention provides a compound of formula I: [Formula 1] JPEG2025534605000041.jpg54170 (in the formula, X 1 is N or N + Y 1 Selected from; X 2 is NH or NY 2 Selected from; X 3 is NH or NY 3 Selected from; Y 1 is -CH2OCO(OCH2CH2)n 1 OM 1 ; or -CH2OCO(CH2CH2O)n 1a Z 1 ; or -CH2OCO(CH2)n 1b COOH; Y 2 is -CH2OCO(OCH2CH2)n 2 OM 2 ; or -CH2OCO(CH2CH2O)n 2a Z 2 ; or -CH2OCO(CH2)n 2b COOH; Y 3 is -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 , Z2 , and Z 3 are independently H, optionally substituted C 1-6 selected from alkyl, and optionally substituted aryl; X 1 , X 2 , and X 3 At least one of the is neither N nor NH; Y 1 , Y 2 , or Y 3 At least one of each is -CH2OCO(CH2CH2O)nZ and pharmaceutically acceptable salts thereof.

Description

[Technical Field]

[0001] This application relates to prodrugs, pharmaceutical compositions containing the prodrugs, and corresponding methods of treatment. [Background technology]

[0002] Tyrosine kinase inhibitors were developed as chemotherapeutic agents to inhibit signal transduction by receptor tyrosine kinases (RTKs), a family of tyrosine protein kinases. RTKs span the cell membrane with an intracellular (inside) portion and an extracellular (outside) portion. Upon ligand binding to the extracellular portion, 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 is related to a family of proteins that bind to VEGF receptor (VEGFR) types, namely VEGFR1–3 (all of which are RTKs), thereby inducing angiogenesis. VEGF-A, which binds to VEGFR2, is the target of the anti-VEGF drugs mentioned above. In addition to VEGFR1-3, several other RTKs are known to induce angiogenesis, such as the platelet-derived growth factor receptor (PDGFR), which is activated by PDGF, or the stem cell growth factor receptor / type III receptor tyrosine kinase (c-Kit), which is activated by stem cell factor.

[0003] Axitinib, a TKI, is used alone to treat advanced renal cell carcinoma (RCC, a type of cancer that begins in the cells of the kidney) in people who have not responded to other medications. Axitinib is used in combination with avelumab or pembrolizumab to treat advanced renal cell carcinoma.

[0004] Several TKIs have been evaluated for the treatment of age-related macular degeneration (AMD) through various routes of administration, including ophthalmic administration of pazopanib (GlaxoSmithKline: NCT00463320), regorafenib (Bayer: NCT02348359), and PAN90806 (PanOptica: NCT02022540), as well as the oral TKI X-82 (Tyrogenex; NCT01674569, NCT02348359). However, topical eye drops tend to have low solution concentrations of TKIs, which tend to be poorly water-soluble, and their short residence time on the ocular surface results in poor penetration into the vitreous and limited distribution to the retina. Furthermore, drug concentrations during topical administration are difficult to control due to washout and user error. Furthermore, systemic administration of TKIs is impractical due to the high doses required to achieve effective drug concentrations in the eye, especially in the desired tissues. This results in unacceptable side effects due to high systemic exposure. Furthermore, drug concentrations are difficult to control. Alternatively, intravitreal injection of TKI suspensions has been used. However, this administration method requires frequent repeated injections, such as daily or at least monthly, due to rapid drug clearance. Furthermore, some TKIs are poorly soluble, so aggregates may form upon intravitreal injection, which may migrate or deposit on the retina, causing local contact toxicity and holes, such as macular or retinal holes.

[0005] Thus, there is a need in the art for novel compounds, pharmaceutical compositions and methods of treatment for 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. Summary of the Invention

[0007] It is an object of certain embodiments of the present invention to provide compounds for the treatment of a disease or condition.

[0008] It is an object of certain embodiments of the present invention to provide pharmaceutical compositions comprising the compounds disclosed herein.

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

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

[0011] It is an object of certain embodiments of the present invention to provide axitinib prodrugs that are more soluble than axitinib, e.g., 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, or within a range of any of these values, e.g., 2-200-fold, 10-100-fold, or 50 to about 150-fold.

[0012] It is an object of certain embodiments of the present invention to provide a method for modulating the release of an active agent from a hydrogel or organogel, comprising incorporating a prodrug into the hydrogel or organogel formulation.

[0013] It is an object of certain embodiments of the present invention to provide prodrugs of axitinib for treating diseases or conditions with axitinib therapy.

[0014] An object of certain embodiments of the present invention is to provide a prodrug of axitinib in a hydrogel or xerogel (which converts in vivo to a hydrogel) matrix to form an implant for sustained delivery of the prodrug to local tissue where it is enzymatically converted to axitinib. The increased solubility of the prodrug serves to speed the release of the drug from the hydrogel implant compared to the more hydrophobic active drug form, axitinib.

[0015] In certain embodiments, the present invention provides a compound of formula I: [ka] (In the formula,

[0016] X 1 is N or N + Y 1 Selected from;

[0017] X 2 is NH or NY 2 Selected from;

[0018] X 3 is NH or NY 3 Selected from;

[0019] Y 1 is -CH2OCO(OCH2CH2)n 1 OM 1 ; or -CH2OCO(CH2CH2O)n 1a Z 1 ; or -CH2OCO(CH2)n 1b COOH;

[0020] Y 2 is -CH2OCO(OCH2CH2)n 2 OM 2 ; or -CH2OCO(CH2CH2O)n 2a Z 2 ; or -CH2OCO(CH2)n 2b COOH;

[0021] Y 3 is -CH2OCO(OCH2CH2)n 3 OM 3 ; or -CH2OCO(CH2CH2O)n 3a Z 3 ; or -CH2OCO(CH2)n 3b COOH;

[0022] n 1 , n 1a , n 1b , n 2 , n2a , n 2b , n 3 , n 3a , and n 3b are independently 0 or an integer from 1 to 8;

[0023] M 1 , M 2 , M 3 , Z 1 , Z 2 , and Z 3 are independently H, optionally substituted C 1-6 selected from alkyl, and optionally substituted aryl;

[0024] X 1 , X 2 , and X 3 At least one of the is neither N nor NH;

[0025] Y 1 , Y 2 , or Y 3 At least one of each is -CH2OCO(CH2CH2O)nZ and pharmaceutically acceptable salts thereof.

[0026] In other embodiments, Y 1 , Y 2 , and Y 3 are independently -(CH2)p 1 OCO(O(CH2)p 2 )n 1 OM; or -(CH2)p 1a OCO((CH2)p 2 O)n 1 (CH2)Z; or --(CH2)p 1 OCO(CH2)q 1 COOH; 1 , p 1a , and p 2 are independently selected from integers of 1 to 4, and q 1 are independently selected from integers of 0 to 4.

[0027] As used herein, the term "sustained-release, biodegradable drug delivery system" refers to a system administered to a patient, e.g., as an implant, that contains an active agent and remains in place for a period of time while releasing the active agent into the surrounding environment. The drug delivery system may be of any predetermined shape (e.g., rod-shaped, spherical, oblate spheroidal, ellipsoidal, disc-shaped, tubular, hemispherical, or irregular) prior to insertion or administration, and this shape may be maintained to some extent upon placement of the system at a desired location, although the dimensions (e.g., length and / or diameter) of the system may change after administration due to hydration and / or biodegradation, as further disclosed herein. Drug delivery systems may be designed to be biodegradable over time (as disclosed below), thereby softening, changing shape, and / or decreasing in size, and ultimately being eliminated by either dissolution or disintegration.

