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WO2008151253A1 - Promédicaments d'agents antinéoplasiques activés par l'hypoxie - Google Patents

Promédicaments d'agents antinéoplasiques activés par l'hypoxie Download PDF

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Publication number
WO2008151253A1
WO2008151253A1 PCT/US2008/065812 US2008065812W WO2008151253A1 WO 2008151253 A1 WO2008151253 A1 WO 2008151253A1 US 2008065812 W US2008065812 W US 2008065812W WO 2008151253 A1 WO2008151253 A1 WO 2008151253A1
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compound
group
formula
alkyl
hyp
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PCT/US2008/065812
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English (en)
Inventor
Hailong Jiao
Jason Lewis
Mark Matteucci
Difei Sun
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Threshold Pharmaceuticals, Inc.
Chen, Tao
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Publication of WO2008151253A1 publication Critical patent/WO2008151253A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention provides compositions and methods for the treatment of cancer, and generally relates to the fields of medicinal chemistry, medicine, pharmacology, molecular biology, and biology.
  • Hypoxia activated (or bioreducible) prodrugs of antineoplastic agents are useful for treating cancer. See, for example, PCT Pat. Pub. No. WO 00/064864, WO 04/087075, WO 06/057946, WO 07/002931, WO 07/137196 and PCT Pat. Appl. No. US07/88645, each of which is incorporated herein by reference.
  • HAPs contain a bioreductive group, a linker, and an antineoplastic agent and are less cytotoxic than the corresponding antineoplastic agents.
  • hypoxic conditions or hypoxia Under hypoxic conditions or hypoxia, the bioreductive group present in the HAP is reduced, and a cytotoxic antineoplastic agent is generated and/or released. Under normoxic conditions or normoxia such as those existing in a normal cell, a HAP can be non toxic or less toxic. Under hypoxic conditions such as those existing in tumor cells within hypoxic zones of solid tumors, the cytotoxin generated and/or released from a HAP can selectively kill cancer cells in and around the hypoxic tumor zone.
  • a certain class of antineoplastic agents known as vascular disrupting agents, tubulin binding agents or anti-tubulin agents, can be cytotoxic to tumor cells by collapsing or otherwise disrupting the tumor vasculature. See, for example PCT Pat. Pub. No. WO 06/057946 and WO 07/137196, each of which is incorporated herein by reference.
  • the collapse of the tumor vasculature reduces blood and oxygen flow into the tumor and can increase tumor hypoxia.
  • Hypoxia activated prodrugs of vascular disrupting agents are reported in PCT Pat. Pub. No. WO 06/057946 and WO 07/137196.
  • the present invention provides HAPs having structures of the formula Hyp-L-M wherein the Hyp moiety is a bioreductive group, L is a releasable linker comprising an ammonium moiety, and M is an antineoplastic agent.
  • L is a releasable linker comprising a methylene-ammonium-methylene moiety.
  • L has a structure of the formula -L 2 -Lr, or in other words the corresponding HAP has a structure of the formula Hyp-L 2 -Li-M, wherein -L ⁇ - has a structure of the formula
  • each Of Ri-R 8 is selected from the group consisting Of Ci-C 6 alkyl, Cj-C 6 heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, or together Ri and R 2 , R 5 and R 6 , and R 7 and R 8 form a C 3 -C 8 cycloalkyl or a heterocyclyl group, or together R 3 and R 4 form a heterocyclyl group and each of Ra-Rd is selected independently from the group consisting of hydrogen, halo, nitro, CO 2 H, Ci-C 6 alkyl, and Ci-C 6 alkoxy.
  • each Ri, R 2 , R 5 , and R 6 is hydrogen.
  • each R 3 and R 4 is alkyl. In another embodiment, each R 3 and R 4 is methyl.
  • L 2 is a bond. In one embodiment, Li has a structure of the formula -CH 2 -NMe 2 CH 2 -. In another embodiment, L has a structure of the formula -CH 2 -NMe 2 CH 2 -.
  • the bioreductive group, Hyp is selected from the group consisting of a nitroaryl, a nitroheteroaryl, an indoloquinonyl, a naphthoquinonyl, an amine oxide, and a disulfide moiety.
  • the HAPs of the present invention contain novel 4-substituted-2-nitroimidazole bioreductive groups.
  • Hyp has a structure of the formula:
  • Ri 5 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, and halo.
  • Rj 5 is a terminal C 2 -C 6 alkenyl moiety.
  • Ri 5 is a terminal C 2 -C 6 alkynyl moiety.
  • the terminal C 2 -C 6 alkynyl moiety has a structure of the formula
  • R 19 is selected from the group consisting Of C)-C 6 alkyl, aryl, and heteroaryl.
  • antineoplastic agents can be employed as M in the HAPs of the present invention.
  • the antineoplastic agent is an aroylindazole compound that can bind tubulin, inhibit microtubule formation, and/or disrupt tumor vasculature (see
  • the present invention provides HAPs wherein M is an aroylindazole moiety having a structure of the formula:
  • R 9 is selected from the group consisting of hydrogen, halo, hydroxy, nitro, cyano, amino, CrQalkylamino, di(C]-C 6 )alkylamino, Ci-C 6 alkoxy, CrQalkyl, Ci-C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the present invention provides a HAP containing as an antineoplastic agent an aroylindazole compound that can bind tubulin and wherein the HAP has a structure of the formula:
  • the HAP compound is compound 36 as disclosed herein.
  • the antineoplastic agent is selected from camptothecin and analogs and Taxol® (paclitaxel, Bristol Meyers Squibs) and analogs.
  • the present invention provides Hyp containing compounds having structures of the formula selected from Hyp-CH 2 -OH and Hyp-CH 2 -Br wherein Hyp has a structure of the formula:
  • R 15 substituents include but are not limited to phenyl, pyridyl, isopropenyl, propenyl, and vinyl.
  • the novel as well as known Hyp-CH 2 -OH and HyP-CH 2 -Br compounds are intermediates useful in the synthesis of the HAP compounds of the present invention.
  • the present invention provides methods of synthesizing HAPs and various intermediates useful in the synthesis of the HAP compounds of the present invention.
  • the present invention provides methods of synthesizing a HAP of the present invention.
  • the present invention provides HAPs in substantially pure forms.
  • the present invention provides a pharmaceutically acceptable formulation comprising a compound of the present invention, including but not limited to the HAPs of the present invention and pharmaceutically acceptable carriers, diluents, and/or excipients.
  • the present invention provides a method of treating cancer and other hyperproliferative diseases comprising administering a therapeutically effective amount of a HAP of the present invention to a patient in need of such treatment.
  • the present invention provides methods of disrupting vasculature associated with cancer or other hyperproliferative diseases by contacting said vasculature with a compound of the present invention.
  • Figure 1 Demonstration of growth reduction of HT29 xenograft tumor in mice upon administration of Compound 15 alone and in combination with CPT-I l.
  • Figure 2 Demonstration of the safe administration of Compound 15 alone and in combination with CPT-11 by plotting the percent change in animal body weight compared to the bodyweight at the beginning of the treatment.
  • Figure 3 Demonstration of growth reduction of HT29 xenograft tumors in mice upon administration of 23 and 36 as single agents.
  • Figure 4 Demonstration of growth reduction of HT29 xenograft tumors in mice upon administration of 23 and 36 in combination with CPT-I l.
  • Section I provides useful definitions
  • Section II describes the compounds of the present invention, including HAPs and prodrugs that are activated by a reaction other than a reduction reaction, and the methods of their synthesis
  • Section III describes therapies provided by the present invention
  • Section IV provides illustrative examples for synthesizing compounds of the present invention, including HAPs and prodrugs that are activated by a reaction other than a reduction reaction, and demonstrates in vitro and in vivo efficacy of compounds of the present invention, including HAPs and prodrugs that are activated by a reaction other than a reduction reaction.
  • > ⁇ refers to a position on a moiety which is covalently bonded to the rest of the molecule via a single bond.
  • C 2 -C 6 alkenyl by itself or as part of another substituent refers to a straight or branched chain, which may be mono or polyunsaturated, having the number of carbon atoms designated.
  • C 2 -C 6 alkenyl means an alkenyl radical having from 2, 3, 4, 5 or 6 atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Examples include, but are not limited to vinyl, 2 propenyl i.e.
  • substituted alkenyl has the same meaning with respect to alkenyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups.
  • a substituted alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.
  • Each site of unsaturation may be either cis or trans configuration about the double bond(s).
