WO2024081410A1 - Promédicaments, formulations et procédés associés - Google Patents

Promédicaments, formulations et procédés associés Download PDF

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Publication number
WO2024081410A1
WO2024081410A1 PCT/US2023/035121 US2023035121W WO2024081410A1 WO 2024081410 A1 WO2024081410 A1 WO 2024081410A1 US 2023035121 W US2023035121 W US 2023035121W WO 2024081410 A1 WO2024081410 A1 WO 2024081410A1
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compound
oco
certain embodiments
pharmaceutical composition
condition
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PCT/US2023/035121
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English (en)
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Peter Jarrett
Rami EL-HAYEK
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Ocular Therapeutix, Inc.
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Publication of WO2024081410A1 publication Critical patent/WO2024081410A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants

Definitions

  • the present application is directed to prodrags, pharmaceutical compositions comprising the prodrugs and corresponding methods of treatment.
  • Tyrosine kinase inhibitors were developed as chemotherapeutics that inhibit signaling of receptor tyrosine kinases (RTKs), which are a family of tyrosine protein kinases.
  • RTKs span the cell membrane with an intracellular (internal) and extracellular (external) portion.
  • receptor tyrosine kinases dimerize and initiate an intracellular signaling cascade driven by autophosphorylation using the coenzyme messenger adenosine triphosphate (ATP).
  • ATP coenzyme messenger adenosine triphosphate
  • Many of the RTK ligands are growth factors such as VEGF.
  • VEGF vascular endothelial growth factor-receptor
  • VEGFR. vascular endothelial growth factor-receptor
  • VEGF-A which binds to VEGF.R2
  • VEGF.R2 vascular endothelial growth factor receptor 2
  • c-Kit stem cell growth factor receptor Z type III receptor tyrosine kinase
  • the TK1 axitmib is used alone to treat advanced renal cell carcinoma (RCC, a type of cancer that begin s in the cells of the kidneys) in peop le who have not been treated successfully with another medication.
  • RCC advanced renal cell carcinoma
  • Axitinib is used in combination with avehimab or pembrolizumab to treat advanced renal cell carcinoma.
  • TKIs have been evaluated for the treatment of age-related macular degeneration (AMD) via different administration routes, including pazopanib (GlaxoSmithKline: NCT00463320), regorafenib (Bayer: NCT02348359), and PAN90806 (PanOptica: NCT02022540) all administered as eye drops, as well as X-82, an oral TKI (Tyrogenex; NCTO 1674569, NCT02348359).
  • pazopanib GaxoSmithKline: NCT00463320
  • regorafenib Bayer: NCT02348359
  • PAN90806 PanOptica: NCT02022540
  • topically applied eye drops result in poor penetration into the vitreous and limited distribution to the retina due to low solution concentration of TKIs, which tend io have low water solubility, and short residence time of the TKIs on the ocular surface.
  • TKI suspensions have been performed.
  • this way of administra tion results in rapid clearance of rhe drug and therefore injections have to be repeated frequently, such as on a daily or at least a monthly basis.
  • TKIs are poorly soluble which leads to the formation of aggregates upon intra vitreal injection, which can migrate or settle onto the retina and lead to local contact toxicity and holes, such as macular or retinal holes.
  • TKI therapy such as renal cell carcinoma and ocular diseases such as AMD, diabetic macular edema (DME) and retinal vein occlusion (RVO).
  • AMD diabetic macular edema
  • RVO retinal vein occlusion
  • axitinib prodrugs that are more soluble than axitinib, e.g., being at least 2 times, 10 times, 25 times, 50 times, 75 times, 100 times, 150 times, 200 times, 250 times, 500 times or 1000 times more soluble or a range of any of these values, e.g., from 2 to 200 times more soluble, from 10 to 100 more times soluble or from 50 to about 150 times more soluble.
  • the increased solubility of the prodrug functions to speed the release of the drug from the hydrogel implant compared to the more hy drophobic active drug form, axitinib.
  • the present invention is directed to a compound of formula I:
  • X 1 is selected from N or N 1 Y 1 ;
  • X 2 is selected from NH or NY 2 ;
  • X 3 is selected from NH or NY 3 ;
  • Y 1 is selected from -CH 2 OCO(OCH 2 CH 2 )n 1 OM 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 selected from -CH 2 OCO(OCH 2 CH 2 )n 2 OM 2 ; or ⁇ CH 2 OCO(CH,CH 2 O)n 2a Z 2 ; or -CH 2 OCO(CH 2 )n 2b COOH;
  • Y 3 is selected from -CH 2 OCO(OCH 2 CH 2 )n 3 OM 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 3 , Z 1 , Z 2 and Z 3 are independently selected from H, optionally substituted
  • Y 1 , Y 2 or Y 3 are the respective -CH 2 OCO(CH 2 CH 2 O)nZ; and pharmaceutically acceptable salts thereof,
  • Y 1 Y 2 and Y 3 are independently selected from the respective
  • sustained release, biodegradable drug-delivery system refers to an object that contains an active agent and that is administered, e.g. , as an implant, to a patient’s body where it remains for a certain period of time while i t releases the acti ve agent into the surrounding environment.
  • a drug-delivery system can be of any predetermined shape (e.g., rod, spherical, oblate, ellipsoidal, disc, tube, hemispherical, or irregularly shaped) before being inserted or administered, which shape may be maintained to a certain degree upon placing the system into the desired location, although dimensions of the sy stem (e.g., length and/or diameter) may change after administration due to hydration and/ biodegradation as further disclosed herein.
  • the drag-delivery system can be designed to be biodegradable over the course of time (as disclosed below), and thus may thereby soften, change its shape and/or decrease in size, and in the end might be eliminated either by dissolution or disintegration,
  • biodegradable refers to a. material or object (such as the drug-delivery system according to the present invention) which becomes degraded 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 X.
  • the drug-delivery system comprising the organogel within which an active agent is contained, slowly biodegrades over time once administered or deposited in the human or animal body.
  • biodegradation takes place at least in part via ester hydrolysis in the aqueous environment of the body.
