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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
  • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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  • 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
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  • 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
  • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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  • 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
  • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
• • 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
  • 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
  • C07D403/14—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 three or more hetero rings
• • 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
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention provides a compound having a formula selected from:
• X is O, -NNHRi 6 , NR 16 , or NORi 6 ;
• Z is -CH- or -N-;
• R 15 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
• R 16 is hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylsulphonyl, arylsulfonyl, C 1 - C 6 alkoxycarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, di C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 acyl, aroyl, aminothiocarbonyl, CrC 6 alkylaminothiocarbonyi, di CrC 6 alkylaminothiocarbonyl, CrC 6 thioacyl, or thioaroyl; with the proviso that when X is NRi 6 , Ri 6 excludes hydrogen;
• R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
• the compounds are tubulin binding compounds.
• each Qi , Q 2 , and Q 6 independently is hydrogen; halo; amino; CrC 6 alkylamino; di Ci-C 6 alkylamino; hydroxyl; Ci-C 6 alkoxy; nitro; cyano; CrC 6 alkyl; CrC 6 heteroalkyl; CrC 6 alkenyl; CrC 6 alkynyl; C 3 -C 8 cycloalkyl; C3-C 8 heterocyclyl; aryl; heteroaryl; CORi 8 ; SO2R18; or PO 3 Ri 5 ; each Q 3 -Q 5 is hydrogen; halo; amino; CrC 6 alkylamino; di CrC 6 alkylamino; hydroxyl; CrC 6 alkoxy; nitro; cyano; aryl; heteroaryl; CORi 8 ; SO 2 Ri8; or PO 3 Ri8 with the proviso that in any one compound, only one of Q 3 - Q 5 is hydrogen;
• R 15 is hydrogen, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, d-C 6 heteroalkyl, C r C 6 alkenyl, C 1 - C 6 alkynyl, C 1 -C 6 cycloalkyl, C 1 -C 6 heterocyclyl, aryl, or heteroaryl;
• R 16 is hydrogen, CrC 6 alkyl, aryl, CrC 6 alkylsulphonyl, arylsulfonyl, C 1 -
• Ci-Ce alkyl or (CrC 6 ) alkyl refers to substituted or unsusbstituted straight or branched chain alkyl groups having 1-6 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methyl pentyl.
• Substituted CrC 6 alkyl groups include, for example, -CH 2 -CH 2 -OH, -CH 2 -CH 2 - halogen,
• Ci-C 6 alkoxy group has the general structure -O-(C- ⁇ -C 6 alkyl) wherein alkyl is as described above.
• CrC 6 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.
• halogen refers to fluorine, chlorine, bromine, and/or iodine.
• heteroaryl refers to substituted or unsusbstituted monocyclic aromatic groups having 5 or 6 ring atoms, or fused ring bicyclic aromatic groups having 8 to 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.
• hypoxic activators include, but are not limited to, groups based on nitrobenzenes, nitrobenzoic acid amides, nitroazoles, nitroimidazoles, nitrothiophenes, nitrothiazoles, nitrooxazoles, nitrofurans, and nitropyrroles, where each of these classes of moieties may be substituted or unsubstituted, such that the redox potential for the group lies within a range where the group can undergo reduction in the hypoxic regions of a tumor.
• hypoxic activators are described in Matteucci et al., PCT Publication No. WO 04/087075 and US Pat. Appl. No. 60/695,755 each of which is incorporated herein by reference.
• substitution refers to replacing a hydrogen atom in a molecular structure with a substituent such that the valence on the designated atom (for example 4 for carbon) is not exceeded, and a chemically stable compound (a compound that can be isolated, characterized, and/or tested for biological activity) results.
• isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
• organic base such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, N- methylglucamine, and the like.
• treating refers to taking steps to obtain beneficial or desired therapeutic results, including clinical results.
• beneficial or desired therapeutic results include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer, diminishment of extent of disease, delay or slowing of disease progression, palliation or stabilization of the disease state, and other beneficial results, as described below.
• reduction of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s) or eliminating the symptom(s).
• administering or "administration of a drug to a subject (and grammatical equivalents of this phrase) can include direct administration, including self-administration and/or indirect administration, including the act of prescribing a drug.
• direct administration including self-administration
• indirect administration including 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.
• a Colchicine-like tubulin binder such as Combretastatin A can selectively target the vascular system of tumors.
• the morphological changes induced in the endothelial cells of the tumor's blood vessels irreversibly shut down the blood flow to cancer cells while leaving the blood supply to healthy cells intact.