[0028] The term "biodegradable" refers to a material or object (such as a drug delivery system according to the present invention) that degrades in vivo, i.e., when placed in the human or animal body, or in vitro, when immersed in an aqueous solution under physiological conditions, such as pH 7.2-7.4 at 37°C. In the context of the present invention, as disclosed in detail herein below, a drug delivery system comprising an organogel containing an active agent slowly biodegrades over time when administered or placed in the human or animal body. In certain embodiments, biodegradation occurs at least in part through ester hydrolysis in the aqueous environment of the body. Biodegradation may also occur through covalent crosslinking and / or hydrolysis or enzymatic cleavage within polymer units. The drug delivery system slowly softens and disintegrates, resulting in clearance via physiological pathways. In certain embodiments, the organogel of the present invention retains its shape for extended periods of time (e.g., about 1 month, 3 months, or 6 months). In certain embodiments, the shape is maintained by covalent crosslinking of the polymeric components forming 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.

[0029] An "organogel" in the present invention is a solid or semi-solid system that forms a covalently crosslinked three-dimensional network of one or more hydrophilic or hydrophobic natural or synthetic polymers (as disclosed herein) containing a hydrophobic organic liquid as disclosed herein. Therefore, in the present invention, "organogel" is limited to so-called chemical organogels, in which the intermolecular interactions between the organogelating molecules are chemical bonds (e.g., covalent bonds) formed during gelation by a chemical reaction that induces crosslinking. As used herein, "organogel" refers to a three-dimensional polymer network of at least two precursors / gelators / precursors, including a hydrophobic organic liquid and, optionally, a hydrophobic organic liquid, covalently crosslinked to each other in the presence of an organic solvent and contained within the covalently crosslinked polymer network.

[0030] The term "polymer network" describes a structure formed from polymer chains (of the same or different molecular structure and of the same or different molecular weight) that are covalently crosslinked to one another. Types of polymers suitable for the purposes of the present invention are disclosed herein below. The term "polymer network" is used interchangeably with the term "matrix."

[0031] For purposes of this disclosure, the term "alkyl" when used by itself or as part of another group refers to alkyl groups containing 1 to 12 carbon atoms (i.e., C1~12 alkyl) or a straight or branched chain aliphatic hydrocarbon containing a specified number of carbon atoms (i.e., C alkyl such as methyl, C alkyl such as ethyl, C alkyl such as propyl or isopropyl, etc.). In one embodiment, an alkyl group is a straight chain C 1~10 In another embodiment, the alkyl group is selected from a 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 a branched C 1~6 In another embodiment, the alkyl group is selected from a linear C1~4 In another embodiment, the alkyl group is selected from a branched C 1~4 In another embodiment, the alkyl group is selected from a straight or branched C 2~4 Non-limiting exemplary C alkyl groups are selected from: 1~10 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. 1~4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

[0032] For purposes of this disclosure, the term "optionally substituted alkyl," when used by itself or as part of another group, means that alkyl, as defined above, is either unsubstituted or substituted with one, two, or three substituents independently selected from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, cycloalkyl, and the like. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. Non-limiting exemplary optionally substituted alkyl groups include -CH2CH2NO2, -CH2CH2CO2H, -CH2CH2SO2CH3, -CH2CH2COPh, -CH2CH6H 11 Examples include:

[0033] For purposes of this disclosure, the term "aryl" when used by itself or as part of another group refers to an alkyl group having 6 to 14 carbon atoms (i.e., C 6~14"aryl" refers to a monocyclic or bicyclic aromatic ring system having a cyclic group (aryl). Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl. In one embodiment, the aryl group is selected from phenyl or naphthyl.

[0034] For purposes of this disclosure, as used herein, the term "optionally substituted aryl" by itself or as part of another group means that aryl, as defined above, is either unsubstituted or substituted with one to five substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)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 groups include 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 is meant to include groups having optionally substituted fused cycloalkyl and optionally substituted fused heterocyclic rings. Examples include: [ka]

[0035] As used herein, the term "pharmaceutically acceptable salt" includes, but is not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc. In certain embodiments, the therapeutically active agent is a free base. [Brief explanation of the drawings]

[0036] [Figure 1] 1 shows the synthesis schemes of the prodrugs of Examples 1 and 2. [Figure 2] 1H-NMR of Compound 6 (Intermediate 1) in Example 1 is shown. [Figure 3] 1H-NMR of Example 1 is shown. [Figure 4] LCMS of Example 1 is shown. [Figure 5] LCMS of Example 1 is shown. [Figure 6-1] HPLC of Example 1 is shown. [Figure 6-2] HPLC of Example 1 is shown. [Figure 7] 1 depicts the stability data of Example 8. DETAILED DESCRIPTION OF THE INVENTION

[0037] In certain embodiments, the present invention relates to compounds that are convertible in vivo to compounds of formula II, and that are more hydrophilic than compounds of formula II.

[0038] In certain embodiments, the compound of formula I is converted in vivo to the compound of formula II (axitinib). [ka]

[0039] In certain embodiments, the present invention provides a compound of formula I: [ka]

[0040] (In the formula,

[0041] X 1 is N or N + Y 1 Selected from;

[0042] X 2 is NH or NY 2 Selected from;

[0043] X 3 is NH or NY3 Selected from;

[0044] Y 1 is -CH2OCO(OCH2CH2)n 1 OM 1 ; or -CH2OCO(CH2CH2O)n 1a Z 1 ; or -CH2OCO(CH2)n 1b COOH;

[0045] Y 2 is -CH2OCO(OCH2CH2)n 2 OM 2 ; or -CH2OCO(CH2CH2O)n 2a Z 2 ; or -CH2OCO(CH2)n 2b COOH;

[0046] Y 3 is -CH2OCO(OCH2CH2)n 3 OM 3 ; or -CH2OCO(CH2CH2O)n 3a Z 3 ; or -CH2OCO(CH2)n 3b COOH;

[0047] 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;

[0048] M 1 , M 2 , M 3 , Z 1 , Z 2 , and Z 3 are independently H, optionally substituted C 1-6 selected from alkyl, and optionally substituted aryl;

[0049] X 1 , X 2 , and X 3 At least one of the is neither N nor NH;

[0050] Y 1 , Y 2 , or Y 3 At least one of each is -CH2OCO(CH2CH2O)nZ

[0051] and pharmaceutically acceptable salts thereof.

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

[0053] X 1 is N + Y 1 and;

[0054] X 2 is NH;

[0055] X 3 is NH;

[0056] Y 1 is -CH2OCO(CH2CH2O)n 1 Z 1 is.

[0057] In certain embodiments, the present invention relates to compounds of formula I, wherein:

[0058] X 1 is N;

[0059] X 2 is NY 2 and;

[0060] X 3 is NH;

[0061] Y 2 is -CH2OCO(CH2CH2O)n 2 Z 2is.