  • Biodegradation may take place by hydrolysis or enzymatic cleavage of the covalent crosslinks and/or within the polymer units.
  • the drug-delivery system slowly softens and disintegrates, resulting in clearance through physiological pathways.
  • the organogel of the present invention retains its shape over extended periods of time (e.g., about 1 month, 3 months or 6 months).
  • the shape is maintained due to covalent crosslinking of the polymer components forming the organogel, e.g., until the active agent or at least a major amount (e.g., at least 50%, at least 75% or at least 90%) thereof has been released.
  • An “organogel” in the present invention is a solid or semi-solid system forming a covalen tly crosslinked three-dimensional network of one or more hydrophilic or hydrophobic natural or synthetic polymers (as disclosed herein) that include a hydrophobic organic liquid as disclosed herein.
  • organogels are limited to so-called chemical organogels, wherein the intermolecular interaction between organogelator molecules is a chemical linkage (e.g., covalent bond) that is formed during gelation by chemical reactions inducing crosslinking.
  • organogel refers to a three- dimensional polymer network of at least two precursors / gelators / precursors that are covalently cross-linked with each other in the presence of a hydrophobic organic liquid and optionally an organic solvent and comprising the hydrophobic organic liquid contained within the covalently crosslinked polymer network.
  • polymer(ic) network describes a structure formed of polymer chains (of the same or different molecular structure and of the same or different molecular weight) that are covalently cross-linked with each other.
  • polymer(ic) network is used interchangeably with the term “matrix”.
  • alkyl refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (t e., alkyl) or the number of carbon atoms designated (ie,, a C; alkyl such as methyl, a C 2 alkyl such as ethyl, a C 3 , alkyl such as propyl or isopropyl, etc.).
  • the alkyl group is chosen from a straight chain C 1-10 alkyl group.
  • the alkyl group is chosen from a branched chain C 1-10 alkyl group.
  • the alkyl group is chosen from a straight chain C 1-6 a lkyl group. In another embodiment, the alkyl group is chosen from a branched chain C 1-6 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C 1-4 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C 1-4 alkyl group. In another embodiment, the alkyl group is chosen from a straight or branched chain C 2-4 alkyl group.
  • Non-limiting exemplary C 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.
  • Non- limiting exemplary CM alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, tert-butyl, and iso-butyl.
  • the term ’’optionally substituted alkyl as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from nitro, haioalkoxy, aryloxy, aralkyloxy, alkylthio, suifonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, tireido, guanidino, carboxy, carboxyalkyl. cycloalkyl and the like.
  • the optionally substituted alkyl is substituted with two substituents.
  • the optionally substituted alkyl is substituted with one substituent.
  • Non-limiting exemplary optionally substituted alkyl groups include -CH 2 CH 2 NO 2 , - CH 2 CH 2 CO 2 H, -CH 2 CH 2 SO 2 CH 3 , -CH 2 CH 2 COPh -CH 2 CH 11 and the like.
  • aryl as used by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (ie., C 6- 14 alkyl).
  • Non-limiting exemplary aryl groups include phenyl
  • Ph naphthyl
  • phenanthryl phenanthryl
  • anthracyl indenyl
  • azulenyh biphenyl biphenylenyl fluorenyl groups.
  • the aryl group is chosen from phenyl or naphthyl.
  • the term “optionally substituted aryl” as used herein by itself or as part of another group means tha t the aryl as defined above is either unsubstituted or substituted with one to five substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylearbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaiyl, heterocyclo, alkoxyalkyl, (a
  • 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-meihoxyphe.nyl, 4-fluorophenyl, 4-chlorophenyl, 2.6-di-fhio.rophenyk 2,6-di- chlorophenyl, 2-methyl, 3-metlioxyphenyI, 2-ethyl, 3-methoxyphenyI, 3.4-di-niethoxyphenyl, 3,5-di-fluorophenyl 3, 5 -di -methylphenyl, 3,5-dimethoxy, 4-nrethylphenyl.
  • optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:
  • pharmaceutically acceptable salt can include, but are not limited to, include, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p- tohtenesulfonate, and the like; and metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'ibenzylethylenediamine salt and the like.
  • the therapeutically effective agent is free base
  • Fig. 1 depicts synthetic schemes of prodrugs of Example I and Example 2.
  • Fig. 2 depicts the 1II-NMR of compound 6 (Int- I) of Example I
  • FIG. 3 depicts the 1H-NMR of Example 1.
  • FIG. 4 and 5 depict the LCM S of Example 1.
  • Fig. 6 depicts the HPLC of Example 1.
  • Fig, 7 depicts stability data of Example 8.
  • the present invention is directed to a compound that is more hydrophilic than the compound of formula II that Is convertible in-vivo to the compound of formula II.
  • the compound of formula I is converted in-vivo to a compound of formula II (axitinib)
  • the present invention is directed to a compound of formula
  • X 1 is selected from N or Y 1 ;
  • X 2 is selected from NH or NY 2 ;
  • X 3 Is selected from NH or NY 3 ;
  • Y 1 is selected from -CH 2 OCO(OCH 2 CH 2 )n 1 OM 1 ; or -CH 2 OCO(OCH 2 CH 2 )n 1a Z 1 ; or - CH 2 OCO(CH 2 )n 1b COOH
  • Y 2 is selected from -CH 2 OCO(OCH 2 CH 2 )n 2 OM 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 selected from -CH 3 OCO(OCH 2 CH 2 )n 3 M 3 ; or CH 2 OCO(CH 2 CH 2 O)n 3a Z 3 ; or -CH 2 OCO(CH 2 )n 3b COOH; [0052] 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;
  • M1, M 2 , M 3 ,Z 1 , Z 2 and Z 3 are independently selected from H, optionally substituted
  • Y 1 , Y 2 or Y 3 are the respective -CH 2 OCO(CH 2 CH 2 O)nZ;
  • the present invention is directed to a compound of formula
  • X 1 is W
  • X 2 is NH
  • Y 1 is-CH 2 OCO(CH 2 CH 2 O)n 1 Z 1 ;
  • the present invention is directed to a compound of form ula
  • X 1 is N
  • X 2 is NY 2 ;
  • X 3 is NH
  • Y 2 is -CH 2 OCO(CH 2 CH 2 O)n 2 Z 2 .