  • C]-C 6 alkoxy refers to a substituted or unsubstituted alkyl group of 1-6 carbon atoms covalently bonded to an oxygen atom.
  • a Ci-C 6 alkoxy group has the general structure -O-(Ci-C 6 )alkyl.
  • Q-C ⁇ alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3- pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • Q-C 6 alkoxycarbonyl refers to an Ci-C 6 alkoxy group covalently bonded to a carbonyl.
  • C I -C O alkyl refers to a substituted or unsusbstituted straight or branched chain alkyl groups having 1-6 carbon atoms.
  • Ci-C 6 alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.
  • a C]-C 6 alkyl substituent may be covalently bonded to an atom within a molecule of interest via any chemically suitable portion of the Q- C 6 alkyl group.
  • Amino refers to a monovalent radical -NR a R b or divalent radical -NR a -.
  • alkylamino refers to the group -NR a R b where R a is alkyl and R b is H or alkyl.
  • arylamino refers to the group -NR a R b where R a is aryl and R b is hydrogen, alkyl, aryl, or heterocyclyl.
  • (alkyl)(aryl)amino” refers to the group -NR a R b where R a is alkyl and R b is aryl.
  • dialkylamino groups the alkyl portions can be the same or different and can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NR a R b is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
  • Ci-C 6 alkylamino refers to a substituted or unsubstituted alkyl group of 1-6 carbon atoms covalently bonded to -NH- .
  • a Ci-C 6 alkylamino group has the general structure -NH- (Ci -C 6 ) alkyl.
  • a di(Ci-C 6 )alkylamino group has the general structure -N-[(Q-C 6 )alkyl]2.
  • Ci-C 6 alkylamino groups include, for example, methylamino, ethylamino, propylamino and butylamino.
  • Ci-C 6 alkylene refers to a linear saturated divalent substituted or unsubstituted hydrocarbon radical or a branched saturated divalent hydrocarbon radical having 1 - 6 carbon atoms.
  • Alkylene groups include, for example, methylene, ethylene, propylene, butylene, 2- methylpropylene, pentylene.
  • a substituted alkylene can be substituted, among other groups, with Ci-C 6 alkyl groups.
  • C 2 -C 6 alkyl ether refers to a substituent with an oxygen atom and 2 - 6 carbon atoms positioned such that at least one carbon atom is located on either side of the oxygen atom.
  • C 2 -C 6 alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, which may be mono- or polyunsaturated, having the number of carbon atoms designated.
  • C 2 -C 6 alkynyl means an alkynyl radial having from 2 to 6 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • substituted alkynyl has the same meaning with respect to alkynyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups.
  • a substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
  • Aroylindazole compound refers to a compound wherein a substituted or unsubstituted benzoyl moiety is covalently bonded to the 3-position of a substituted or unsubstituted indazole moiety.
  • Aroylindazole compounds are described for example in PCT Pat. Pub. WO 06/057946 and WO 07/137196 (each of which is incorporated herein by reference).
  • Aryl refers to a substituted or unsubstituted cyclic moiety that includes one or more monocyclic or fused ring aromatic systems. Such moieties include any moiety that has one or more monocyclic or bicyclic fused ring aromatic systems, including but not limited to phenyl and naphthyl.
  • Bioreductive group in one aspect, refers to a substituted or unsubstituted nitroaryl, nitroheteroaryl, indoloquinonyl or a naphtoquinonyl moiety that can undergo reduction.
  • bioreductive group refers to a substituted or unsubstituted , amine oxide or a disulfide moiety that can undergo reduction. Bioreductive groups are described for example in the US Pat. Nos. 5,750,782; 5,780,585; 5,872,129; 6,251,933; 5,306,727; 5,403,932; 5,190,929; and 6,656,926; PCT Pat. Appl. Pub. Nos.
  • C 1-6 designating a number of atoms e.g. "C 1-6 " is meant to include all possible embodiments that have one fewer atom.
  • Non-limiting examples include Ci -6 , C 2-6 , C 2-6 , C 3 _ 6 , C 3-6 and the like.
  • each of the terms herein is meant to include both “unsubstituted” and optionally “substituted” forms of the indicated radical, unless otherwise indicated.
  • each radical is substituted with 0, 1, 2 3 4 or 5 substituents, unless otherwise indicated. Examples of substituents for each type of radical are provided below.
  • Substituted refers to a group as defined herein in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atom "substituents" such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy, and acyloxy groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amino, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, alkoxyamino, hydroxyamino, acylamino, sulfonylamino, N-oxides, imides, and en
  • Substituents also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple- bond) to a heteroatom such as oxygen in oxo, acyl, amido, alkoxycarbonyl, aminocarbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • “Substituents” further include groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to a cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
  • substituted alkyl groups include, among others, groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluoro, chloro, or bromo group. Another representative “substituent” is the trifluoromethyl group and other groups that contain the trifluoromethyl group. Other representative “substituents” include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group.
  • substituted or unsubstituted alkylamine dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group.
  • Still other representative "substituents” include those in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group.
  • the herein-defined groups may include prefixes and/or suffixes that are commonly used in the art to create additional well-recognized substituent groups.
  • "alkylamino" refers to a group of the formula -NR a R b .
  • R a , and R b are each independently selected from H, alkyl, alkoxy, thioalkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl or are optionally joined together with the atom(s) to which they are attached to form a cyclic group.
  • R a and R b are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.
  • -NR a R b is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • R c , R d , R e and R f are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or alkylenearyl as defined herein.
  • a particular radical will have 0, 1, 2 or 3 substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, a radical will be unsubstituted or monosubstituted. Most preferably, a radical will be unsubstituted.
  • substituteduents refers to an atom or group, including, for example, amino, Ci-C 6 alkylamino or di(Ci-C 6 )alkylamino, C]-C 6 alkoxy, Ci-C 6 alkylthio, aryl, -COOH, -CONH 2 , cyano, ethenyl, ethynyl, halo, heteroaryl, hydroxy, mono- or di(Cr C 6 )alkylcarboxamido, mono or di(Ci-C 6 )alkylsulfonamido, nitro, -OSO 2 -Ry, and -SO 2 NH 2 .
  • substituted aryl and heteroaryl groups are varied and are selected from: -halogen, -OR 3 , -OC(O) R a , -NR a R b , -SR 3 , -R a , -CN, -NO 2 , -CO 2 R 3 ,
  • Two of the "substituents "on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH 2 )q-U-, wherein T and
  • U are independently -NH-, -O-, -CH 2 . or a single bond, and q is O, 1 or 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2) r _B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O) 2 ., -S(O) 2 NR a - or a single bond, and r is 1, 2 or 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) S -X-(CH 2 )I- -, where s and t are independently integers of from O to 3, and X is -0-, -NR a -, -S- , -S(O)-, -S(O) 2 -, or -S(O) 2 NR a -.
  • the substituent R a in -NR a - and -S(O) 2 NR 3 - is selected from hydrogen or unsubstituted Ci . ⁇ alkyl. Otherwise, R' is as defined above.
  • Cycloalkyl or “carbocycle”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl”, “alkenyl” and “alkynyl” in which all ring atoms are carbon.
  • Cycloalkyl or “carbocycle” refers to a mono- or polycyclic group. When used in connection with cycloalkyl substituents, the term “polycyclic” refers herein to fused and non-fused alkyl cyclic structures.
  • Cycloalkyl or “carbocycle” may form a bridged ring or a spiro ring.
  • the cycloalkyl group may have one or more double or triple bond(s).
  • cycloalkenyl refers to a cycloalkyl group that has at least one site of alkenyl unsaturation between the ring vertices.
  • cycloalkynyl refers to a cycloalkyl group that has at least one site of alkynyl unsaturation between the ring vertices.
  • cycloalkyl When “cycloalkyl” is used in combination with “alkyl”, as in C 3 _ 8 cycloalkylC 3 - 8 alkylene-, the cycloalkyl portion is meant to have the stated number of carbon atoms (e.g., from three to eight carbon atoms), while the alkylene portion has from one to eight carbon atoms. Typical cycloalkyl substituents have from 3 to 8 ring atoms. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • Halo or "halogen” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl”, are meant to include alkyl in which one or more hydrogen is substituted with halogen atoms which can be the same or different, in a number ranging from one up to the maximum number of halogens permitted e.g. for alkyl, (2m'+l), where m' is the total number of carbon atoms in the alkyl group.
  • haloC ⁇ .galkyl is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m'+l) halogen atoms, where m 1 is the total number of carbon atoms in the alkyl group.