[0062] In certain embodiments, the present invention relates to compounds of formula I, wherein:

[0063] X 1 is N;

[0064] X 2 is NH;

[0065] X 3 is NY 3 and;

[0066] Y 3 is -CH2OCO(CH2CH2O)n 3 Z 3 is 。

[0067] 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 to 3 or 4 to 6 or 7 to 8.

[0068] 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 to 3 or 4 to 6 or 7 to 8.

[0069] 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 to 3 or 4 to 6 or 7 to 8.

[0070] 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 to 3 or 4 to 6 or 7 to 8.

[0071] In certain embodiments, the present invention relates to compounds of formula I, wherein n 2ais 0, 1, 2, 3, 4, 5, 6, 7 or 8, or 1 to 3 or 4 to 6 or 7 to 8.

[0072] 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 to 3 or 4 to 6 or 7 to 8.

[0073] 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 to 3 or 4 to 6 or 7 to 8.

[0074] 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 to 3 or 4 to 6 or 7 to 8.

[0075] 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 to 3 or 4 to 6 or 7 to 8.

[0076] In certain embodiments, M 1 is methyl, ethyl, propyl, or phenyl.

[0077] In certain embodiments, M 2 is methyl, ethyl, propyl, or phenyl.

[0078] In certain embodiments, M 3 is methyl, ethyl, propyl, or phenyl.

[0079] In certain embodiments, Z 1 is methyl, ethyl, propyl, or phenyl.

[0080] In certain embodiments, Z 2is methyl, ethyl, propyl, or phenyl.

[0081] In certain embodiments, Z 3 is methyl, ethyl, propyl, or phenyl.

[0082] In certain embodiments, the compound of Formula 1 is axitinib-N-mPEG-succinoyloxymethyl or a pharmaceutically acceptable salt thereof.

[0083] In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of Formula I disclosed herein and a pharmaceutically acceptable excipient.

[0084] In certain embodiments, the pharmaceutical composition is in the form of an oral solid dosage form, such as a tablet, capsule, or powder.

[0085] In certain embodiments, the pharmaceutical composition is in the form of an ophthalmic formulation, such as an implant, injection, solution, suspension, or ointment, which can be administered intravitreally, topically, or to the anterior or posterior segment of the eye of a mammal (e.g., a human).

[0086] In certain embodiments, the prodrug is contained in a hydrogel (eg, a polyethylene glycol-based system as disclosed herein) or organogel, for example, for ocular administration.

[0087] The prodrug contained in the hydrogel or organogel can be a prodrug of axitinib disclosed herein, or any other prodrug of axitinib known in the art, or a prodrug of a different active agent. In certain embodiments, the hydrogel or organogel and prodrug selection 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.

[0088] In certain embodiments, the prodrugs included in the hydrogel or organogel can be as described in US2021 / 0078970, which is incorporated herein by reference. These prodrugs include compounds of Formula I below, or pharmaceutically acceptable salts, esters, solvates, or polymorphs thereof: [ka]

[0089] (In the formula, R 1 and R 2 are independently hydrogen (H) or a protecting group (P), and R 3 (which may or may not be present) is a protecting group, and 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 embodiments where both are protecting groups (P), the protecting groups may be the same or different.

[0090] In one embodiment, the compound of formula I is a compound of formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: [ka]

[0091] (In the formula, R 1 and R 2 are independently hydrogen (H) or a protecting group (P), and R 1 and R 2 are protecting groups, the protecting groups may be the same or different).

[0092] In another embodiment, the compound of formula I is a compound of formula III, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: [ka]

[0093] (In the formula, R 3 is a protecting group (P) and a counterion).

[0094] 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, substituted or unsubstituted acyl groups derived from natural or unnatural amino acids, acyl groups of peptide residues, phosphonyl, phosphinyl, aminophosphinyl, alkylaminophosphinyl, sulfonyl, cycloalkane-carbonyl, heterocycloalkane-carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, heteroaryloxycarbonyl, and O-substituted hydroxymethyl groups with or without substituents.

[0095] In another embodiment, the protecting group is 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 a lower alkyl group; R 4 teeth, [ka]

[0096] where X is an oxygen (—O—), sulfur (—S—), nitrogen (—NH—), or methylene (—CH—) group; R 6 and R 7 are independently hydrogen, a substituted or unsubstituted alkyl or cycloalkyl, a substituted or unsubstituted aryl or heteroaryl group, a PEG moiety (R 10 -(OCH2CH2)n - (wherein n=1 to 10, and R 10 is hydrogen or lower alkyl), an ester-forming group such as a lower alkyl or aryl group, or when X is oxygen or sulfur, a salt-forming moiety such as sodium, potassium, tetraethylammonium, or tetrabutylammonium, or 6 and X in combination are alkyl or aryl groups, with or without further substitution, with the proviso that the compound of Formula I, II, or III is not axitinib.

[0097] In some embodiments, the counterion is a halide ion (F - , Cl - , Br - , and I - ), sulfate, methanesulfonate, toluenesulfonate, oxalate, and other pharmaceutically acceptable anionic moieties.

[0098] 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 Formula I below. [ka]

[0099] (In the formula,

[0100] R 12 , R 13 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 selected from the group consisting of aryl, 4- to 15-membered heterocyclyl, and 5- to 15-membered heteroaryl;

[0101] R 14 is selected from the group consisting of R', OR', SR', and N(R')2;

[0102] R' is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 aryl, 4- to 15-membered heterocyclyl, 5- to 15-membered heteroaryl, hydroxyl C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkylamide, and phosphate group).

[0103] In some embodiments, R 12 , R 13 is H and R 14 is selected from the group consisting of N,N-dimethylaminomethyl, t-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, cyclobutoxy, pentylamino, pentylthio, pentyloxy, isopentylamino, neopentylamino, t-butylamino, cyclopentylamino, cyclopentylthio, cyclopentyloxy, cyclohexylamino, cyclohexylthio, cyclohexyloxy, p-methoxyphenyl, p-chlorophenyl, and o-fluorophenyl.

[0104] In certain embodiments, the increased solubility of the axitinib prodrug allows for the tailoring of the release of the active agent from the hydrogel compared to the base drug (i.e., axitinib). For example, the release rate can be at least 1.1-fold, at least 1.2-fold, at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 250-fold, at least 500-fold, or at least 1000-fold greater, including all ranges between any of the foregoing values. In certain embodiments, the present invention relates to methods of treating a disease or condition, comprising administering a compound of Formula I or a pharmaceutical composition disclosed herein.

[0105] In certain embodiments, the disease or condition is cancer, such as advanced renal cell carcinoma.

[0106] In certain embodiments, the disease or condition is an ocular disease or condition, such as AMD, DME, or RVO.

[0107] 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. [ka]

[0108] In certain embodiments, the present invention relates to methods of treating a disease or condition with axitinib therapy, comprising administering a compound or pharmaceutical composition disclosed herein.

[0109] In certain embodiments, the present invention relates to hydrogels comprising the compounds disclosed herein.

[0110] In certain embodiments, the present invention relates to xerogels comprising the compounds disclosed herein.