  • the present invention is directed to a compound of formula
  • X 1 is N
  • X 2 is NH
  • X 3 is NY 3 ;
  • Y 3 is -CH 2 OCO(CH 2 CH 2 O) n 3 Z 3
  • the present invention is directed io a compound of formula
  • n 1 is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8,
  • the present invention is directed to a compound of formula
  • n 2 is 0, 1 , 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.
  • the present invention is directed to a compound of formula
  • n 3 is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or I -3 or 4-6 or 7-8.
  • the present invention is directed to a compound of formula
  • n 1a is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.
  • the present invention is directed to a compound of formula
  • n 2a is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.
  • the present i nvention is directed to a compound of formula
  • n 3a is 0, 1 , 2, 3. 4, 5, 6, 7 or 8; or 1 -3 or 4-6 or 7-8.
  • the present invention is directed to a compound of formula
  • n 1b ’ is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.
  • the present invention is directed to a compound of formula
  • n 2b is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8,
  • the present invention is directed to a compound of formula
  • n 3b is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.
  • M 1 is methyl, ethyl, propyl or phenyl.
  • M 2 is methyl, ethyl, propyl or phenyl.
  • M 5 is methyl ethyl, propyl or phenyl.
  • Z 1 is methyl, ethyl, propyl or phenyl.
  • Z 2 is methyl, ethyl, propyl or phenyl.
  • Z 3 is methyl, ethyl, propyl or phenyl.
  • the compound of formula 1 is axitinib-N-mPEG- succinoyloxymethyl; or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a pharmaceutical composi tion comprising a compound of formula I as disclosed herein and a pharmaceaticaUy acceptab le excipient.
  • the pharmaceutical composition is in the form of an oral solid dosage form such as a tablet, a capsule or a powder.
  • the pharmaceutical composition is in the form of an ocular formulation such as an implant, an injection, a solution, a suspension or an ointment.
  • the formulation can be administered intravitreally, topically or to any anterior or posterior section of the eye of a mammal (e.g., human).
  • a prodrug is included in a hydrogel (e.g., a polyethylene glycol based system as disclosed herein) or organogel, e.g., for ocular administration.
  • a hydrogel e.g., a polyethylene glycol based system as disclosed herein
  • organogel e.g., for ocular administration.
  • the prodrug included in the hydrogel or organogel can be a prodrug of axitinib as disclosed herein or any other prodrug of axitinib or prodrug of a different active agent known in the art.
  • the selection of the hydrogel or organogel and the prodrug can be selected to manipulate the release of acti ve agent from the dosage form.
  • the prodrug can increase or decrease the solubility of the base drug.
  • the prodrug included in a hydrogel or organogel can be as described in US2021/0078970, hereby incorporated by reference.
  • These prodrugs include compounds of Formula I below, or pharmaceutically acceptable salts, esters, solvates, or polymorphs thereof:
  • R 5 and R 2 are independently a hydrogen (H) or a protecting group CP); R 5 , which may be present or absent, is a protecting group., and when R 3 is present; the nitrogen atom is positively charged and a counterion is also present; provided that the compound of Formula I is not axitmib.
  • R 1 and R 2 are a protecting group (P)
  • the protecting groups may be the same or different.
  • a compound of Formula I is a compound of Formula II below, or a pharmaceutically acceptable salt, ester, solvate, or polymorph thereof:
  • R 1 and R 2 are independently a hydrogen (H) or a protecting group (P), and when both R 1 and R 2 are a protecting group, the protecting groups may be the same or different
  • a compound of Formula. I is a compound of Formula III below, or a pharmaceutically acceptable salt, ester, solvate, or polymorph thereof: (HI)
  • R 3 is a protecting group (P), and is a counterion.
  • a protecting group is selected from acyl group, alkylcarbonyl group, arylcarbonyl group, alkylthiocarbonyl group, awhltiocarbonyl group, alkylcarbanroyl group, arylcarbamoyl group, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted a- aminoal kanoy I, acyl group derived from a natural or an unnat ural amino acid with or w i thout substitution, acy l group of a peptide residue, phosphonyl, phosphinyl, aminopliophinyl, alkylaniinophophinyl, sulfonyl, cycloalkane-carbonyl, heterocycloalkane-carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbony
  • a protecting group is selected from R 4 W(R 5 R 6 C) m --, where: 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 a hydrogen or a lower alkyl group; and R 4 is
  • X is oxygen ( — O — ), sulfur nitrogen ( — NH — ), or a methylene ( —
  • a PEG moiety such as R 10 - - (OCH 2 CH 2 ) a , where
  • a counterion is selected, from, but not limited to, halide ion (F , Cl , Br , and I ), sulfate ion, methanesulfonate ion, toluenesulfonate ion, oxalate ion, and other pharmaceutically accepted anionic moiety.
  • the prodrug included in a hydrogel or organogel can be as described in US20180022734, hereby incorporated by reference.
  • These prodrugs include sunitinib compounds of Formula I below.
  • R 12 , R 13 are selected from the group consisting of H, C 1 C 6 alkyl, C 2 -C 6 alkenyl, C 2 C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocyclyl and 5-15 membered heteroaryl
  • R 14 is selected from the group consisting of R ' , OR', SR' and N(R') 2 ; and [0107] R' is selected from the group consisting of H, C 1 C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 , alkynyl, C 3 C 8 cycloalkyl, C 6 - C 16 ary l, 4-15 membered heterocyclyl, 5-15 membered heteroaryl, hydroxyl C 1 -C 6 , alkyl, carboxyl C 1 C 6 alkyl, C 1 C 6 , alkyl amido and phosphate group.