  • perhaloCi.galkyl is meant to include trifluoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.
  • haloalkoxy refers to an alkoxy radical substituted with one or more halogen atoms.
  • Halide refers to the acid or anionic form of a halo group.
  • Heteroaryl refers to a substituted or unsubstituted monocyclic aromatic system having 5 or 6 ring atoms, or a fused ring bicyclic aromatic system having 8 - 20 atoms, in which the ring atoms are C, O, S, SO, SO 2 , or N and at least one of the ring atoms is a heteroatom, i.e., O, S, SO, SO 2 , or N.
  • Heteroaryl groups include, for example, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothio-furanyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl
  • Heterocyclyl refers to a monocyclic or fused ring multicyclic cycloalkyl group at least a portion of which is not aromatic and in which one or more of the carbon atoms in the ring system is replaced by a heteroatom selected from O, S, SO, SO 2 , P, or N.
  • heterocyclyl groups include but are not limited to imidazolinyl, morpholinyl, piperidinyl, piperidin-2-only, piperazinyl, pyrrolidinyl, pyrrolidine-2-onyl, tetrahydrofuranyl, and tetrahydroimidazo [4,5-c] pyridinyl.
  • Heteroalkyl means an alkyl radical as defined herein with one, two or three substituents independently selected from cyano, -OR W , -NR X RY, and -S(O) n R 2 (where n is an integer from 0 to 2 ), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom of the heteroalkyl radical.
  • R w is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- or di-alkylcarbamoyl.
  • R x is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or araalkyl.
  • Ry is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, mono- or di-alkylcarbamoyl or alkylsulfonyl.
  • R z is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, amino, mono- alkylamino, di-alkylamino, or hydroxyalkyl. Representative examples include, for example, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-methoxyethyl, benzyloxymethyl, 2-cyanoethyl, and
  • R w , R x ,RY, and R z can be further substituted by amino, fluorine, alkylamino, di-alkylamino, OH or alkoxy.
  • the prefix indicating the number of carbon atoms refers to the total number of carbon atoms in the portion of the heteroalkyl group exclusive of the cyano, ⁇ OR W , -NR X RY, or - S(O) n R 2 portions.
  • leaving group refers to a moiety that can be replaced by a nucleophile. Examples of leaving groups include but are not limited to halo and sulfonate.
  • Secondary amine refers to an amine having structure of the formula R X 2NH wherein each R x is independently selected from the group consisting of Ci-C 6 alkyl, CpC 6 heteroalkyl, C 3 -C 8 cycloalkyl, heteroalkyl, aryl, heteroaryl, or together two R x groups form a C]-C 6 heteroalkyl moiety.
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like ⁇ see, e.g., Berge, S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19, 1977).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • Substituent refers to an atom or group, including, for example, amino, C]-C 6 alkylamino or di(C r C 6 )alkylamino, Cj-C 6 alkoxy, C]-C 6 alkylthio, aryl, COOH, CONH 2 , cyano, ethenyl, ethynyl, halo, heteroaryl, hydroxy, mono- or di(Ci-C 6 )alkylcarboxamido, mono or di(Ci-C 6 )alkylsulfonamido, nitro, -OSO 2 -R y , and -SO 2 NH 2 .
  • Carboxy or “carboxyl” refers to the group -CO 2 H.
  • Carboxylate refers to the acid or anionic form of the group R 0 CO 2 H wherein R c is Ci-C 6 alkyl, C 2 -C 6 alkenyl, alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, C r C 6 heteroalkyl, heteroaryl or heterocyclyl.
  • Phosphanyl refers to the group -PO(R f ) 3 where R f is hydroxyl or alkoxy.
  • Phosphate refers to the acid or anionic form of a phosphanyl group.
  • Ni refers to -NO 2 .
  • Nirate refers to the acid or anionic form of a nitro group.
  • Sulfonyloxy refers to the group -OSO 2 -R 0 where R° is C r C 6 alkyl, C 2 -C 6 alkenyl, alkynyl, C 3 -Cscycloalkyl, C 3 -C 8 cycloalkenyl, aryl, Ci-Qheteroalkyl, heteroaryl or heterocyclyl.
  • Sulfonate refers to the acid or anionic form of a sulfonyloxy group.
  • Sulfanyl refers to the group -SO 2 R f 2 where R f is hydroxyl or alkoxy.
  • Sulfate refers to the acid or anionic form of a sulfanyl group.
  • administering or "administration of a drug to a patient (and grammatical equivalents of this phrase) refers to direct administration, which may be administration to a patient by a medical professional or may be self-administration, and/or indirect administration, which may be the act of prescribing a drug.
  • direct administration which may be administration to a patient by a medical professional or may be self-administration
  • indirect administration which may be the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • “Pharmaceutically acceptable carrier, excipient, or diluent” refers to a carrier, excipient, or diluent that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier, excipient, or diluent that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier, excipient, or diluent” includes both one and more than one such carrier, excipient, or diluent.
  • Prodrug refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property.
  • a prodrug, relative to the drug is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered.
  • a prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
  • a prodrug may be synthesized using reactants other than the corresponding drug.
  • QnD or qnd refers to drug administration once every n days.
  • QD or qd refers to once every day or once daily dosing
  • Q2D or q2d refers to a dosing once every two days
  • Q7D refers to a dosing once every 7 days or once a week
  • Q5D refers to dosing once every 5 days.
  • Reduction of a symptom or symptoms refers to decreasing the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • Therapeutically effective amount of a drug refers to an amount of a drug that, when administered to a patient with cancer or another hyperproliferative disease, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of cancer or another hyperproliferative disease in the patient.
  • a therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.
  • Treating" or “treatment of” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer or another hyperproliferative disease; diminishment of extent of disease; delay or slowing of disease progression; amelioration, palliation, or stabilization of the disease state; or other beneficial results.
  • the present invention provides HAPs having structures of the formula Hyp-L-M wherein the Hyp moiety is a bioreductive group, L is a releasable linker comprising an ammonium moiety, and M is an antineoplastic agent.
  • the bioreductive group of a HAP compound of the present invention is reduced, the releasable linker undergoes a fragmentation and eliminates a tertiary amine molecule, thereby releasing the antineoplastic agent.
  • a variety of bioreductive groups, releasable linkers, and antineoplastic agents can be combined in the HAPs of the present invention.
  • a variety of combinations of Hyp, L, and M, and the resulting structure of the HAPs of the present invention will be apparent to one of skill in the art upon reading this disclosure.
  • the present invention provides HAPs of tubulin binding aroylindazole compounds, wherein the aroylindazole moiety is covalently bonded to the bioreductive group via a releasable ammonium linker.
  • the bioreductive group and releasable ammonium linkers of the HAPs of the present invention are described in the following subsections.
  • the present invention provides HAPs wherein the Hyp moiety is selected from the group consisting of a nitroaryl, a nitroheteroaryl, an indoloquinonyl, a naphthoquinonyl, an amine oxide, and a disulfide moiety.
  • Hyp moiety is selected from the group consisting of:
  • Ri 5 is selected from hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, and halo and Rn is Ci-C 6 alkyl Ci-C 6 heteroalkyl, C 3 -Cg cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • Rn is Ci-C 6 alkyl Ci-C 6 heteroalkyl, C 3 -Cg cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • substituents include, but are not limited to, groups that as part of the compounds of the present invention enhance aqueous solubility of these compounds.
  • substituents include electron withdrawing groups such as nitro, halo, cyano, haloalkyls, and the like. Certain other suitable substituents include electron donating substituents such as alkoxy, amino, alkylamino, dialkylamino, and the like.
  • Hyp has a structure of the formula:
  • Ri 5 is a terminal C 2 -C 6 alkenyl moiety.
  • the terminal C 2 -C 6 alkenyl moiety has a structure of the formula each of Ri8a-c independently is selected from hydrogen, Ci-C 6 alkyl, and Cj-C 4 alkyl provided that however, at least one of Ri 8a - c is Cj-C 4 alkyl.
  • R 15 is a terminal C 2 -C 6 alkynyl moiety.
  • the terminal C 2 -C 6 alkynyl moiety has a structure of the formula: wherein R 19 is selected from the group consisting of Q-C ⁇ alkyl, aryl, and heteroaryl.
  • Rj 9 is selected from a phenyl and a furanyl moiety wherein the phenyl and furanyl moieties can be suitably substituted. Suitable substituents include, but are not limited to, CpC 6 alkyl and halo.