[0111] In certain embodiments, hydrogels or xerogels may be formed from precursors having functional groups that form crosslinks to form a polymer network. These crosslinks between polymer strands or arms may be chemical (i.e., covalent) and / or physical (e.g., ionic bonds, hydrophobic associations, hydrogen bridges, etc.) in nature.

[0112] Polymer networks can be prepared from either one type of precursor or two or more types of precursors that can react. The precursors are selected based on the desired properties of the resulting hydrogel. A variety of suitable precursors exist for use in preparing hydrogels and xerogels. Generally, any pharmaceutically acceptable crosslinkable polymer that forms a hydrogel can be used for the purposes of the present invention. Hydrogels and the components incorporated therein (including the polymers used to create the polymer network) should be physiologically safe, e.g., so as not to induce an immune response or other adverse effects. Hydrogels and xerogels can be formed from natural polymers, synthetic polymers, or biosynthetic polymers. Natural polymers can include glycosaminoglycans, polysaccharides (e.g., dextran), polyamino acids, proteins, or mixtures or combinations thereof.

[0113] Synthetic polymers can generally be any polymers that are synthetically produced from a variety of feedstocks 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 may be initiated by some initiators, light and / or heat, or may be mediated by a catalyst.

[0114] Generally, for the purposes of the present invention, one or more synthetic polymers from the group comprising one or more units of polyalkylene glycol can be used, such as polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers, or any combination / mixture thereof, but this list is not intended to be limiting.

[0115] Precursors may be covalently crosslinked to one another to form a covalently crosslinked polymer network. In certain embodiments, precursors having at least two reactive centers (e.g., in free radical polymerization) can function as crosslinkers because each reactive group can participate in the formation of a different growing polymer chain.

[0116] The precursor may have a biologically inert and hydrophilic portion, e.g., a core. In the case of a branched polymer, the core refers to a continuous portion of the molecule connected to arms extending from the core, the arms having functional groups often at the ends of the arms or branches. Multi-arm PEG precursors are examples of such precursors and are further disclosed herein below.

[0117] Thus, hydrogels for use in the present invention can be prepared, for example, from one multi-arm precursor having a (set of) first functional group(s) and another multi-arm precursor having a (set of) second functional group(s). By way of example, the multi-arm precursor may have hydrophilic arms such as polyethylene glycol units terminated with primary amines (nucleophilic) or may have activated ester end groups (electrophilic). Polymer networks according to the present invention may comprise identical or different polymer units crosslinked to one another.

[0118] Certain functional groups can be prepared with high reactivity by using activating groups. Such activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N-hydroxysuccinimidyl esters, succinimidyl esters, epoxides, aldehydes, maleimides, imidoesters, acrylates, and the like. N-hydroxysuccinimide ester (NHS) is a useful group for crosslinking nucleophilic polymers, such as primary amine- or thiol-terminated polyethylene glycol. The NHS-amine crosslinking reaction can be carried out in aqueous solution in the presence of a buffer solution, 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).

[0119] In certain embodiments, each precursor may contain only nucleophilic or only electrophilic functional groups, so long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if the crosslinker 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 crosslinker has electrophilic functional groups, such as sulfosuccinimide, the functional polymer may have nucleophilic functional groups, such as amines or thiols. Thus, functional polymers (e.g., proteins, poly(allylamine), or amine-terminated di- or multifunctional poly(ethylene glycol)) can also be used to prepare the polymer networks of the present invention.

[0120] In one embodiment, the first reactive precursors each have about 2 to about 16 nucleophilic functional groups (referred to as functionality), and the second reactive precursors that react with the first reactive precursors to form the polymer network each have about 2 to about 16 electrophilic functional groups. Reactive precursors having a number of reactive (nucleophilic or electrophilic) groups that is a multiple of four, e.g., 4, 8, and 16 reactive groups, are particularly suitable for the present invention. Any number of functional groups (e.g., containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups) is possible for the precursor to be used in accordance with the present invention while ensuring sufficient functionality for the formation of a suitable crosslinked network.

[0121] In certain embodiments of the present invention, the polymer network forming the hydrogel comprises polyethylene glycol (PEG) units, which are known in the art to form hydrogels when crosslinked, and these PEG hydrogels are suitable for pharmaceutical applications, for example, as matrices for drugs intended to be administered to any part of the human or animal body.

[0122] The polymer network of the hydrogel implants of the present invention can include one or more multi-armed PEG units having 2-10 arms, or 4-8 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 hydrogels of the present invention have 4 and / or 8 arms. In certain embodiments, a combination of 4-armed and 8-armed PEG units is utilized.

[0123] The number of PEG arms used contributes to controlling the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking four-armed PEGs are generally softer and more flexible than those formed from eight-armed PEGs of the same molecular weight. A softer hydrogel, e.g., a four-armed PEG, may be used, optionally in combination with another multi-armed PEG, e.g., an eight-armed PEG as disclosed above, particularly when it is desired to stretch the hydrogel before or after drying, as described below in the section on implant fabrication.

[0124] In certain embodiments of the present invention, the polyethylene glycol units used as precursors have an average molecular weight in the range of about 2,000 to about 100,000 daltons, or about 10,000 to about 60,000 daltons, or about 15,000 to about 50,000 daltons. In certain embodiments, the polyethylene glycol units have an average molecular weight in the range of about 10,000 to about 40,000 daltons, or about 20,000 daltons. PEG precursors of the same average molecular weight may be used, or PEG precursors of different average molecular weights may be combined with each other. The average molecular weight of the PEG precursors used in the present invention is given as the number average molecular weight (Mn), which, in certain embodiments, may be determined by MALDI.

[0125] In a four-arm PEG, each arm may have an average arm length (or molecular weight) equal to the total molecular weight of the PEG divided by four. Thus, one precursor that can be used in the present invention, the 4a20kPEG precursor, has four arms, each with an average molecular weight of approximately 5,000 daltons. Thus, an 8a20kPEG precursor that can be used in addition to the 4a20kPEG precursor in the present invention has eight arms, each with an average molecular weight of 2,500 daltons. Longer arms may be more flexible than shorter arms. PEGs with longer arms may swell more than PEGs with shorter arms. Also, PEGs with fewer arms may swell more than PEGs with more arms and may be more flexible. In certain embodiments, combinations of PEG precursors with different numbers of arms, such as a combination of a four-arm PEG precursor and an eight-arm precursor, may be utilized in the present invention. Furthermore, longer PEG arms have a higher melting point when dried, which may provide greater dimensional stability during storage. For example, an eight-arm PEG with a molecular weight of 15,000 daltons cross-linked with trilysine may not maintain an extended conformation at room temperature, whereas a four-arm PEG with a molecular weight of 20,000 daltons cross-linked with an eight-arm PEG with a molecular weight of 20,000 daltons is dimensionally stable in an extended conformation at room temperature.

[0126] When referring to a PEG precursor having a particular average molecular weight, such as a precursor of 15kPEG or 20kPEG, the indicated average molecular weight (i.e., Mn of 15,000 or 20,000, respectively) refers to the PEG portion of the precursor before end groups are added (where "20k" means 20,000 daltons and "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 substitution with the end groups disclosed herein is determined after end group functionalization. 1 It may be determined by H-NMR.