  • Rn, Rn are fl
  • RM is selected from the group consisting of N,N-dimethylaminomethyl, t-butyl, phenyl, p-fluorophenyl, biphenyl, dimethylamino, cyelopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclbbutyl, pentyl, isopentyl, neopentyl, cyclopentyl, 1 -methylcyclobutyl, N -methylamino, N-ethylamino, N,N- mefhylethylamino, n-hexyl, cyclohexyl, methylthio, ethylthio, propylthio, isopropylthio, cyclopropylthio, butyl thio, isobutyl thio
  • the increase in solubility of the axitinib prodrug allows for the adjustment of the release of the active from the hydrogel as compared to the base drug (i.e., axitinib).
  • the release rate can be at least 1.1 times higher, at least .1.2 times higher, at least 1.5 times higher, at least 2 times higher, at least 5 times higher, at least 10 times higher, at least 20 times higher, at least 50 times higher, at least 100 times higher, at least 250 times higher, at least 500 times higher or at least 1000 times higher, including all ranges between any of die previous val ues, I n c ertain embodiments, the present i nvention is directed to a method of treating a disease or condition comprising administering a compound of formula I or pharmaceutical composition as disclosed herein.
  • the disease or condition is a cancer such as advanced renal cell carcinoma.
  • the disease or condition is an ocular disease or condition such as AMD, DME or R VO.
  • the present invention is directed to a method of treating a disease or condition by axitinib therapy comprising administering a compound or pharmaceutical composition as disclosed herein.
  • the invention is directed to a hydrogel comprising a compound as disclosed herein,
  • the invention is directed to a xerogel comprising a compound as disclosed herein,
  • the hydrogel or xerogel may be formed from precursors having functional groups that form crosslinks to create a polymer network.
  • These crosslinks between polymer strands or arms may be chemical (i,e., may be covalent bonds) and/or physical (such as ionic bonds, hydrophobic association, hydrogen bridges etc.) in nature.
  • the polymer network may be prepared from precursors, either from one type of precursor or from two or more types of precursors that are allowed to react. Precursors are chosen in consideration of the properties that are desired for the resultant hydrogel. There are various suitable precursors for use in making the hydrogels and xerogels. Generally, any pharmaceutically acceptable and crosslinkable polymers forming a hydrogel may be used for the purposes of the present invention. The hydrogel and thus the components incorporated into it, including the polymers used for making the polymer network, should be physiologically safe such that they do not elicit e.g. an immune response or other adverse effects. Hydrogels and xerogels may be formed from natural, synthetic, or biosynthetic polymers. Natural polymers may include glycosaminoglycans, polysaccharides (e.g. dextran), polyaminoacids and proteins or mixtures or combinations thereof.
  • Natural polymers may include glycosaminoglycans, polysaccharides (e.g. dex
  • Synthetic polymers may 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.
  • the polymerization may be initiated by certain initiators, by light and/or heat, and may be mediated by catalysts.
  • one or more synthetic polymers of the group comprising one or more units of polyalkylene glycol 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 combinations/mixtures of any of these can be used, while this list is not intended to be limiting.
  • PEG polyethylene glycol
  • polypropylene glycol poly(ethylene glycol)-block-poly(propylene glycol) copolymers
  • polyethylene oxide polypropylene oxide
  • polyvinyl alcohol poly (vinylpyrrolidinone)
  • polylactic acid polylactic-co-glycolic acid
  • the precursors may be covalently crosslinked with each other.
  • precursors with at least two reactive centers can serve as crosslinkers since each reacti ve group can participate in the formation of a different growing polymer chain.
  • the precursors may have biologically inert and hydrophilic portions, e.g., a core.
  • a core refers to a contiguous portion of a molecule joined to arms that extend from the core, where the arms carry a functional group, which is often at the terminus of the arm or branch .
  • MnUi-armed PEG prec ursors are examples of such precursorsand are further disclosed herein below,
  • a hydrogel for use in the present invention can be made e.g. from one multiarmed precursor with a first (set of) functional group(s) and another multi-armed precursor having a second (set of) functional group(s).
  • a multi-armed precursor may have hydrophilic arms, e.g.. polyethylene glycol units, terminated with primary amines (nucleophile), or may have activated ester end groups (electrophile).
  • the polymer network according to the present invention may contain identical or different polymer units crosslinked with each other.
  • Certain functional groups can be made more reactive by using an activating group.
  • activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N-hydroxysuccinimidyl ester, succinimidyl ester, epoxide, aldehyde, maleirnides, imidoesters, acrylates and the like.
  • the N- hydroxysuccinimide esters (NHS) are useful groups for crosslinking of nucleophilic polymers, e.g., primary amine-terminated or thiol -terminated polyethy lene glycols.
  • An NHS- amine crosslinking reaction maybe carried out in aqueous solution and in the presence of buffers, e.g., 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- 1.0.0).
  • buffers e.g., 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- 1.0.0).
  • each precursor may comprise only nucleophilic or only electrophilic functional groups, so long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction.
  • the precursor polymer may have electrophilic functional groups such asN-hydroxysuccinim ides.
  • the functional polymer may have nucleophilic functional groups such as amines or thiols.
  • functional polymers such as proteins, poly (allyl amine), or amine-tenninated di-or multifunctional poly(ethylene glycol) can be also used to prepare the polymer network of the present invention.
  • a first reactive precursor has about 2 to about 16 nucleophilic functional groups each (termed functionality), and a second reactive precursor allowed to react with the first reactive precursor to form the polymer network has about 2 to about 16 electrophilic functional groups each.
  • the polymer network forming the hydrogel contains polyethylene glycol (PEG) units.
  • PEGs are known in the art to form hydrogels when crosslinked. and these PEG hydrogels are suitable for pharmaceutical applications e.g. as matrix for drugs intended to be administered to all parts of the human or animal body.
  • the polymer network of the hydrogel implants of the present invention may comprise one or more multi-arm PEG units having from 2 to 10 arms, or 4 to 8 arms, or 4, 5. 6, 7 or 8 arms.
  • the PEG units may have a different or the same number of arms.
  • the PEG units used in the hydrogel of the present invention have 4 and/or 8 arms.
  • a combination of 4- and 8-arm PEG units is utilized.