  • Hyp has a structure of the formula:
  • the Hyp moiety is reduced under hypoxia. In another embodiment, the Hyp moiety is reduced by cytochrome P450 reductase, cytochrome P450, DT diaphorase, nitric oxide synthase, and/or a thiol.
  • the present invention provides HAPs having structures of the formula Hyp-L-N wherein L has a structure of the formula -L 2 -Li- wherein -Li- has a structure of the formula
  • RpR 8 is selected from the group consisting of CpC 6 alkyl, Ci-C 6 heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, or together Ri and R 2 , R 5 and R 6 , and R 7 and R 8 form a C 3 -C 8 cycloalkyl or a heterocyclyl group, or together R 3 and R 4 form a heterocyclyl group and each of R a -R d is selected independently from the group consisting of hydrogen, halo, nitro, CO 2 H, Ci-C 6 alkyl, and C r C 6 alkoxy.
  • each R 1 , R 2 , R 5 , and R 6 is hydrogen.
  • each R 3 and R 4 is alkyl.
  • each R 3 and R 4 is methyl.
  • Li has a structure of the formula -CH 2 -NMe 2 CH 2 -.
  • the present invention provides HAPs having structure of the formula (I) wherein L has the structure of the formula:
  • L has a structure of the formula -CH 2 -NMe 2 CH 2 -.
  • Anions suitable for the HAPs of the present invention include any pharmaceutically acceptable anion including but not limited to carboxylates, halides, phosphates, nitrate, sulphonates, and sulphates.
  • the HAPs of the present invention are more water soluble than the corresponding antineoplastic agents due in part to the presence of the Li moiety containing an ammonium group.
  • antineoplastic agents including, but not limited to, taxanes and analogs and epothilone and analogs, are lipophilic, sparingly soluble in water, and difficult to formulate for human administration
  • the enhanced water solutbility of the HAPs of the present invention including these antineoplastic agents provide an advantage in administering these HAPs compared to the corresponding antineoplastic agents.
  • the present invention provides HAPs having structure of the formula Hyp-L-N wherein the releasable linker, L, comprises a heteroaryl ammonium moiety.
  • the heteroaryl ammonium moiety has a structure of the formula:
  • each Yj - Y 3 is independently selected from N and CR X wherein each R x is independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C 3 -
  • antineoplastic agent M moieties are useful in the HAPs of the present invention.
  • the M moiety is covalently bonded to the releasable linker L via a nitrogen, oxygen, sulfur, and/or a carbon atom of the M moiety.
  • Antineoplastic agents useful in the HAPs of the present invention in accordance with the present teachings are described, for example, in Physicians' Desk Reference, 2003, 57th Ed., Medical Economics Company, Inc., Oradell, N.J; Goodman & Gilman's The Pharmacological Basis of Therapeutics" 2001, 10th Edition, McGraw-Hill, New York.
  • the present invention provides HAPs wherein the antineoplastic agent M is selected from antineoplastic agents containing one or more NH, amino, C)-C 6 alkylamino, di(Ci-C 6 )alkylamino, mercapto, hydroxyl, and phenoxy moieties.
  • M is selected from campthothecin, Taxol® (paclitaxel, Bristol Meyer Squibs) and other taxanes, epothilone and its analogs, and etoposide and its analogs.
  • the analogs are clinically useful analogs.
  • M is selected from antiandrogens and their analogs.
  • Suitable antiandrogens include flutamide, nilutamide, and bicalutamide.
  • Other suitable antineoplastic agents useful in HAPs of the present invention are described in U.S. Pat. Pub. No. 2006/0258656 (incorporated herein by reference).
  • the present invention provides HAPs of antineoplastic agents that are tubulin binding, and/or microtubule inhibiting agents, and/or vascular disrupting agents, as described below.
  • the antineoplastic agent M is a tubulin binding aroylindazole compound.
  • the tubulin binding aroylindazole compound has a structure of the formula:
  • R 9 is selected from the group consisting of hydrogen; halo, hydroxy, nitro, cyano, amino, C r C 6 alkylamino, di Ci-C 6 alkylamino, Ci-C 6 alkoxy, Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • R 9 is selected from the group consisting of: H, halo, amino, CO 2 H, cyano, nitro, C-C 6 alkyl,
  • each Rio is independently selected from the group consisting of hydrogen, Cj-C 6 alkyl, Ci-C 6 heteroalkyl, C 3 -Cg cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • Rio has a structure of the formula -(CH 2 ) n -Rn wherein n is 1-4 and Rn is selected from the group consisting of hydroxy, acyloxy, amino, acylamino, and OMe.
  • R 9 is selected from the group consisting of:
  • R 9 is propynyl.
  • the antineoplastic agent M is a tubulin binding aroylindazole compound described in claim 6, pages 129-30, PCT Pat. Pub. No. WO 06/057946.
  • the antineoplastic agent is a camptothecin analog having a structure of the formula:
  • each of Ri 2a - d is selected from the group consisting of hydrogen, fluoro, hydroxy, nitro, amino, Q-Qalkoxy, Ci-C 6 alkylamino, and di (Ci-C 6 )alkylamino, or together any two of R 12a-d that are adjacent to each other form a methylenedioxy moiety
  • the heterocyclic group is selected from piperazine and (Ci-C 6 ) alkylpiperazine.
  • each of Ri 2c and Ri 2d is hydrogen.
  • R ]2b is hydroxyl.
  • Ri 2a is di (C 1 - C 6 ) alkylamino.
  • R] 2a is dimethylaminomethyl.
  • the camptothecin analog has a structure of the formula selected from:
  • the camptothecin analog is irinotecan.
  • the antineplastic agent is a taxane or analog having a structure of the formula selected from:
  • the antineplastic agent is a combretastatin analog.
  • the combretastatin analog is combretastatin A-4 or one of its analogs.
  • the combretastatin analog has a structure of the formula:
  • the antineoplastic agents are selected from epothilone analogs.
  • Epothilone analogs are described for example in Nicolaou et al., Angew Chem. Int Ed., 1998, 37: 2014-45; Waltman et al., Curr. Pharm. Design, 2005, 11: 1595-613; and Watkins et al., Curr. Pharm. Design, 2005, 1 1: 1615-53.
  • a suitable epothilone analog useful in the HAPs of the present invention include, but is not limited to, epothilone-B.
  • the HAPs of epothilone analogs are compounds wherein the Hyp-L- moiety is attached to a nitrogen atom in a heterocycle moiety present in the epothilone analogs.
  • Suitable heterocycle moieties include, but are not limited to, pyridines, benzthiazoles, benzoxazoles, and quinalines ⁇ see Watkins et al. supra).
  • a HAP of epothilone-B has a Hyp-CRiR 2 - moiety covalently bonded to a thiazole ring in epothilone-B.
  • the present invention provides a HAP having a structure of the formula:
  • Rio is selected from the group consisting of hydrogen, CpC 6 alkyl, CpC 6 heteroalkyl, C ⁇ -Cs cycloalkyl, heterocyclyl, aryl, and heteroaryl; each of R 3 and R 4 is selected from alkyl; and Hyp is selected from the group consisting of:
  • R 15 is selected from the group consisting of hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, and halo.
  • R1 5 is selected from the group consisting of hydrogen, phenyl and bromo.
  • Ri 0 is methyl.
  • each of R 3 and R 4 is methyl.
  • Hyp has a structure of the formula:
  • Ri 5 is defined as in any embodiment above.
  • the present invention provides HAPs having a structure of the formulas:
  • R 12a , Ri 2 b, and R i3 and each of R 3 , R 4 , and Hyp is defined as in any embodiment above or are defined as in formula (IA).
  • HAPs of the present invention including a tubulin binding antineoplastic agent are shown below:
  • HAPs of the present invention including a camptothecin antineoplastic agent are shown below:
  • the L moiety having a structure of the formula -CH 2 -N(Me 2 )-CH 2 -, in the examples of the HAPs shown above, is positively charged, these HAPs exemplified above, and similar compounds described elsewhere in this disclosure, are associated with an anion.
  • the compounds of the present invention are salts.
  • Other anions, which may not be shown which are suitable for the HAPs of the present invention include any pharmaceutically acceptable anion including, but not limited to, carboxylates, halides, phosphates, nitrate, sulfonates, and sulfates.
  • compound 23 contains a bromide anion and compound 36, a compound having the same Hyp, L, and M moieties as in compound 23, contains a carboxylate anion, e.g. lactate.