[0127] In certain embodiments, electrophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are N-hydroxysuccinimidyl (NHS) esters, including, but not limited to, "SAZ" (referring to succinimidyl azelaic acid end groups), "SAP" (referring to succinimidyl adipic acid end groups), "SG" (referring to succinimidyl glutarate end groups), and "SS" (referring to succinimide succinic acid end groups).

[0128] In certain embodiments, nucleophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are amine (denoted as "NH") end groups. Thiol (-SH) end groups or other nucleophilic end groups are also possible.

[0129] In certain preferred embodiments, a four-armed PEG having an average molecular weight of about 20,000 daltons and having electrophilic end groups as disclosed above, and an eight-armed PEG also having an average molecular weight of about 20,000 daltons and having nucleophilic end groups as disclosed above, are crosslinked to form a polymer network, i.e., a hydrogel, in accordance with the present invention.

[0130] Reaction of a nucleophile-containing PEG unit with an electrophile-containing PEG unit, such as an amine-terminated PEG unit with an active ester-containing PEG unit, provides multiple PEG units crosslinked by hydrolyzable linkers having the formula: [ka] (where m is an integer from 0 to 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In one particular embodiment, for example, when SAZ-terminated PEG is used, m is 6. For SAP-terminated groups, m will be 3, for SG-terminated groups, m will be 2, and for SS-terminated groups, m will be 1. All crosslinks in the polymer network can be the same or different.

[0131] In certain preferred embodiments, SAZ end groups are utilized in the present invention. These end groups may extend the duration of the implant in the eye, and certain embodiments of the present invention, including hydrogels containing PEG-SAZ units, may biodegrade in the eye, e.g., in the vitreous humor of the human eye, after an extended period of time, e.g., 9-12 months as further disclosed below, and may persist even longer in certain circumstances. SAZ groups are more hydrophobic than SAP, SG, SS, and other end groups due to the large number of carbon atoms in the chain (m is 6, and the total number of carbon atoms in the amide and ester groups is 7).

[0132] In a particularly preferred embodiment, a 20,000 dalton 4-arm PEG precursor is combined with a 20,000 dalton 8-arm PEG precursor, e.g., a 20,000 dalton 4-arm PEG precursor having a SAZ group (as defined above) is combined with a 20,000 dalton 8-arm PEG precursor having 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 as follows: [ka]

[0133] (where R represents the pentaerythritol core structure). The chemical structure of 8a20kPEG-NH2 (with a hexaglycerol core) is as follows: [ka]

[0134] In the above formula, n is determined by the molecular weight of the individual PEG arms.

[0135] In certain embodiments, the molar ratio of nucleophilic and electrophilic end groups reacting with each other is about 1:1, i.e., one amine group is provided for every SAZ group. In the case of 4a20kPEG-SAZ and 8a20kPEG-NH2, the weight ratio is about 2:1 because the eight-arm PEG contains twice as many end groups as the four-arm PEG. However, an excess of either the electrophilic end groups (e.g., NHS end groups, such as SAZ) or the nucleophilic end groups (e.g., amines) can be used. In particular, an excess of the nucleophile, e.g., the amine-end-group-containing precursor, can be used; i.e., the weight ratio of 4a20kPEG-SAZ to 8a20kPEG-NH2 can be less than 2:1.

[0136] Each and any combination of the electrophilic group-containing PEG precursors and nucleophilic group-containing PEG precursors disclosed herein can be used to prepare implants according to the present invention. For example, any 4-arm or 8-arm PEG-NHS precursor (e.g., having SAZ, SAP, SG, or SS end groups) can be combined with any 4-arm or 8-arm PEG-NH precursor (or any other PEG precursor with nucleophilic groups). Furthermore, the PEG units of the electrophilic group-containing precursor and the nucleophilic group-containing precursor can have the same or different average molecular weights.

[0137] Instead of PEG-based crosslinkers, other nucleophilic group-containing crosslinkers can be used, for example, low molecular weight amine linkers such as trilysine (or a trilysine salt or derivative, such as trilysine acetate) or other low molecular weight multi-arm amines.

[0138] In certain embodiments, the nucleophilic group-containing crosslinker may be linked or conjugated to a visualization agent. A visualization agent is an agent containing a fluorophore or other visualization group. For example, fluorescent dyes such as fluorescein, rhodamine, coumarin, and cyanine may be used as visualization agents. The visualization agent may be conjugated to the crosslinker, for example, via some of the nucleophilic groups on the crosslinker. Because a sufficient number of nucleophilic groups are required for crosslinking, the term "conjugated" or "conjugate" generally includes partial conjugation, meaning that only a portion of the nucleophilic groups are used to conjugate with the visualization agent. For example, about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups on the crosslinker may be conjugated to the visualization agent. In other embodiments, the visualization agent may be conjugated to the polymer precursor, for example, via specific reactive (e.g., electrophilic) groups on the polymer precursor.

[0139] The disclosure herein regarding hydrogels is also applicable to xerogels. Extruded dosage form

[0140] The materials for the hydrogels disclosed herein can also be extruded with a prodrug.

[0141] Certain embodiments relate to a method for preparing a sustained-release biodegradable ophthalmic insert, comprising extruding a polymer composition and a prodrug to form an insert suitable for ocular administration.

[0142] In other embodiments, the method includes feeding the polymer composition and the prodrug into an extruder, mixing the ingredients in the extruder, extruding strands, and cutting the strands into unit dose inserts or implants.

[0143] 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, e.g., melt blended, prior to being introduced into the extruder.

[0144] In certain embodiments, the method further comprises cooling the strands, eg, prior to cutting the strands.

[0145] In certain embodiments, the method further comprises stretching the strands, eg, prior to cutting the strands.

[0146] In certain embodiments, stretching is performed under wet conditions, heated conditions, or a combination thereof. In other embodiments, stretching is performed under dry conditions, heated conditions, or a combination thereof.

[0147] In certain embodiments, the extruded composition is subjected to a curing step, such as exposure to moisture, which in certain embodiments crosslinks the polymer composition.

[0148] In certain embodiments, the method further comprises drying the strands after stretching the strands.

[0149] In other embodiments, all of the steps of the methods disclosed herein may be performed simultaneously or sequentially in any order.

[0150] In certain embodiments, the method further comprises melting the polymer in the extruder at a temperature below the melting point of the prodrug. The temperature can be, for example, less than about 100°C, less than about 90°C, less than about 80°C, less than about 70°C, less than about 60°C, or less than about 50°C. In some embodiments, the temperature is from about 50°C to about 80°C. In certain embodiments, the extrusion is carried out at a temperature above the melting points of the polymer and the prodrug.

[0151] In certain embodiments, the extruded composition is dried in strand form or unit dose form. In certain embodiments, drying is performed after stretching the strands. Drying can be, for example, evaporative drying at ambient temperature, or can include heat, vacuum, or a combination thereof.

[0152] In certain embodiments, the hydrogel strands are stretched by a stretch factor ranging from about 0.25 to about 10, 0.5 to about 6, or about 1 to about 4.

[0153] In certain embodiments, the strands are cut into segments having an average length of 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 or less.

[0154] In certain embodiments, the prodrug is suspended in the polymer composition.