  • the number of arms of the PEG used contributes to controlling the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking 4-arm PEGs are generally softer and more flexible than those formed from 8-arm PEGs of the same molecular weight.
  • a more flexible hydrogel may be used, such as a 4-arm PEG, optionally m combination with another multi-arm PEG, such as an 8-arm PEG as disclosed above.
  • polyethylene glycol units used as precursors have an average molecular weight in the range from about 2,000 to about 100,000 Daltons, or in a range from about 10,000 to about 60,000 Daltons, or in a range from about 15,000 to about 50,000 Daltons. In certain particular embodiments the polyethylene glycol units have an average molecular weight in a range from about 1.0,000 to about 40,000 Daltons, or of about 20,000 Daltons. PEG precursors of the same average molecular weight may be used, or PEG precursors of different average molecular weight 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 MALDL
  • each of the arms may ha ve an average arm length (or molecular weight) of the total molecular weight of the PEG divided by 4.
  • a 4a20kPEG precursor which is one precursor that can be utilized in the present invention thus has 4 arms with an average molecular weight of about 5.000 Daltons each.
  • An 8a20k PEG precursor which may be used in addition to the 4a20kPEG precursor in the present invention, thus has 8 arms each having an average molecular weight of 2,500 Daltons. Longer arms may provide increased flexibility as compared to shorter arms. PEGs with longer arms may swell more as compared to PEGs with shorter arms.
  • a PEG with a lower number of arms also may swell more and may be more flexible than a PEG with a higher number of arms.
  • combinations of PEG precursors with differen t numbers of arms such as a combination of a. 4-arm PEG precursor and an 8-arm precursor, may be utilized in the present invention.
  • longer PEG arms ha ve higher melting temperatures when dry, which may provide more dimensional stability during storage.
  • an 8-arm PEG with a molecular weight of 15,000 Dalton crosslinked with trilysine may not be able to maintain a stretched configuration at room temperature
  • a 4-arm 20,000 Dalton PEG crosslinked with an 8-arm 20,000 Dalton PEG may be dimensionally stable in a stretched configuration at room temperature
  • the indicated average molecular weight refers to the PEG part of the precursor, before end groups are added ( “20k” here means 20,000 Daltons, and “15k” means 15,000 Daltons — the same abbreviation is used herein for other average molecular weights of PEG precursors).
  • the Mn of the PEG part of the precursor is determined by MALDI.
  • the degree of substitution with end groups as disclosed herein may be determined by means of 'H -NMR after end group functionalization.
  • electrophilic end groups for use with PEG precursors for preparing the hydrogels of the present in vention are N-hydroxysuccinimidyl (NHS) esters, including but not limited to: “SAZ” referring to a succinimidylazelate end group, “S AP” referring to a succinim idyladipate end group, “SG” referring to a succinimidylglutarate end group, and “SS” referring to a succinimidylsuccinate end group.
  • NHS N-hydroxysuccinimidyl
  • nucleophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are amine (denoted as “NH 2 ”) end groups. Thiol (-SH) end groups or other nucleophilic end groups are also possible.
  • 4-arm PEGs with an average molecular weight of about 20,000 Daltons and an electrophilic end group as disclosed above and 8-arm PEGs also with an average molecular weight of about 20,000 Daltons and with a nucleophi lic end group as disclosed above are crosslinked for forming the polymer network and thus the hydrogel according to die present invention,
  • m is 6, e.g. in the case a SAZ-end group-containing PEG is used.
  • m would be 3
  • m would be 2
  • SS-end group m would be 1. All crosslinks within the polymer network may be the same, or may be different,
  • the SAZ end group is utilized in the present invention.
  • This end group may provide for increased duration in the eye, and the implant of certain embodiments of the present invention comprising a hydrogel comprising PEG-SAZ units is biodegraded in the eye, such as in the vitreous humor of a human eye, only after an extended period of time, e.g. , 9 to 12 months as further disclosed below, and may in certain circumstance persist even longer.
  • the SAZ group is more hydrophobic than e.g.
  • 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 having a SAZ group (as defined above) combined with an 8-arm 20,000 Dalton PEG precursor having an amine group (as defined above).
  • SAZ group as defined above
  • 8-arm 20,000 Dalton PEG precursor having an amine group as defined above.
  • R represents a pentaerythritol core structure.
  • the chemical structure of 8a20kPEG-NH 2 (with a hexaglycerol core) is:
  • R hexaglycerol core structure
  • n is determined by the molecular weight of the respective PEG-arm.
  • the molar ratio of the nucleophilic and the electrophilic end groups reacting with each other is about 1 :1, i.e. , one amine group is provided per one S AZ group.
  • the electrophilic (e.g. the N HS end groups, such as the SAZ) end groups or of the nucleophilic (e.g. the amine) end groups may be used.
  • an excess of the nucleophilic, such as the amine-eud group containing precursor may be used, i.e., the weight ratio of 4a20kPEG-SAZ and 8a20kPEG-NH 2 may also be less than 2:1.
  • Each and any combination of electrophilic- and nucleophilic-group containing PEG precursors disclosed herein may be used for preparing the implant according to the present invention.
  • any 4-arm or 8 ⁇ arm PEG-NHS precursor e.g. having a SAZ, SAP, SG or SS end group
  • any 4-arm or 8-arm PEG-N H 2 precursor or any other PEG precursor having a nucleophilic group.
  • the PEG units of the electrophilic- and the nucleophilic group-containing precursors may have the same, or may have a different average molecular weight.
  • nucleophilic group-containing crosslinking agent may be used instead of a PEG-based crosslinking agent.
  • a low-molecular weight amine linker can be used, such as trilysine (or a trilysine salt or derivative, such as trilysine acetate) or other low- molecular weight multi-arm amines,
  • the nucleophilic group-containing crosslinking agent may be bound to or conjugated with a visualization agent
  • a visualization agent is an agent that contains a fluorophorlc or other visualization -enabling group. Fluorophores such as fluorescein, rhodamine, coumarin, and cyanine may for example be used as visualization agents.