  • the present invention provides HAPs that under normoxic conditions are 5-10,000, 10-1,000, 20-500, and 50-100 times less cytotoxic than the corresponding antineoplastic agents.
  • HAPs that under normoxic conditions are 5-10,000, 10-1,000, 20-500, and 50-100 times less cytotoxic than the corresponding antineoplastic agents.
  • a bioreductive group of a HAP compound of the present invention is reduced under hypoxia, the releasable linker fragments and the cytotoxic antineoplastic agent is released. Because tumors contain regions of hypoxia, a HAP compound of the present invention is more cytotoxic to hypoxic tumors compared to normal tissue residing in normoxic conditions, and demonstrate tumor selective cytotoxicity.
  • the HAPs of the present invention are 5-10,000, 10-1,000, 10-50 times 20-500, and 50-100 times more cyctoxic under hypoxia than under normoxia.
  • HAPS of the present invention that are 10-50 fold or more cyctoxic under hypoxia than under normoxia include but are not limited to compounds 1, 3, 13, 15, 23, 25, 26, 28, 30 and 36.
  • releasable linker, L useful in the HAPs of the present invention can also be employed in other prodrugs of antineoplastic agents as described below.
  • the present invention provides prodrugs having structure of the formula Q-L-M wherein M is an antineoplastic agent, L is a releasable linker, and Q is an activating group that upon activation, by a reaction other than a reduction reaction, leads to a fragmentation of the releasable linker and release of the antineoplastic agent.
  • the Q moiety is an aliphatic or and aromatic ester, or a phenolic carbamate and the activation occurs upon hydrolysis of the ester.
  • the hydrolysis can be catalyzed by an esterase or a carbamase.
  • the Q moiety is a carbohydrate moiety and the activation occurs upon hydrolysis.
  • the hydrolysis can be catalyzed by a glycosidase.
  • the carbohydrate moiety is a monosaccharide, including, but not limited to, glucose and glucuronic acid.
  • the present invention also provides methods of synthesizing the HAPs and the other compounds of the present invention as described below:
  • the present invention provides a method of synthesizing a HAP compound of the present invention having structure of the formula Hyp-L-M wherein the Hyp moiety is a bioreductive group; L has a structure of the formula
  • -L]- has a structure of the formula -CRiR 2 -N(R 3 R-O-CR 5 R 6 - and -L 2 - is selected from a bond and a moiety having a structure of the formula:
  • each of Ri-R 8 and R a -R d is defined as in any embodiment above and M is an antineoplastic agent, said method comprising the steps of:
  • Zf + N(R 3 R 4 ) CR 5 R 6 ; and a base, wherein Z 1 " is an anion selected from the group consisting of halide and sulfonate to obtain a compound having a structure of the formula M-CR 5 R O - N(R 3 R 4 ) and
  • step (ii) reacting the compound obtained in step (i) with a compound having the formula:
  • the reacting in step (ii) is performed using Z 2 -CR) R 2 -Hyp.
  • Z 2 is selected from the group consisting of chloro, bromo, and iodo.
  • -CRiR 2 - is -CH 2 -.
  • Z 2 is a substitutued or unsusbstituted 2-nitroimidazole moiety.
  • Z 2 -CR[R 2 -Hyp has a structure of the formula: wherein Z 2 is selected from the group consisting of bromo and chloro.
  • the present invention provides a method of synthesizing a HAP compound of the present invention having structure of the formula Hyp-L-M comprising the steps of:
  • step (i) reacting an antineoplastic agent, a secondary amine, and formaldehyde to yield a compound of step (i) as described above, and
  • step (ii) reacting the compound obtained in step (i) and a compound having the formula:
  • the antineoplastic agent is an aroylindazole compound; and the secondary amine is selected from the group consisting of dimethylamine, diethylamine, piperidine, and pyrrolidine.
  • the present invention provides a method of making a compound having a structure of the formula: Hyp-L-M; comprising the steps of reacting an antineoplastic agent derivative having a structure of the formula:
  • Z 2 is a leaving group; with a compound having a structure of the formula selected from the group consisting of Hyp-CR]R 2 -N(R 3 R 4 ) and
  • Z 2 is a halo group.
  • -CR 5 R 6 -Z 2 is -CH 2 Cl or -CH 2 Br.
  • 20-chloromethyl campthothecin and analogs, 1-chloromethyl aroylindazole antineoplastic agents, and various other chloromethylated antineoplastic agents can be employed according to the present methods in the compounds of the present invention.
  • Various chloromethyl ethers of hydroxyl groups can be conveniently synthesized via a methylthiomethyl ether by reacting the methylthiomethyl ether with a halogen molecule.
  • a suitable, nonlimiting, halogen molecule is bromine.
  • the methylthiomethyl ethers can be synthesized following a reaction of an antineoplastic agent containing the hydroxyl group, dimethyl sulfoxide, and a carboxylic acid anhydride.
  • Suitable carboxylic acid anhydrides include, but are not limited to, acetic anhydride and trifluoromethyl acetic anhydride.
  • the present invention provides a method of synthesizing a compound having a structure of the formula:
  • R 15 has a structure of the formula -CH(Ri 8a )Me wherein Ris a is selected from hydrogen and C 2 -C 5 alkyl, and R ]7 is selected from Ci-C 6 alkyl, Cj-C 6 heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, said method comprising the steps of:
  • step (ii) reacting the compound yielded in step (i) with a compound having a structure of the formula:
  • step (iii) reacting the compound yielded in step (ii) with potassium diazodicarboxylate and an acid to yield the compound having the structure of the formula:
  • the bioreductive group, Hyp has a structure of the formula selected from the group consisting of: wherein Ri 5 and Ri 7 is defined as in any one of the embodiments above.
  • Hyp has structure of the formula selected from the group consisting of:
  • R 1S is defined as in any embodiment above.
  • Suitable R 15 moieties useful in the present methods include, but are not limited to, those described in the Examples section below.
  • Hyp-CH 2 0H intermediates such as Compounds i-vii can also be converted to the corresponding Hyp-CH 2 Br or Hyp-CH 2 C1 compounds by a variety of routine synthetic procedures known to one of skill in the art.
  • the Hyp-CH 2 OH compounds can be reacted with PPh 3 and Br 2 or CBr 4 in a suitable solvent to yield Hyp-CH 2 Br compounds.
  • Example IA-F The synthesis of various Hy ⁇ -CH 2 OH and other intermediates useful in the present methods are described in Example IA-F below.
  • the present invention provides novel Hyp-CH 2 OH intermediates.
  • prodrugs of the present invention having structure of the formula Q-L-M, that are activated by reactions other than reduction reactions, can be synthesized employing the methods useful for synthesizing HAPs of the present invention and suitably substituting the bioreductive group, Hyp, with a suitably substituted Q moiety.
  • prodrug compounds of the present invention including other HAPs can be synthesized following synthetic methods described in literature and/or upon reading this disclosure and upon suitable substitution of reactants. Syntheses of HAPs of the present invention employing the methods of the present invention are described in the EXAMPLES Section below.
  • the present invention provides methods of treating cancer and other hyperproliferative diseases comprising administering a therapeutically effective amount of a prodrug compound of the present invention to a patient in need of such treatment.
  • the prodrug compound is a HAP of the present invention.
  • the HAP has a structure of the formula Hyp-L-N, wherein N is an antineoplastic agent having a structure of the formula (I), (IA), (II), (IIIA), (HIB) as shown above, and Hyp and L are defined as in any embodiments above.
  • the therapeutically effective amount is administered as a pharmaceutically acceptable formulation comprising a HAP compound of the present invention and one or more pharmaceutically acceptable diluents or excipients.
  • the therapeutically effective amount is administered in a daily dose.
  • the therapeutically effective daily dose can be administered by employing suitable unit dose forms of the HAPs of the present invention.
  • the daily dose is administered from once every day, once every two weeks, up to, once every month.
  • the daily dose is administered parenterally or orally.
  • Examples of administering compounds of the formula (I) and (IA) in accordance with the present methods for treating lung and colon cancer is described, for example, in Examples 6A-D below.
  • Treatment methods including administration of compounds of the formula (I) and (IA) in accordance with the present methods for treating diseases that result from, and/or cause, angiogenesis and/or neovasculature is described, for example, in Example 6E below.
  • a compound having a structure of the formula (II), 33 was administered to HT29 tumor bearing mice alone and in combination with 5-FU.
  • the monotherapy and the combination therapy demonstrated tumor regression in comparison with vehicle administration. Dosing once daily was toxic under the conditions tested. Less frequent dosing, twice weekly, was better tolerated.