[0155] In certain embodiments, the prodrug is homogeneously dispersed in the polymer composition.

[0156] In certain embodiments, the extrusion process is carried out without a solvent (e.g., water), hi certain embodiments, a solvent is used in an amount of less than about 10% w / w, less than about 5% w / w, or less than about 1% w / w.

[0157] In certain embodiments, the content uniformity of the unit dose inserts is within 10%, within 5%, or within 1%.

[0158] In certain embodiments, the dosage form has a duration of about 7 days to about 6 months after intraocular administration.

[0159] In certain embodiments, the polymorphic form of the prodrug is unchanged or substantially unchanged, hi certain embodiments, the purity of the prodrug after curing is greater than 99%, greater than 99.5%, or greater than 99.9% compared to the prodrug before extrusion.

[0160] 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.

[0161] 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. Organogel

[0162] In certain embodiments, the prodrugs herein can be used in organogels.

[0163] In certain embodiments, the present invention provides a sustained-release biodegradable drug delivery system comprising an organogel and a prodrug, wherein the organogel comprises a hydrophobic organic liquid and a biodegradable, covalently crosslinked polymer network, and wherein the hydrophobic organic liquid and the prodrug are contained in the biodegradable, covalently crosslinked polymer network. In certain embodiments, the present invention provides a sustained-release biodegradable drug delivery system comprising an organogel and a prodrug, wherein the organogel comprises a hydrophobic organic liquid and a biodegradable, covalently crosslinked polymer network, and wherein the hydrophobic organic liquid and the prodrug are immobilized in the biodegradable, covalently crosslinked polymer network.

[0164] In certain embodiments, the sustained release biodegradable drug delivery system comprises at least three components: a biodegradable covalently crosslinked polymer network, a hydrophobic organic liquid, and a prodrug.

[0165] In certain embodiments, organogels are formed by polymerization of non-linear, multifunctional monomeric or polymeric precursor components, as described herein below, to form a covalently crosslinked polymer network containing a hydrophobic organic liquid, which remains immobilized within the polymeric network until released from the network, e.g., in vivo. Thus, organogels of the present invention are like hydrophobic analogs of hydrogels, which contain water instead of a hydrophobic organic phase. Organogels are similar to hydrogels in that the matrix is ​​composed of a network-forming polymeric component (gelator) and a non-reactive component. The non-reactive component, whereas in hydrogels it is water, is a hydrophobic organic compound, such as an oil, with a glass transition temperature (Tg) and melting transition temperature (Tm) below body temperature.

[0166] In certain embodiments, covalent crosslinking of the polymer network forming the precursor restricts the mobility of the hydrophobic organic liquid (e.g., oil) component. This can provide continuous control of drug release by limiting drug delivery to diffusion through the organogel and / or eliminating the development of defects that provide a rapid escape route for the drug. In certain embodiments, the drug delivery systems of the present invention are fully or partially diffusion-controlled delivery systems, i.e., the release of the oil and / or prodrug is primarily controlled by diffusion processes. Degradation of the polymer matrix may additionally occur in the organogels of the present invention, but does not primarily control the release of the prodrug. In non-crosslinked gels, such as extruded linear polymers, the release of the prodrug is primarily controlled by the degradation of the polymer matrix, which releases the prodrug in a degradation-controlled system. The network-forming precursor must be miscible with the hydrophobic organic liquid component and, upon crosslinking, "holds" the components together to form a solid or semi-solid, forming the organogel. In certain embodiments, the compatibility of the hydrophobic organic liquid with the polymer network influences the rate at which the hydrophobic organic liquid escapes into the surrounding tissue fluids in vivo and may be gradually replaced by aqueous liquids, providing an additional method of controlling prodrug solubility and drug release kinetics relative to network degradation.

[0167] In certain embodiments, the use of organogels in the sustained-release biodegradable drug delivery systems of the present invention therefore allows for the modification of the release of prodrugs from the drug delivery system by adjusting or appropriately selecting the precursor components that form the crosslinked polymer network according to their hydrophilic and / or hydrophobic properties. Furthermore, in certain embodiments, the release of prodrugs from the drug delivery system can be modified or controlled by appropriately selecting the hydrophobic organic liquid according to its properties, such as hydrophobicity, viscosity, compatibility with the prodrug, and solubility or insolubility of the prodrug in the hydrophobic organic phase.

[0168] Such organogel-based drug delivery systems of certain embodiments of the present invention offer several advantages over hydrogels: for example, because certain organogels are anhydrous, they can stabilize water-degradable (hydrolyzable) components, such as water-sensitive prodrugs, for long-term storage and do not require hydration upon implantation.

[0169] Water-soluble compounds have low solubility or are insoluble in organogel, allowing drugs to be incorporated as particulate solids embedded in the organogel matrix. The low solubility of drugs in the organogel matrix provides a mechanism for controlling the drug release rate. This property significantly increases the range of compounds that can be incorporated into the implant.

[0170] Manipulating the lipophilicity / hydrophilicity of organogels can tune drug release rates and affect diffusion rates. Pure hydrogels are not amenable to this tunability because they are water-based; therefore, in these systems, tailoring drug / matrix solubility requires modifying the drug itself into a prodrug form. Organogel technology circumvents this. Furthermore, altering the lipophilicity / hydrophilicity of organogel can affect the degradation rate of the polymer matrix, further impacting the drug release rate.

[0171] Organogels can be designed to slowly release hydrophobic organic liquids (e.g., oils) from the matrix in vivo, allowing for their slow transformation into hydrogels that subsequently degrade, thereby providing a new mode of controlled drug release and improving biocompatibility. To overcome compatibility issues, solvents can be added to organogel formulations during production, and the resulting organogel can be freed of the oil. While solvent removal can be achieved by thermal treatment, this is not possible for materials that melt or undergo glass transitions at high temperatures. Solvent removal can also be achieved by methods typically used for non-crosslinked polymers, such as water extraction, vacuum drying, freeze-drying, and evaporation. This significantly simplifies the manufacturing process, eliminating the need for careful solvent removal.

[0172] In certain embodiments, organogels have the physical properties of low modulus, dimensional stability, and good drug release kinetics. In certain embodiments, organogels are thermally dimensionally stable and do not melt. Therefore, implant manufacturing processes such as hot-melt extrusion can be used to form certain organogels of the present invention.

[0173] The drug delivery systems of the present invention, including organogels, can be used to deliver a variety of drugs, including steroids, nonsteroidal anti-inflammatory drugs (NSAIDS), ocular hypotensives, antibiotics, peptides, etc. Organogels can be used to deliver drugs and therapeutic agents, such as anti-inflammatory drugs (e.g., diclofenac), analgesics (e.g., bupivacaine), calcium channel blockers (e.g., nifedipine), antibiotics (e.g., ciprofloxacin), cell cycle inhibitors (e.g., simvastatin), proteins or peptides (e.g., insulin), enzymes, anti-tumor agents, local anesthetics, hormones, angiogenic agents, anti-angiogenic agents, growth factors, antibodies, neurotransmitters, psychotropic drugs, anti-cancer drugs, chemotherapeutic agents, drugs that affect the reproductive organs, genes, oligonucleotides, or other structures, and viruses such as AAV for gene delivery. The release rate from the organogel may depend on one or more properties of the prodrug, the hydrophobic organic liquid, and the polymer network, and other possible factors include one or more of the size and relative hydrophobicity of the drug, the density of the organogel, and the solids content of the organogel.