  • the visualization agent may be conjugated with the crosslinking agent e.g. through some of the nucleophilic groups of the crosslinking agent.
  • conjugated in general Includes partial conjugation, meaning that only a part of the nucleophilic groups are used for conjugation with the visualization agent, such as about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinking agent may be conjugated with a visualization agent.
  • a visualization agent may also be conjugated with the polymer precursor, e.g. through certain reactive (such as electrophilic) groups of the polymer precursors.
  • hydrogels can also be applicable to xerogels.
  • the materials disclosed herein for hydrogels can also be extruded with a prodrug.
  • In certain embodiments is directed to a method of preparing a sustained release biodegradable ocular insert comprising extruding a polymer composition and a prodrug to form an insert suitable for ocular administration.
  • the method comprises feeding the polymer composition and the prodrug into an extruder; mixing the components in the extruder; extruding a strand; and cutting the strand into unit dose inserts or implants.
  • the polymer composition and the prodrug are fed separately into the extruder. In other embodiments, the polymer composition and prodntg are fed simultaneously into the extruder. In certain embodiments. the polymer composition are premixed, e.g., melt blended, prior to introduction into the extruder,
  • the method further comprising cooling the strand, e.g., prior to cutting the strand.
  • the method further comprises stretching the strand, e.g., prior to cutting the strand.
  • the stretching is performed under wet conditions, heated conditions, or a combination thereof. In other embodiments, the stretching is performed under dry conditions, heated conditions, or a combination thereof.
  • the extruded composition is subject to a curing step, e.g., humidity exposure.
  • the curing crosslinks the polymer composition.
  • the method further comprises drying the strand after stretching the strand.
  • any of the method steps disclosed herein can be performed simultaneously or sequentially in any order.
  • the method further comprises melting the polymer in the extruder at a tempera ture below the melting point of the prodrug.
  • the temperature can be, e.g., 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° to about 80°C.
  • the extrusion is performed above the melting point of the polymer and the prodrug.
  • the extruded composition is dried, when in strand form or in unit doses. In certain embodiments, the drying is performed after stretching the strand.
  • the drying can be, e.g., evaporative drying at ambient temperatures or can include heat, vacuum or a combination thereof
  • the hydrogel strand is stretched by a stretch factor in the range of about 0.25 to about 10, 0.5 to about 6 or about 1 to about 4.
  • the strand is cut into segments having an average length of 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.
  • the prodrug is suspended in the polymer composition.
  • the prodrug is homogenousely dispersed in the polymer composition.
  • the extrusion process is performed without solvent (e.g., water).
  • 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.
  • the content uniformity of the unit dose insert is within 10%, with 5% or within 1%.
  • the persistence of the dosage form is from about 7 days to about 6 months after ocular administration.
  • the polymorphic form of the prodrug does not change or does not substantially change.
  • the purity of the prodrug after curing is greater than 99%, greater than 99.5% or greater than 99.9% as compared to the prodrug prior to extrusion.
  • the prodrug has an average particle diameter of less than about 100 pin, less than about 50 ⁇ m, less than about 25 ⁇ m, or less than about 10 ⁇ m.
  • the prodrug has a D50 particle size of less than about 10 ⁇ m and/or a D99 particle size ofless than about 50 gm, or a D90 particle size of about 5 ⁇ m or less and/or a D98 particle size of about 10 ⁇ m or less.
  • the prodrugs herein can be used in an organogel.
  • 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 crosslinked polymeric network, wherein the hydrophobic organic liquid and the prodrug are contained in the biodegradable, covalently crosslinked polymeric network.
  • a sustained release, biodegradable drug-delivery system comprising an organogel and a prodrug, the organogel comprising a hydrophobic organic liquid, and a biodegradable, covalently crosslinked polymeric network, wherein the hydrophobic organic liquid and the prodrug are immobilized in the biodegradable, covalently crosslinked polymeric network.
  • the sustained release, biodegradable drug-delivery system in certain embodiments comprises at least three constituents, a biodegradable covalently crosslinked polymer network, a hydrophobic organic liquid and a prodrug.
  • the organogel in certain embodiments is formed by polymerization of non-linear, multifunctional monomeric or polymeric precursor components as disclosed herein later and forms a covalently crosslinked polymeric network that includes the hydrophobic organic liquid and immobilizes it within the polymeric network, e.g., until it is released from the network in vivo.
  • the organogels of the present invention are thus like a hydrophobic analog to hydrogels that include 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. In a hydrogel the non-reactive component is water, whereas in the organogel of the present invention it is a hydrophobic organic compound with glass (Tg) and melt (I'm) transition temperatures below body temperature, such as an oil,
  • Covalent crosslinking of the polymer network forming precursors in certain embodiments provides a limited mobility to the hydrophobic organic liquid (e.g., oil) component. This may provide continuous control of drug release by limiting drug transport to diffusion through the organogel and/or eliminating development of defects that provide fast escape routes for the drug from developing.
  • the drug-delivery system of die present invention is a fully or partly diffusion controlled deli very system, i.e. the release of the oil and/or the 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.
  • the release of the prodrug is mainly controlled by degradation of the polymeric matrix that releases the prodrug mainly in a degradation controlled system.
  • the network forming precursors should be miscible in the hydrophobic organic liquid component, such that when crosslinked it “holds” the component to create a solid or semi-solid, that forms the organogel, in certain embodiments, the hydrophobic organic liquid compatibility with the polymer network has an impact on the rate the hydrophobic organic liquid escapes into the surrounding tissue fluid in vivo, and may gradually be replaced by aqueous fluid, providing an additional method of controlling drug release kinetics to prodrug solubility and network degradation.
  • the use of an organogel in the sustained release, biodegradable drug-delivery system of the invention thus allows to modify the release of a prodrug from the drag-delivery system by tailoring or suitably selecting the precursor components forming the crosslinked polymeric network according to their hydrophilic and/or hydrophobic properties.
  • the release of a prodrug fr om the drag-delivery system can be modified or controlled by suitably selecting the hydrophobic organic liquid according to its properties such as hydrophobicity, viscosity, compatibility with the prodrug, solubility or insolubility of the prodrug in the hydrophobic organic phase, and the like.