  • cancers can be treated according to the methods of the present invention by administering the HAPs the present invention.
  • the cancer treated is selected from the group consisting of cancer of the adrenal gland, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidneys, larynx, liver, lung, neural tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid.
  • the cancer treated is selected from the group consisting of acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and in situ carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant cell tumor, glioblastoma multiforma, hairy-cell tumor, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemias, lymphomas, malignant carcinoid, malignant melanomas, malignant hypercalcemia, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteo sarcoma, osteogenic and other sarcoma, ovarian tumor, pheochromocytoma, polycythemia ver
  • the HAP compound of the present invention is administered for the treatment of cancer in combination with other anticancer agents or other anticancer therapies.
  • Suitable anticancer therapies useful in accordance with the present methods include radiation therapy and surgery.
  • Methods for treating cancer employing other hypoxia activated prodrugs are described, for example, in PCT Pat. Appl. No. US06/025881; PCT Pat. Pub. Nos. WO 06/57946 and WO 04/87075; WO 07/002931; and WO 07/137196, incorporated herein by reference, and can be used for the treatment of cancer according to the present methods upon appropriate substitution of those other hypoxia activated produgs with the HAPs of the present invention.
  • the present invention provides methods of treating non- cancer hyperproliferative diseases characterized by cellular hyperproliferation (e.g., an abnormally increased rate or amount of cellular proliferation) in accordance with the present methods.
  • the hyperproliferative disease is selected from the group consisting of allergic angiitis and granulomatosis (Churg-Strauss disease), asbestosis, asthma, atrophic gastritis, benign prostatic hyperplasia, bullous pemphigoid, coeliac disease, chronic bronchitis and chronic obstructive airway disease, chronic sinusitis, Crohn's disease, demyelinating neuropathies, dermatomyositis, eczema including atopic dermatitis, eustachean tube diseases, giant cell arteritis, graft rejection, hypersensitivity pneumonitis, hypersensitivity vasculitis (Henoch-Schonlein purpura), irritant dermatitis,
  • the hyperproliferative disease treated is psoriasis, a disease characterized by the cellular hyperproliferation of keratinocytes which builds up on the skin to form elevated, scaly lesions.
  • the hyperproliferative disease treated is multiple sclerosis, a disease characterized by progressive demyelination in the brain.
  • the hyperproliferative disease treated is rheumatoid arthritis, a multisystem chronic, relapsing, inflammatory disease that can lead to destruction and ankylosis of joints affected.
  • a HAP compound of the present invention is administered to prevent a hyperproliferative disease resulting from cellular proliferation on a prosthesis implanted in a patient by coating the prosthesis with a composition containing a HAP compound of the present invention.
  • the hyperproliferative disease treated is benign prostatic hyperplasia, a disease in which prostate epithelial cells grow abnormally and thereby block urine flow.
  • the present invention provides methods of treating a variety of cancer and other hyperproliferative diseases by disrupting existing vasculature and/or neovasculature.
  • existing vasculature and/or neovasculature are useful for transporting nutrients and oxygen to the diseased tissue.
  • Compounds of the present invention can disrupt and/or shut down such vasculature (see, for example Example 6E), and disrupt the flow of nutrients to the diseased tissue and inhibit the growth of, and/or kill, such tissue.
  • the compounds of the present invention also disrupt oxygen transport into such diseased tissue and make the tissue increasingly hypoxic and increasing susceptible to certain HAP compounds of the present invention.
  • inflammatory diseases and diseases that cause and/or result from angiogenesis are treatable by administering the compounds of the present invention in accordance with the present methods.
  • R 15 is selected from the group consisting of bromo, Ci-C 6 alkyl, CpC 6 alkenyl, substituted or unsubstituted phenyl; that are useful in the synthesis of compounds of the present invention.
  • Ri 5 is an aryl or a heteroaryl moiety
  • Ri 5 is an aryl or a heteroaryl moiety
  • Hyp-CH 2 OH compounds wherein R1 5 is selected from the group consisting of 4-fluorophenyl, 2-pyridyl, and 2-fluoro-5-methoxyphenyl were synthesized starting from compound ii and following this method.
  • Example 1C
  • Hyp- CH 2 OH compound having a structure of the formula:
  • Hyp-CH 2 OH intermediates wherein R 15 is a terminal alkenyl moiety can be synthesized according to the foregoing method.
  • Compound iv was also synthesized according to this method and employing:
  • a Hyp-CH 2 OH compound was converted to the corresponding Hyp-CH 2 Br compound by reacting with thionyl bromide.
  • Compound v 162 mg was added to thionyl bromide (SOBr 2 , 1 mL) and stirred at room temperature (15 min). Then, the mixture was quenched with ice and extracted with ethyl acetate (EtOAc). Next, the organic layer was washed with water and brine, dried, concentrated, and the residue separated by column chromatography on silica gel using EtOAc/Hexanes (0-100%) to yield the compound vi (67 mg), as a yellow syrup.
  • Example 2 [0152] This Example describes in parts A-C below the synthesis of compounds of the present invention in accordance with the methods described in Section II above.
  • Example 2A describes the synthesis of Compound 1 according to Method 1 described in Section II above.
  • Compounds of the present invention including but not limited to Compounds 2-9, 13, 15, 23, 25, 27, and 30 were synthesized following the method described in Example 2 upon appropriate substitution of 5-bromomethyl-2-nitrofuran with other halomethylated bioreductive groups, such as, bromomethylated and chloromethylated 2-nitroimidazole groups.
  • the bromomethylated compound vi was reacted with antineoplastic compound A (100 mg) according to the method described in Example 2A to yield, Compound 23 (62 mg) after separation by column chromatography using MeOH/DCM (0- 10%).
  • This Example describes the synthesis of Compound 12 using a secondary amine and aqueous formaldehyde, instead of using an Eschenmoser salt like reagent according to Method 2 described in Section II above.
  • antineoplastic agent A 140 mg
  • K 2 CO 3 112 mg
  • DCM 5 mL
  • diethylamine 12 ⁇ L
  • aqueous formaldehyde 37%, 33 ⁇ L
  • Analysis of the reaction mixture by 1 H-NMR demonstrated the formation of a diethylaminomethyl intermediate as described above, of the antineoplastic agent A.
  • reaction mixture was filtered, the residue washed with dry toluene (10 mL) and the filtrate evaporated in vacuo to yield a residue to which was added MeCN (4 mL) and 5-bromomethyl-2-nitrofuran (86 mg) and heated at 5O 0 C for 2h. The reaction mixture was cooled down to room temperature and the residue collected by filtration to yield compound 12.
  • This example describes the synthesis of compound 36 by reacting compound 23,that contains a bromide anion, with silver lactate. After the reaction, silver bromide precipitates out and compound 36 containing a lactate anion is isolated in the filtrate after filtration.
  • a solution of compound 23 (40 mg) in MeOH/MeCN (1: 1, 2 mL) was added a solution of silver lactate (11.5 mg) in water (1 mL) and stirred vigorously for 3 days. The reaction mixture was filtered through a celite pad and the filtrate concentrated to yield compound 36 (35 mg) that was characterized by 1 H-NMR.
  • Compound 23 was transformed into its citrate salt by using silver citrate and following this method.
  • H460 10,000 - 15,000 cells/well/500 ⁇ L, ATCC HTB-177) and HT 29 cells (20,000 - 30,000 cells/well/500 ⁇ L, ATCC HTB-38) were seeded in glass inserts on 24- well plates in RPMI1640 medium supplemented with 10% FBS and 1% Penicillin/Streptomycin (Invitrogen Corporation, Carlsbad, CA).
  • control group no test compound
  • treatment groups in which the cells were kept in contact with the test compound at various concentrations for 2 h.
  • the fluorescence intensities determined were background corrected by subtracting FO, and normalized by dividing with F 1 -F 0 .
  • the background corrected and normalized fluorescence intensities of the control group after 3 days of incubation, and the various treatment groups after 3 days of incubation, were plotted against the corresponding concentrations of the test compound.
  • the IC 50 value for the test compound i.e., the concentration of the test compound that killed, or made unviable, 50% of the cells, was calculated based on a best-fit plot using an F test (GraphPad Prism4 software, San Diego, CA).
  • HAPs of the present invention were also demonstrated in other cell lines following the methods described for H460 cells.