• the present invention also provides prodrugs of known and novel tubulin binding compounds of this invention.
• Cancer cells generally divide more frequently than normal cells.
• Tubulin binding-drug mediated cancer therapies include cytotoxic agents selective for dividing cells.
• tubulin binding compounds target cancer cells, as opposed to normal cells, generally because cancer cells undergo cell division more frequently than normal cells.
• drugs targeting dividing cells do not kill all of the cancer cells in the solid tumor.
• cancer cells can acquire mutations that confer drug resistance.
• Another is that not all cancer cells divide more frequently than normal cells.
• These slowly-dividing cancer cells are generally located in the hypoxic region of the tumor and can be as, or even more, insensitive to such inhibitors as normal cells. The formation and consequences of the tumor hypoxic region is described below.
• the hypoxic region acts as a drug-factory to produce a cytotoxin within a tumor for killing adjacent normoxic cancer cells leading to a higher concentration of the cytotoxin within the tumor, relative to normal tissues.
• a prodrug to generate the cytotoxin within the tumor, toxic side-effects arising due to normal cell toxicity can be reduced.
• a hypoxic region can become normoxic and start dividing.
• tubulin binding cytotoxins generated from the prodrug compounds of this invention, or by administering compounds of this invention in combination with other cytoxins, including for example, tubulin binding compounds and other anti-cancer cytotoxins.
• the compound when alkylated with N-1-methyl-2-nitro-5-imidazolemethyl group can yield a hypoxia activated prodrug. Under hypoxic conditions the hypoxic activator is reduced and removed yielding the potent toxin.
• X is O, -NNHR 16 , or NR 16 , or NORi 6 ;
• Ri 3 is hydrogen; CrC 6 alkyl, Ci-C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, Ci- C 6 alkoxy, amino, Ci-C 6 alkylamino, di CrC 6 alkylamino, NHCORi 5 , or CORi 8 ; and
• R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 - C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino; COR 18 Or NHCOR 15 ;
• R 15 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
• R 3 is hydrogen, halo, C 1 -C 6 alkyl, aryl or heteroaryl;
• R 13 is hydrogen; CrC 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, Cr Ce alkoxy, amino, CrC 6 alkylamino, di CrC 6 alkylamino; NHCORi 5 or COR 18 ;
• the present invention provides a compound of formula (XV), wherein each Q 2 - Q 5 independently is hydrogen, CrC 6 , alkoxy; halo; amino; or hydroxy; with the proviso that in any compound only one of the Q 3 , Q 4 and Q 5 is hydrogen; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
• the present invention provides a compound of formula (XV), wherein Ri 8 is hydrogen, Ci-C 6 alkyl, CrC 6 heteroalkyl, CrC 6 alkenyl, CrC 6 alkynyl, Ci -C 6 cycloalkyl, CrC 6 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
• Ri 8 is hydrogen, Ci-C 6 alkyl, CrC 6 heteroalkyl, CrC 6 alkenyl, CrC 6 alkynyl, Ci -C 6 cycloalkyl, CrC 6 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or
• Ri 3 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 - C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHCOR 15 Or COR 18 ;
• the present invention provides a compound of formula (XXI)-(XXVII), wherein Qi is hydrogen; halo; cyano; nitro; CORi 8 ;
• each Q 3 , Q 4 and Q 5 independently is hydrogen, C 1 -C 6 alkoxy, halo, amino, or hydroxyl provided that in any compound only one of the Q 3 , Q 4 and Q 5 is hydrogen;
• Q 7 is C 1 -C 6 alkyl optionally substituted independently with one or more aryl, heteroaryl, hydroxyl, amino, C 1 -Ce alkylamino, di CrC 6 alkylamino, CO2H, Or CONH 2 ; CORi 8 ; SO 2 R 18 ; or PO 3 Ri 8 ; or a monosaccharide;
• the present invention provides compounds of the invention wherein X is -NN(Hyp)R wherein Hyp and R are defined as above.