[0174] The drug delivery system of the present invention may be in the form of an implant, a medical implant, or a pharmaceutically acceptable implant, implant coating, or oral dosage form, or the like. Treatment method

[0175] In certain embodiments, the prodrugs disclosed herein are utilized in the treatment of ocular diseases associated with neovascularization.

[0176] 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.

[0177] In some embodiments, the ocular 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; and the ocular disease is acute multifocal macular pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, Lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple ephemeral white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, creeping choroiditis, subretinal The eye disease is a vascular or exudative disease including Coats' disease, parafoveal telangiectasia, papillophlebitis, dendritic vasculitis, sickle cell retinopathy and other hemoglobinopathies, vascular streaks, and familial exudative vitreoretinopathy, or the eye disease is due to trauma or surgery including sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, intraoperative hypoperfusion, radiation retinopathy, or bone marrow transplant retinopathy.

[0178] In another embodiment, the prodrugs utilized herein may be used to treat tumor-related ocular conditions, including, for example, tumor-related retinal diseases, solid tumors, tumor metastases, benign tumors such as hemangiomas, neurofibromas, trachoma, and pyogenic granulomas, congenital RPE hypertrophy, posterior uveal melanoma, choroidal hemangiomas, choroidal osteomas, choroidal metastases, combined hamartomas of the retina and retinal pigment epithelium, retinoblastoma, angioproliferative tumors of the fundus, retinal astrocytomas, or intraocular lymphomas.

[0179] In other embodiments, the prodrugs of the present invention can be used to treat any ocular disease associated with vascular leakage.

[0180] 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 certain embodiments, the ocular disease is neovascular age-related macular degeneration. In other embodiments, the ocular condition is dry eye.

[0181] The compounds and pharmaceutical compositions disclosed herein can be administered by any route, including oral, parenteral, ocular, transdermal, nasal, pulmonary, or rectal. In certain embodiments, they can be administered into the vitreous or other sites. Other spaces include, for example, the punctum (canaliculus, superior / inferior canaliculus), fornix, superior / inferior fornix, sub-Tenon's space, choroid, suprachoroid, Tenon, cornea, cancerous tissue, organs, prostate, breast, surgically created spaces or lesions, empty spaces, and potential spaces. In certain embodiments, the dosage form is a punctal plug, intracanalicular insert, intracameral insert, or intravitreal insert.

[0182] In certain embodiments, the prodrugs and formulations herein are used by intravitreal, suprachoroidal, subretinal, subconjunctival, or subtenon administration (eg, for tumor treatment).

[0183] In certain embodiments, the present invention relates to a prodrug (e.g., a prodrug of axitinib disclosed herein) administered in combination with a base drug (e.g., axitinib) in the same formulation (e.g., an ophthalmic formulation) or in a different formulation to provide a more rapidly 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 effect than administration of the base drug alone.

[0184] In certain embodiments, axitinib prodrugs can be formulated and / or administered according to US Pat. No. 11,439,592 B2. [Example]

[0185] Example 1

[0186] Example 1: Axitinib-N-mPEG-succinoyloxymethyl prodrug

[0187] The compound of Example 2 was prepared according to the following scheme:

[0188] Scheme 2A: Preparation of Intermediate-1 [ka]

[0189] Scheme 2B: Preparation of axitinib-N-mPEG-succinoyloxymethyl prodrug [ka]

[0190] For each step in the process, the sample number, batch size, conditions, yield, and discussion are provided below: [Table 1] [Table 2] [Table 3] [Table 4]

[0191] Scheme 1b (alternative route): Preparation of axitinib-N-mPEG-succinoyloxymethyl prodrug [ka] [Table 5]

[0192] Example 2 Solubility Experiments

[0193] The solubility test was carried out using the following test materials and conditions:

[0194] Test article: axitinib (99.99% purity by HPLC); Axitinib-N-mPEG-succinoyloxymethyl prodrug (93.6% purity by HPLC)

[0195] Test medium: Phosphate buffered saline pH 7.4

[0196] Incubation conditions: 22°C, 24 hours with continuous shaking

[0197] Test concentration: 1 mg / mL

[0198] Data Analysis: The solubility of the test articles was determined by HPLC analysis using a calibration curve.

[0199] The HPLC conditions were as follows: [Table 6]

[0200] The results are as follows: [Table 7]

[0201] The reported solubility of axitinib in the literature is approximately 0.2 mcg / mL. The results showed that the N-mPEG-oxymethyl prodrug improved the solubility of the prodrug by approximately 500-fold.

[0202] Example 3 (Prophetic)

[0203] Conversion of the axitinib-N-mPEG-succinoyloxymethyl prodrug to axitinib is shown below. method

[0204] A concentration (1 μM in the final incubation) of each prodrug was incubated with hrCES (a combination of hrCES-1 and hrCES-2, 0.1 mg protein / mL per hrCES) in phosphate buffer (100 mM, pH 7.4) containing 5 mM MgCl2. The incubation mixture was equilibrated at 37°C for 5 min in a shaking water bath. 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 min. 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 of mass spectrometry, respectively).

[0205] After centrifugation at 1,640 g (3,000 rpm) for 10 min at 4 °C to remove proteins, 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 formation per 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 using 1 mM of the nonspecific esterase probe substrate PNPB and determining the time-dependent formation of PNP (0, 3, 5, and 10 min) based on the absorbance at 410 nm. The experimental conditions for the phenotypic analysis of the CES reaction and sample analysis are summarized below.

[0206] CES reaction conditions and sample analysis using hrCES [Table 8]

[0207] Data analysis The percent prodrug remaining is calculated using the following formula:

[0208] Prodrug remaining % = 100 × At / A0

[0209] where At is the peak area ratio (prodrug to IS) at time t and A0 is the peak area ratio (prodrug to IS) at time zero.

[0210] The elimination rate constant of the prodrug is estimated from first-order kinetics: Ct = C0 · e-kt

[0211] where C0 and Ct are the concentrations of the prodrug (expressed as the peak area ratio of the prodrug to IS) at time zero and incubation time t (min), and k is the elimination rate constant ( / min).

[0212] The elimination half-life of the prodrug (if applicable) before the plot begins to flatten is calculated using the following formula: t1 / 2=0.693 / k

[0213] where t1 / 2 is the half-life (minutes) and k is the elimination rate constant ( / minute).

[0214] The in vitro intrinsic clearance of the prodrug (if applicable) is calculated using the following formula:

[0215] CLint=k / P

[0216] where CLint is the in vitro intrinsic clearance, k is the elimination rate constant ( / min), and P is the enzyme concentration in the incubation medium (mg protein / mL).

[0217] All intrinsic clearance parameters are estimated using GraphPad® Prism (GraphPad Software, San Diego, CA, USA) and Microsoft Office Excel (Microsoft Corporation, Redmond, WA, USA).