  • organogel based drug-delivery system of certain embodiments of the present invention offers several advantages over hydrogels.
  • certain organogels are anhydrous, so water degradable (hydrolysable) components such as water sensitive prodrugs can be stabilized and made storage stable over extended periods of time and don’t require hydration at the time of implantation,
  • Water soluble compounds have low solubility or are insoluble in organogels, allowing the drug to be incorporated as a particulate solid embedded in the organogel matrix.
  • the low solubility of the drug in the organogel matrix provides a mechanism to control the rate of drug release. This property vastly increases the range of compounds that can be contained in an implant.
  • Manipulation of the lipophilicity/hydrophilicity of the organogel can be used to adjust the release rate of a drug and to influence diffusion rates. Pure hy drogels cannot be adj usted this way, since they are water- based, thus in these systems the drug itself has to be modified to aprodrug form for such adjustment of drug/matrix solubility. In organogels, this can be avoided. Additionally, varying the lipophilicity/hydrophilicity of the organogel can be further used influence degradation rate of the polymer matrix, also having an additional influence on the release rate of a drug.
  • the organogel can be designed to release the hydrophobic organic liquid (e.g., oil) from the matrix slowly in vivo, allowing a slow conversion to hydrogel that is then degraded. This provides a new mode of drug release control and increases biocompatibility.
  • hydrophobic organic liquid e.g., oil
  • a solvent in organogels can be used during manufacture to overcome compatibility issues of the co mponents, and the solvent can be removed to yield an organogel with an immobilized oil. Removal of the solvent can be accomplished by heat treatment, which is not possible for materials that undergo melting or glass transitions at elevated temperatures. Solvent removal can also be accomplished by methods typically employed for non-crosslinked polymers, such as water extraction, vacuum drying, lyophilization, evaporation, etc. Elimination of the need for careful removal of solvent greatly simplifies the fabri cation process.
  • organogels possess the physical qualities of low modulus, dimensional stability, and favorable drug release kinetics.
  • organogels can be dimensionally stable to heat and will not melt.
  • implant fabrication processes such as hot melt extrusion can be used to form certain organogels of the present invention.
  • the drug-delivery system of the present invention comprising an organogel may be used to de li ver classes of drugs including st ero ids, non-steroidal anti -inflamma tory drugs (N SAIDS), intraocular pressure lowering drugs, antibiotics, peptides, or others.
  • the organogel may be used to deliver drugs aid therapeutic agents, e.g. , an anti-inflammatory (e.g.. Diclofenac), a pain reliever (e.g., Bupivacaine), a calcium channel blocker (e.g,, Nifedipine), an Antibiotic (e.g.. Ciprofloxacin), a cell cycle inhibitor (e.g...
  • Simvastatin a protein or peptide (e.g., Insulin), enzymes, antineoplastic agents, local anesthetics, hormones, angiogenic agents, anti-angiogenic agents, growth factors, antibodies, neurotransmitters, psychoactive drugs, anticancer drugs, chemotherapeutic drugs, drugs affecting reproductive organs, genes, and oligonucleotides, or other configurations, as well as viruses such as AAV for gene delivery.
  • the rate of release from the organogel may depend on the properties of one or more of the prodrug, the hydrophobic organic liquid and the polymer network, with other possible factors including one or more of drug sizes, relative hydrophobicity, organogel density, organogel solids content, and. the like.
  • the drug-delivery system of the present invention may be in the form of an implant, a medical implant or a pharmaceutically acceptable implant, an implant coating, or an oral dosage form, etc.
  • the prodrugs disclosed herein are utilized in the treatment of Ocular disease involving angiogenesis
  • the ocular disease may lie mediated by one or more receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • the ocular disease is a retinal disease including Choroidal Neovascularization, Diabetic Retinopathy, Diabetic Macula Edema, Retinal Vein Occlusion, Acute Macular Neuroretinopathy, Central Serous Chorioretinopathy, and Cystoid Macular Edema; wherein the ocular disease is Acute Multifocal Placoid Pigment Epitheliopathy, Behcet’s Disease, Birdshot Retinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), Intermediate Uveitis (Pars Planitis), Multifocal Choroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis, Serpignous Choroiditis, Subretinal Fibrosis, Uveitis Syndrome, or Vogt-Koyanagi-Harada Syndrome; wherein the ocular disease is a vascular disease or
  • the prodrags utilized herein can be utilized in the treatment of ocular conditions associated with rum.
  • Such conditions include e.g., Retinal Disease Associated with Tumors, Solid Tumors, Tumor Metastasis, Benign Tumors, for example, hemangiomas, neurofibromas, trachomas, and pyogenic granulomas.
  • the prodrugs of the present invention can be utilized in the treatment o f any ocular disease involving vascular leakage.
  • the ocular disease is selected from neovaseular age-related macular degeneration (AMD), diabetic macula edema (DME), and retinal vein occlusion ( R VO).
  • AMD neovaseular age-related macular degeneration
  • DME diabetic macula edema
  • R VO retinal vein occlusion
  • the ocular disease is neovascular age-related macular degeneration.
  • the ocular condi tion is dry eye.
  • the compounds and pharmaceutical compositions disclosed herein can be administered by any route such as oral, parenteral, ocular, transdermal, nasal, pulmonary or rectal.
  • the administration can be to a vitreous body, or other location.
  • pancta canaliculus, upperdower canaliculus
  • oc ular fornix upper/lower ocular fornix
  • subtenon space choroid
  • suprachoroid suprachoroid
  • tenon cornea.
  • the dosage form is a punctal plug, intracanalicular insert, mtraeameral insert or intravitreal insert
  • the prodrugs and formulations herein are used (e.g., for oncology treatment) by intravitreal, suprachoroidal, subretinal, subconjunctival, or subtenon administration.
  • the invention is directed to a prodrug (e.g., a prodrug of axitinib as disclosed herein) administered in combination with the base drag (e.g., axitinib) in the same formulation (e.g., an ocular formulation) or a different formulation in order to provide a quicker releasing loading dose when there is a lag time in the release or therapeutic effect of the base drag.