• the present invention provides a prodrug of the compound of formula (l-i):
• X is O, -NNHR 16 , NR 16 , -NN(Hyp)R 16 , or NOR 16 wherein R 16 is C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylsulphonyl, arylsulfonyl, C 1 -C 6 alkoxycarbony, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, di C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 acyl, aroyl, aminothiocarbonyl, C 1 -C 6 alkylaminothiocarbonyl, di C 1 -C 6 alkylaminothiocarbonyl, C 1 -C 6 thioacyl, or thioaroyl; with the proviso that when X is NR 16 , R 16 excludes hydrogen;
• Y is hydrogen, hydroxyl, or halogen
• Z is -CH- or -N-;
• R 15 is hydrogen, C 1 -C 6 alkoxy, amino, Ci-C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 -Cs cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl;
• Ri 6 is hydrogen, Ci-C 6 alkyl, aryl, C 1 -C 6 alkylsulphonyl, arylsulfonyl, Ci- C 6 alkoxycarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, di CrC 6 alkylaminocarbonyl, CrC 6 acyl, aroyl, aminothiocarbonyl, Ci-C 6 alkylaminothiocarbonyl, di C 1 -C 6 alkylaminothiocarbonyl, C 1 -C 6 thioacyl, or thioaroyl; with the proviso that when X is NRi 6 , R 16 excludes hydrogen;
• R 18 is hydrogen, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHOH, NHNH 2 , C 1 -C 6 alkyl, CrC 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
• the present invention provides a compound of formulas (XXVIII)-(XXXII), wherein Qi is hydrogen; halo; cyano; nitro; CORi 5 ;
• the present invention provides a compound of formula:
• Hyp is as defined above.
• each Q 3 -Q 5 is hydrogen; halo; amino; Ci-C 6 alkylamino; di C-i- C 6 alkylamino; hydroxyl; Ci-Ce alkoxy; nitro; cyano; aryl; heteroaryl; COR-is; SO2R18, or PO3R18; Q3 and Q 4 together form C 3 -C 8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C 3 -C 8 heterocycle, an aryl, or a heteroaryl; (-OHyp) or (-NHyp) with the proviso that in any one compound, at least one of Q3-Q 5 is (-OHyp) or (-NHyp); Q-i, Q2, R- 13 , R- I 5 and Hyp are as defined above; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a
• each Q 2 - Q 5 independently is hydrogen, CrC 6 alkoxy; halo; amino; or hydroxy; with the proviso that in any compound at least one of Q 3 -Q 5 is (-OHyp) or (-NHyp); or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
• Q2 is CrC 6 alkoxy; halo; amino; or hydroxy; each Q 3 , Q 4 , and Q 5 independently is hydrogen; halo; amino; Ci-C 6 alkylamino; di CrC 6 alkylamino; hydroxyl; CrC 6 alkoxy; nitro; cyano; aryl; heteroaryl; CORi 8 ; SO 2 Ri 8 ; or PO 3 R18; Q3 and Q 4 together form C3-C8 heterocycle, an aryl, or a heteroaryl; or Q 4 and Q 5 together form a C3-C 8 heterocycle, an aryl, or a heteroaryl; with the proviso that in any one compound, only one of Q 3 -Q 5 is hydrogen;
• Ri is CH 2 or CO
• R 15 is hydrogen, hydroxyl, CrC 6 alkoxy, amino, CrC 6 alkylamino, di CrC 6 alkylamino, NHOH, NHNH 2 , CrC 6 alkyl, Ci-C 6 heteroalkyl, C r C 6 alkenyi, C 1 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocyclyl, aryl, or heteroaryl;
• Q 7 is hydrogen; amino; CrC 6 alkylamino; di CrC 6 alkylamino; hydroxyl; CrC 6 alkoxy; nitro; cyano; CrC 6 alkyl; C 1 -C 6 heteroalkyl; CrC 6 alkenyl; CrC 6 alkynyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocyclyl; aryl; heteroaryl; CORi 5 ; SO 2 Ri 8 ; or PO 3 Ri 8 ; or a monosaccharide;
• R 6 is formyl or a protected form thereof;
• R 13 is hydrogen; C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, aryl, or heteroalkyl each optionally substituted with hydroxyl, C 1 - C 6 alkoxy, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, NHCOR 15 Or COR 15;
• Q 2 is hydrogen, hydroxyl, fluoro or methoxy
• Q 6 is hydrogen, hydroxyl, fluoro, methoxy or amino
• Ri 8 is hydrogen, C-i-C- 6 alkyl, C 1 -C 6 heteroalkyl, CrC 6 alkenyl, CrC 6 alkynyl, Ci -C 6 cycloalkyl, CrC 6 heterocyclyl, aryl, or heteroaryl; or a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
• R 10 is CI-C ⁇ alkyl and Hyp is hypoxic activator; and a tautomer or an individual isomer or a racemic or non-racemic mixture of isomers, a polymorph, a hydrate, a prodrug or a pharmaceutically acceptable salt or solvate thereof.