  • Certain compounds, under the conditions tested and in an H460 cell line, may not show enhanced cytotoxicity under hypoxia than under normoxia, but can be more cytotoxic under hypoxia than under normoxia when different test conditions and/or cell lines are used.
  • Such different test conditions and cell lines useful for these purposes are known to one of skill in the art and described elsewhere in this disclosure and, for example, in PCT Pat. App. Pub. No. WO 07/002931.
  • HAP compounds of the present invention were demonstrated in a parental, sensitive cell lines, H69, MESSA, and HEK293/pcDNA and the corresponding resistant cell lines, H69AR that over expresses multi-drug resistance-associated protein (MRP), MDRi that over expresses MDR-I efflux pump, and HEK293/pcDNA/BCRP that over expresses the BCRP efflux pump.
  • MRP multi-drug resistance-associated protein
  • MDRi multi-drug resistance-associated protein
  • HEK293/pcDNA/BCRP that over expresses the BCRP efflux pump.
  • HAPs of the present invention were equally cytotoxic to the parental, sensitive cell lines and the resistant cell lines, demonstrating that these compounds were not susceptible to the various resistance mechanisms that protect cancer cells and were useful in cancer therapy.
  • HAP compounds of the present invention were demonstrated by incubating these compounds with mouse plasma and in mouse liver microsome (MLM).
  • MLM mouse liver microsome
  • the pharmacokinetics of the compounds of the present invention were demonstrated by injecting these compounds in mice intraperitoneally (i.p.) and intravenously (Lv.). The results are tabulated below.
  • This Example describes in parts A-F below the formulation, administration, and efficacy of compounds of the present invention in the treatment of cancer and other hyperproliferative diseases in accordance with the present invention.
  • This example describes a formulation of Compound 1 and the in vivo administration of that formulation for treating cancer.
  • Compound 1 was formulated in the vehicle employed in this experiment, 5% DMSO, 5% Tween/80-D5W.
  • the formulation of compound 1 was administered parenterally, by intraperitoneal (i.p.) administration, alone and in combination with CPT-11, to colorectal, HT 29, xenograft tumor bearing nude mice.
  • Compound 1 was administered, for 2 weeks, at doses of 7.5mg/Kg,daily for 8 days, followed by 10 and 15 mg/kg, daily for 2 days each.
  • CPT-11 was administered i.p., once a week, for 2 weeks, at a dose of 50 mg/kg, and was given 24 hours earlier if combination therapy is scheduled.
  • This example describes a formulation of Compound 3 and the in vivo administration of that formulation for treating cancer.
  • Compound 3 was formulated in the vehicle employed in this experiment, 5%DMSO5%Tw80 in D5W, and administered to H460 xenograft tumor bearing mice at 10 mg/kg, i.p., Q2D x 6, alone and in combination with Gemcitabine at 60 mg/kg, i.p., Q3Dx4.
  • Administration of Compound 3 alone reduced tumor growth in tumor bearing mice compared to administration of the vehicle.
  • This example demonstrated the efficacy of Compound 15, a HAP of the present invention, to treat xenografted HT29 colon carcinoma in nude mice, by administering Compound 15 as a monotherapy, i.e. as a single agent, and in combination with irinotecan (CPT-11).
  • Compound 15 was formulated (1.5 mg/mL and 1.0 mg/mL) in 5% DMSO/5%Tween80 in WFI (vehicle).
  • CPT-11 was formulated in 2%Tween80-saline. The drug formulations were diluted and filtered though a 0.2 ⁇ m filter and administered to animals within about an hour's preparation.
  • HT29 cells (5 x 10 6 ) were implanted subcutaneously on the right flank of the mice. Tumor lumps were measurable on the seventh day post-implantation and were about 150 mm 3 on the fifteenth day. Mice with similar tumor size were randomized for treatment and treated as follows: Compound 15 was administered intraperitoneally (i.p.), every other day for total 6 doses (q2Dx6), at dosages of 15 and 10 mg/kg, alone and in combination with
  • CPT-11 (i.p., 50 mg/kg, q7Dx3); totally 4 groups of 10 mice each were thus treated. A group of 10 tumor bearing mice were used as no-treatment control.
  • the tumor growth delays were between 8 and 9 days for mice undergoing monotherapy with Compound 15 at the two regimens administered ( Figure 1).
  • the TGDs were 14 days for the "10 mg/kg” group and 19 days for the "15 mg/kg group.”
  • Tumor growth was about 56% and 59% inhibited by administering Compound 15 alone at 15 mg/kg and 10 mg/kg respectively, and about 86% and 74% inhibited by administering Compound 15 at 15 mg/kg and 10 mg/kg respectively in combination with CPT-11.
  • the body weight changes of Compound 15 treated groups are presented in ( Figure 2). The treatment groups lost body weight loss but the lost body weights were recovered when the treatment was stopped demonstrating the safety of the administration of Compound 15.
  • This example demonstrated the efficacy of 23 and 36, compounds of the present invention, to treat xenografted HT29 colon carcinoma in nude mice, by administering them as monotherapy, i.e. as a single agents, and in combination with irinotecan (CPT-11).
  • Compound 36 is a HAP having the same structure as that of 23 and having lactate as a counter anion.
  • Compounds 23 and 36 were administered to HT29 xenograft tumor bearing mouse, alone and in combination with CPT-11, in substantial accordance with the method described in Example 7B as modified below.
  • the HAPs were formulated in 5% DMSO/ 2%Tween80-D5W, and CPT-11, in 2%Tween80-saline.
  • the HAPs were administered at 15 mg/kg 6 times over a period of 2 weeks at a frequency of q2d, 3 times a week, in an administration cycle wherein every sixth and seventh days in a cycle were drug-free holidays.
  • the 3rd-6th administrations employed 20 mg/kg, instead of 15 mg/kg of the drug.
  • CPT-11 was administered once every week for 3 weeks.
  • Various administration parameters were as tabulated below. The effect of drug administration on tumor growth was demonstrated by comparison with vehicle administration.
  • Mouse doses can be converted to human equivalent doses by dividing the mouse dose by -12.
  • a compound of the present invention having a structure of the formula (IA) can be administered in a therapeutically effective amount in a range of about 0.05 mg/kg - about 40 mg/kg for treating cancer in a human patient.
  • the cancer treated is a solid tumor.
  • the cancer treated is selected from lung cancer and colon cancer.
  • VDA Vascular disrupting agents
  • disrupting vasculature refers to shrinking the diameter of vasculature and/or impeding the flow of blood through the vasculature.
  • a disruption of the function of tumor vasculature leads to lowered delivery of oxygen and nutrients to cancer and other hyperproliferative diseases.
  • Compound 36 is a HAP of the antineoplastic agent, Aroylindazole A (see, example 2A), which is a VDA and microtubule inhibitor.
  • HT29 cells (3x10 6 ) were subcutaneously implanted into the mice.
  • mice were treated with Vehicle, CPT-11 alone (50mg/Kg, Q7D x3, ip), compound 36 alone (Mono, 15 mg/Kg, Q2Dx3/wk x 2wks), and combination of the two compounds (Combo).
  • time course and dose response experiments were performed.
  • Combretastatin A-4 phosphate (CA4P) a VDA, served as a positive control.
  • TGIs tumor growth inhibitions
  • Tumor vessel perfusion status was demonstrated by Hoechst 33342 staining. Untreated tumor samples were well perfused throughout the tumor area in both time course and dose response studies. 1 hour after treatment with compound 36, vessels were shut down to much greater extent compared to the partial of vessel closure observed after 24 hours. In dose response study, 5mg/Kg and 1.5mg/Kg of compound 36 induced partial shut down or collapse of the vessels.
  • This example demonstrates compound 36' s efficacy to kill hypoxic tumor cells.
  • the HT29 cells are prepared in 50% matrigel in PREVI medium. 3 x 10 6 cells are implanted in the subcutaneous space of the right flank in 100 mice (0.2ml/mouse). Mice bearing similar tumor sizes, preferably 300-500 mm 3 , are selected.
  • Compound 36 is formulated appropriately as disclosed in Example 6 herein and a single dose is administrated intraperitoneally at 1.5 -15mg/Kg.

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Abstract

La présente invention concerne des promédicaments d'agents antinéoplasiques activés par l'hypoxie et utilisables en vue du traitement des cancers et d'autres maladies hyperprolifératives.