  • the prodrug has a slower release than the base drag
  • the combination can provide a longer duration of effect than administration of the base drug alone.
  • the axitinib prodrug can be formulated and/or admibnsisted in accordance with U.S. Patent No. 11,439,592 B2,
  • Scheme 2A Preparation of Intermediate- 1
  • Scheme 2B Preparation of axttinib-N-mPEG -suscinoyloxyinethyl prodrug
  • Test items axitinib (99.99% purity by HPLC); axitinib-N-mPEG- succinoyloxymethyl prodrug (93.6% purity by HPLC)
  • Test media phosphate buffer saline pH 7.4
  • Test concentration 1 mg/mL
  • Data analysis Solubility of test item was determined by HPLC analysis with calibration curve
  • HPLC conditions were as follows:
  • Each prodrug is incubated with hrCESs (a combination of hrCES-1 and hrCES-2, 0.1 mg protein/mL per hrCES) in phosphate buffer ( 100 m.M, pH 7.4) containing MgC12 (5 mM).
  • phosphate buffer 100 m.M, pH 7.4
  • MgC12 5 mM
  • the incubation mixture is equilibrated in a shaking water bath at 37°C for 5 minutes.
  • the reaction is initiated by the addition of the prodrug, followed by incubation at 37°C. Aliquots of the incubation solutions are sampled at 0, 15, 30, 60, and 120 minutes.
  • reaction is terminated by the addition of 50% ice-cold acetonitrile (ACN)/0.1% formic acid containing an internal standard (1S, 0.2 ⁇ M metoprolol or 0.2 ⁇ M tolbutamide for the positive or negative ionization mode in mass spectrometry, respectively),
  • ACN ice-cold acetonitrile
  • At is the peak area ratio (prodrug to 1S) at time t and A0 is the peak area ratio (prodrug to 1S) at time zero,
  • CO and Ct are the concentrations of the prodrug ( expressed as the peak area ratios of prodrug to 1S) at time zero and incubation time t (min) and k is the elimination rate constant (mln- 1),
  • CLint is the in vitro intrinsic clearance
  • k is the elimination rate constant (min ⁇ l )
  • P is the enzyme concentration in the incubation medium (mg protein/mL).
  • Test articles are prepared in suspension in a mixture of DMSO (5%) and 0.5%- CMC-Na (95%, v/v), at a concentration of 3 m gZmL axitinib- molar-equivalence for an inventive prodrug.
  • Male ICR mice 64, body weight ranging 18-22 g
  • Test articles are administered to animals through oral- gavage, at a dose of molar-equivalent to 30 mg/kg of axltinib, after the animals were fasted for 12 h.
  • Blood samples are collected from orbit to heparinized EP tube at time points of 0.25, 0.5. 1 , 2, 4, 6.
  • Plasma sample (10 ⁇ L) is mixed well with acetonitrile ( 110 ⁇ L), The sample is then centrifuged at 12,000 rpm and 4° C. The supernatant is analyzed with an LC-MS/MS instrument, and the target analytes are axitinib and its corresponding prodrug molecules.
  • mice Male ICR. mice (body weight: 18 to 22 g) are divided into 6 groups randomly with 6 animals pet group, with blood sample collection from 6 animals at each time point for a total of 6 time points. Dosing solution of a test article is prepared by dissolving or suspending a compound in a solvent system. For all the compounds, the concentration of dosing solution is 3 mg/mL of axitinib molar equivalent, and the dose is 30 mg/kg of axitinib molar equivalent.
  • Animals are fasted for 12 h, and then given the test article in dosing media at a dosing volume calculated according to the above information. After dosing, blood samples are collected at the pre-set time points of 0.5, 1 , 2, 4. 6, and 8 h. Blood samples are centrifuged at 5,000 rpm and 4° G. for 10 min, and plasma samples are collected and kept at C.
  • Plasma sample (20 ⁇ L) is mixed well with acetonitrile (220 ⁇ L). The sample is then centrifuged at 12,000 rpm and4 ° C. The supernatant is analyzed with an LC- MS/MS instrument, and the target analytes.
  • Step 3 Step 4
  • D90 12.4 ⁇ m
  • D50 5.2 ⁇ m
  • D 10 1.1 ⁇ m .
  • Axitinib prodrugs of the present invention were tested for solubility in phosphate buffer saline (PBS, pH-7.40). The results are set forth in the table below:
  • Axitinib prodnigs of the present invention were tested for stability in phosphate buffer saline (PBS, pH-7.40). The results are set forth in the table below and Figure 7:

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Abstract

Dans certains modes de réalisation, l'invention concerne un composé de formule (I) : dans laquelle; X1 est sélectionné parmi N ou N-Y1; X2 est choisi parmi NH ou NY2; X3 est choisi parmi NH ou NY3; Y1<sp /> est choisi parmi -CH2OCO(OCH2CH2)n1OM1; ou -CH2OCO(CH2CH3O)n1aZ1; ou - CH2OCO(CH2)n1bCOOH; Y2 est choisi parmi -CH2OCO(OCH2CH2)n2OM2; ou -CH2OCO(CH2CH2O)n2aZ2; ou - CH2OCO(CH2)n2bCOOH; Y3 est choisi parmi -CH2OCO(OCH2CH2)n3OM3; ou - CH2OCO(CH2CH2O)n3aZ3; ou - CH2OCO(CH2)n3bCOOH; n1, n1a; n1b, n2,n2a, n2b, n3, n3a et n3b sont indépendamment 0 ou un nombre entier de 1 à 8; M1, M2, M3, Z1, Z2 et Z3 sont indépendamment choisis parmi H, alkyle en C1- 6 éventuellement substitué et aryle éventuellement substitué; où au moins l'un parmi X1, X2 et X3 n'est pas N ou NH; où au moins l'un parmi Y1, Y2 ou Y3 sont les •-CH2OCO(CH2CH2O)nZ; et des sels pharmaceutiquement acceptables de ceux-ci.
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