[0218] Example 4 (Prophetic)

[0219] The test article was prepared in a suspension of a mixture of DMSO (5%) and 0.5%-CMC-Na (95%, v / v) at a concentration of 3 mg / mL, the molar equivalent of axitinib, a prodrug of the present invention. Male ICR mice (n=64, weighing 18-22 g) were randomly divided into four groups (16 mice per group). After fasting for 12 hours, the test article was administered to the animals by oral gavage at a molar equivalent of 30 mg / kg axitinib. Blood samples were collected via the orbit 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 at 4°C for 10 minutes, and plasma samples were collected and stored at -80°C. Sample analysis: Plasma samples (10 μL) were thoroughly mixed with acetonitrile (110 μL). The sample is then centrifuged at 12,000 rpm at 4° C. The supernatant is analyzed by LC-MS / MS instrument, and the target analytes are axitinib and its corresponding prodrug molecules.

[0220] Example 5 (Prophetic)

[0221] Male ICR mice (weight: 18-22 g) were randomly divided into six groups, with six mice per group. Blood was collected from six mice at each time point, for a total of six time points. Test article dosing solutions were prepared by dissolving or suspending the compound in a solvent system. For all compounds, the dosing solution concentration was 3 mg / mL in axitinib molar equivalents, and the dose was 30 mg / kg in axitinib molar equivalents. After fasting for 12 hours, the animals were administered the test article in the dosing vehicle at a dose calculated according to the information above. Blood samples were collected at predetermined time points: 0.5, 1, 2, 4, 6, and 8 hours after administration. The blood samples were centrifuged at 5,000 rpm at 4°C for 20 minutes, and plasma samples were collected and stored at -80°C. Sample analysis: Plasma samples (10 μL) were thoroughly mixed with acetonitrile (220 μL). The sample is then centrifuged at 12,000 rpm at 4° C. The supernatant is analyzed on an LC-MS / MS instrument to analyze the target analytes.

[0222] Example 6

[0223] Axitinib-N-mPEG2-oxymethyl prodrug

[0224] The compound of Example 6 was prepared according to the following scheme: [ka]

[0225] For each step in the process, the sample number, batch size, conditions, yield, and discussion are provided below:

[0226] Step 1 [ka] [Table 9]

[0227] Steps 2-5 [ka]

[0228] Step 2 [Table 10]

[0229] Step 3 [Table 11]

[0230] Step 4 [Table 12]

[0231] Step 5 [Table 13]

[0232] The micronization of axitinib-Nm(PEG)2-oxymethyl prodrug obtained in Example 6 in the dry dispersion was D90=12.4 μm; D50=3.6 μm and D10=0.6 μm, and that dispersed in water was D90=12.2 μm; D50=5.2 μm and D10=1.1 μm.

[0233] Example 7

[0234] The axitinib prodrugs of the present invention were tested for solubility in phosphate buffered saline (PBS, pH-7.40). The results are shown in Table 2 below: [Table 14]

[0235] Example 8

[0236] The axitinib prodrugs of the present invention were tested for stability in phosphate buffered saline (PBS, pH-7.40), and the results are shown in the following table and in Figure 7: [Table 15]

[0237] Example 9

[0238] The purity by HPLC of the axitinib prodrug of the present invention is shown below: [Table 16]

Claims

1. Compounds of Formula I: 【Chemical 1】 (In the formula, X １ is N or N ＋ Y １ Selected from: X ２ is NH or NY ２ Selected from: X ３ is NH or NY ３ Selected from: Y １ is -CH ２ OCO (OCH ２ CH ２ ) n １ O.M. １ or -CH ２ OCO (CH ２ CH ２ O)n １ａ Z １ or -CH ２ OCO (CH ２ ) n １ｂ COOH; Y ２ is -CH ２ OCO (OCH ２ CH ２ ) n ２ O.M. ２ or -CH ２ OCO (CH ２ CH ２ O)n ２ａ Z ２ or -CH ２ OCO (CH ２ ) n ２ｂ COOH; Y ３ is -CH ２ OCO (OCH ２ CH ２ ) n ３ O.M. ３ or -CH ２ OCO (CH ２ CH ２ O)n ３ａ Z ３ or -CH ２ OCO (CH ２ ) 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 H, optionally substituted C １－６ selected from alkyl, and optionally substituted aryl; X １ , X ２ , and X ３ at least one of is not N or NH; Y １ , Y ２ , or Y ３ At least one of each is —CH ２ OCO (CH ２ CH ２ O) nZ) and pharmaceutically acceptable salts thereof.

2. X １ But, N ＋ Y １ and X ２ is NH; X ３ is NH; Y １ But -CH ２ OCO (CH ２ CH ２ O)n １ Z １ 2. The compound of claim 1, wherein:

3. X １ is N; X ２ But, NY ２ and X ３ is NH; Y ２ But -CH ２ OCO (CH ２ CH ２ O)n ２ Z ２ 2. The compound of claim 1, wherein:

4. X １ is N; X ２ is NH; X ３ But, NY ３ and Y ３ But -CH ２ OCO (CH ２ CH ２ O)n ３ Z ３ is 、 The compound of claim 1.

5. n １ , n ２ , or n ３ 2. A compound according to any preceding claim, wherein

6. n １ａ , n ２ａ , or n ３ａ 2. A compound according to any preceding claim, wherein

7. n １ｂ , n ２ｂ , or n ３ｂ 2. A compound according to any preceding claim, wherein

8. 10. A pharmaceutical composition according to any preceding claim, comprising a compound of formula I and a pharmaceutically acceptable excipient.

9. 9. The pharmaceutical composition of claim 8 in the form of an oral solid dosage form.

10. 10. The pharmaceutical composition of claim 9, in the form of a tablet.

11. 9. The pharmaceutical composition of claim 8 in the form of an ophthalmic formulation.

12. 12. The pharmaceutical composition of claim 11, in the form of an implant, injection, solution, suspension, or ointment.

13. 10. A method of treating a disease or condition comprising administering a compound or pharmaceutical composition according to any preceding claim.

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

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

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

17. When said compound of formula I is reacted in vivo with a compound of formula II 【Chemistry 2】 10. The method of any preceding claim, wherein

18. 10. A method of treating a disease or condition with axitinib therapy comprising administering a compound or pharmaceutical composition according to any of the preceding claims.

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

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

21. A compound that is convertible in vivo to said compound of formula II and that is more hydrophilic than said compound of formula II.

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

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

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

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

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

27. 10. A compound or pharmaceutical composition according to any preceding claim for use in a method of therapy.

28. 10. Use of a compound or pharmaceutical composition according to any preceding claim for use in the manufacture of a medicament for a method of treatment.

29. 28. The compound or pharmaceutical composition of claim 27 for use in the treatment of advanced renal cell carcinoma.

30. 28. A compound or pharmaceutical composition according to claim 27 for use in treating an ophthalmic disease or condition.

31. 28. The compound or pharmaceutical composition of claim 27, wherein the ocular disease or condition is AMD, DME, or RVO.

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

33. 29. The use of claim 28, wherein the method of treatment is for an eye disease or condition.

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

35. 20. The hydrogel of claim 19, comprising the following compound: 【Chemistry 3】 where the variables are as disclosed herein.

36. 21. The xerogel of claim 20, comprising the following compound: 【Chemistry 4】 where the variables are as disclosed herein.

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