PCT/US2008/065812 2007-06-04 2008-06-04 Promédicaments d'agents antinéoplasiques activés par l'hypoxie WO2008151253A1 (fr)

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WO2010048330A1 (fr) 2008-10-21 2010-04-29 Threshold Pharmaceuticals, Inc. Traitement du cancer à l’aide de promédicaments activés par l’hypoxie
WO2010104406A1 (fr) * 2009-03-11 2010-09-16 Auckland Uniservices Limited Formes promédicaments d'inhibiteurs de kinase et leur utilisation en thérapie
WO2011088448A1 (fr) * 2010-01-18 2011-07-21 Firestone Industrial Products Company, Llc Ressorts pneumatiques au fonctionnement amélioré aux hautes températures
JP2013503859A (ja) * 2009-09-02 2013-02-04 オークランド ユニサーヴィスィズ リミテッド キナーゼインヒビター、そのプロドラッグ型および治療におけるそれらの使用
WO2016161342A2 (fr) 2015-04-02 2016-10-06 Threshold Pharmaceuticals, Inc. Dérivés de nitrobenzyle d'agents anticancéreux
WO2016210175A1 (fr) * 2015-06-24 2016-12-29 Threshold Pharmaceuticals, Inc. Agents d'alkylation d'adn contenant de l'aziridine
US10131683B2 (en) 2014-07-17 2018-11-20 Molecular Templates, Inc. TH-302 solid forms and methods related thereto
US10364261B2 (en) 2015-03-10 2019-07-30 Obi Pharma, Inc. DNA alkylating agents
US10409869B2 (en) 2012-10-29 2019-09-10 Obi Pharma, Inc. (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N'-bis (ethylene)phosphoramidate, compositions and methods for their use and preparation
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2023025312A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Patient résistant aux inhibiteurs de parp traités avec th-302
WO2023025291A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Solution de formulation lyophilisée, formulation lyophilisée, procédé et utilisation associés
WO2023174319A1 (fr) 2022-03-15 2023-09-21 深圳艾欣达伟医药科技有限公司 Méthode de traitement d'un patient atteint d'un cancer à mutation de brca
WO2023198188A1 (fr) 2022-04-15 2023-10-19 深圳艾欣达伟医药科技有限公司 Méthode de traitement du cancer faisant appel à th-302 seul ou en association avec un inhibiteur de parp
WO2023226959A1 (fr) 2022-05-23 2023-11-30 深圳艾欣达伟医药科技有限公司 Méthode de traitement du cancer par combinaison d'un promédicament d'agent alkylant et d'un inhibiteur de cycle cellulaire
WO2024061346A1 (fr) 2022-09-22 2024-03-28 深圳艾欣达伟医药科技有限公司 Utilisation d'un composé activé par hypoxie dans la préparation d'un médicament pour le traitement d'un patient atteint d'un cancer

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WO2010048330A1 (fr) 2008-10-21 2010-04-29 Threshold Pharmaceuticals, Inc. Traitement du cancer à l’aide de promédicaments activés par l’hypoxie
US9073916B2 (en) 2009-03-11 2015-07-07 Auckland Uniservices Limited Prodrug forms of kinase inhibitors and their use in therapy
CN102348708A (zh) * 2009-03-11 2012-02-08 奥克兰联合服务有限公司 激酶抑制剂的前药形式及其在治疗中的用途
JP2012520295A (ja) * 2009-03-11 2012-09-06 オークランド ユニサーヴィスィズ リミテッド プロドラッグ形態のキナーゼインヒビターおよび治療におけるそれらの使用
CN105541836A (zh) * 2009-03-11 2016-05-04 奥克兰联合服务有限公司 激酶抑制剂的前药形式及其在治疗中的用途
EP3031807A1 (fr) 2009-03-11 2016-06-15 Auckland UniServices Limited Formes promédicaments d'inhibiteurs de kinase et leur utilisation en thérapie
WO2010104406A1 (fr) * 2009-03-11 2010-09-16 Auckland Uniservices Limited Formes promédicaments d'inhibiteurs de kinase et leur utilisation en thérapie
JP2013503859A (ja) * 2009-09-02 2013-02-04 オークランド ユニサーヴィスィズ リミテッド キナーゼインヒビター、そのプロドラッグ型および治療におけるそれらの使用
US9101632B2 (en) 2009-09-02 2015-08-11 Auckland Uniservices Limited Kinase inhibitors, prodrug forms thereof and their use in therapy
JP2016094432A (ja) * 2009-09-02 2016-05-26 オークランド ユニサーヴィスィズ リミテッド キナーゼインヒビター、そのプロドラッグ型および治療におけるそれらの使用
WO2011088448A1 (fr) * 2010-01-18 2011-07-21 Firestone Industrial Products Company, Llc Ressorts pneumatiques au fonctionnement amélioré aux hautes températures
US10409869B2 (en) 2012-10-29 2019-09-10 Obi Pharma, Inc. (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N'-bis (ethylene)phosphoramidate, compositions and methods for their use and preparation
US10131683B2 (en) 2014-07-17 2018-11-20 Molecular Templates, Inc. TH-302 solid forms and methods related thereto
US10654876B2 (en) 2014-07-17 2020-05-19 Molecular Templates, Inc. TH-302 solid forms and methods related thereto
US10364261B2 (en) 2015-03-10 2019-07-30 Obi Pharma, Inc. DNA alkylating agents
US10766914B2 (en) 2015-03-10 2020-09-08 Obi Pharma, Inc. DNA alkylating agents
US10829437B2 (en) 2015-04-02 2020-11-10 Obi Pharma, Inc. Nitrobenzyl derivatives of anti-cancer agents
US11535585B2 (en) 2015-04-02 2022-12-27 Obi Pharma, Inc. Nitrobenzyl derivatives of anti-cancer agents
JP2018511612A (ja) * 2015-04-02 2018-04-26 アセンタ ファーマシューティカルズ リミテッド 抗がん剤のニトロベンジル誘導体
TWI730957B (zh) * 2015-04-02 2021-06-21 大陸商深圳艾欣達偉醫藥科技有限公司 硝基苄基衍生物抗癌試劑
WO2016161342A3 (fr) * 2015-04-02 2016-11-10 Threshold Pharmaceuticals, Inc. Dérivés de nitrobenzyle d'agents anticancéreux
WO2016161342A2 (fr) 2015-04-02 2016-10-06 Threshold Pharmaceuticals, Inc. Dérivés de nitrobenzyle d'agents anticancéreux
CN112142692A (zh) * 2015-04-02 2020-12-29 深圳艾欣达伟医药科技有限公司 硝基苄基衍生物抗癌试剂
WO2016210175A1 (fr) * 2015-06-24 2016-12-29 Threshold Pharmaceuticals, Inc. Agents d'alkylation d'adn contenant de l'aziridine
US10668047B2 (en) 2015-06-24 2020-06-02 Molecular Templates, Inc. Aziridine containing DNA alkylating agents
CN108024974A (zh) * 2015-06-24 2018-05-11 分子模板公司 含有dna烷化剂的氮丙啶
CN108024974B (zh) * 2015-06-24 2023-11-14 免疫原公司 含有dna烷化剂的氮丙啶
JP2018527301A (ja) * 2015-06-24 2018-09-20 スレッシュホールド ファーマシューティカルズ， インコーポレイテッド Ｄｎａアルキル化剤を含有するアジリジン
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2023025291A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Solution de formulation lyophilisée, formulation lyophilisée, procédé et utilisation associés
WO2023025312A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Patient résistant aux inhibiteurs de parp traités avec th-302
WO2023174319A1 (fr) 2022-03-15 2023-09-21 深圳艾欣达伟医药科技有限公司 Méthode de traitement d'un patient atteint d'un cancer à mutation de brca
WO2023198188A1 (fr) 2022-04-15 2023-10-19 深圳艾欣达伟医药科技有限公司 Méthode de traitement du cancer faisant appel à th-302 seul ou en association avec un inhibiteur de parp
WO2023226959A1 (fr) 2022-05-23 2023-11-30 深圳艾欣达伟医药科技有限公司 Méthode de traitement du cancer par combinaison d'un promédicament d'agent alkylant et d'un inhibiteur de cycle cellulaire
EP4529926A1 (fr) 2022-05-23 2025-04-02 Ascentawits Pharmaceuticals, Ltd. Méthode de traitement du cancer par combinaison d'un promédicament d'agent alkylant et d'un inhibiteur de cycle cellulaire
WO2024061346A1 (fr) 2022-09-22 2024-03-28 深圳艾欣达伟医药科技有限公司 Utilisation d'un composé activé par hypoxie dans la préparation d'un médicament pour le traitement d'un patient atteint d'un cancer

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