• Ri 0 is methyl.
• the present invention provides novel prodrug compounds of the following tubulin binders: wherein each -NH- or OH moiety in a structure above is replaced with - N(Hyp)- wherein Hyp is defined as above.
• one -NH- moiety in each structure is replaced with -N(Hyp)-.
• two of those are replaced with - N(Hyp)-.
• the compounds and prodrugs suited for use in the invention are tubulin binding compounds when administered to a human, non-human primate, or other mammal.
• a compound e.g., a tubulin binding compound
• Active forms can be identified by routine screening of the compounds of the invention for the activity.
• assays and tests can be used to assess pharmacological activity of a compound or novel prodrug of the invention, including in vitro assays, such as those described below and elsewhere herein, in vivo assays in humans, non-human primates and other mammals, and/or clinical studies.
• a tubulin binding compound with similar apoptosis-inducing activity similar to that of Combretastatin A-4 phosphate is selected.
• a topoisomerase inhibitor that induces apoptosis in cancer cells such as H460, PC3, CCRF, LNCaP, HT29, MESSA and PWR-1 E is administered to treat cancer.
• said antiproliferation assays employ cancer cell including but not limited to gastric, colon, breast, and non-small cell lung cancer.
• the gastric cancer cell used is MESSA or doxorubicin resistant MESSA/DX5 cell;
• the colon cancer cell is HT29 cell;
• the breast cacner cell is T47D cell; and
• the non-small cell lung cancer cell is H460 cell.
• the present invention provides a compound having a Gl 50 or IC 50 of about 1 to about 50 nM in a cancer cell antiproliferation assay, such as, for example, compounds 30, 37, 39, 54, 55, 66, 68, 70, 71 , and 72.
• a tubulin binding compound having an IC 50 of tubulin polymerization of about 0.1 to about 10 ⁇ M as determined in a tubulin polymerization inhibition assay, such as for example, compounds 30 and 39.
• the present invention provides a compound which when subjected to a liver microsomal stability study, remains about 10 to about 100, about 20 to about 80, about 80 to about 100% unmetabolized.
• the liver microsomal study is conducted for between 10-60, 20- 40, or 25-35 minutes.
• mouse liver microsome is employed in the study. Examples of compounds remaining 80-100% unchanged in a mouse liver microsomal stability study include but are not limited to, compounds 30, 60, 66, and 70.
• the present invention provides novel methods for the synthesis of the compounds of this invention.
• step (iii) optionally reducing product-2 obtained in step (ii) to yield the compound or prodrug of the invention.
• methods for the synthesis of the compounds of this invention can be identified in accordance with the present invention via search tools such as SciFinderfrom the American Chemical Society and Beilstein from MDL Software.
• search tools such as SciFinderfrom the American Chemical Society and Beilstein from MDL Software.
• Illustrative methods for making anti-cancer compounds of the present invention in accordance with this disclosure are provided in the EXAMPLES section below.
• a compound of the present invention disclosed herein is usually formulated as a pharmaceutical composition comprising the compounds or the prodrugs of this invention and a pharmaceutically-acceptable carrier.
• pharmaceutically acceptable carrier is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
• Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
• compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.
• Pharmaceutical preparations for oral use can be obtained through combining active compounds with solid excipient and, optionally, other compounds.
• Pharmaceutical formulations suitable for parenteral administration can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline.
• Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
• penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
• a variety of routes, dosage schedules, and dosage forms are appropriate for administration of pharmaceutical compositions of the invention. Appropriate dosage schedules and modes of administration will be apparent to the ordinarily skilled practitioner upon reading the present disclosure and/or can be determined using routine pharmacological methods and/or methods described herein.
• the dose, schedule and duration of administration of the compound and/or prodrug of the invention will depend on a variety of factors. The primary factor, of course, is the choice of a specific compound or prodrug of the present invention.
• Other important factors include the age, weight and health of the subject, the severity of symptoms, if any, the subject's medical history, co-treatments, goal (e.g., prophylaxis or prevention of relapse), preferred mode of administration of the drug, the formulation used, patient response to the drug, and the like.
• a compound and/or a prodrug of the invention can be administered at a dose in the range of about 0.1 mg to about 500 mg of a compound and/or prodrug of the invention per kg of body weight of the patient to be treated per day, optionally with more than one dosage unit being administered per day, and typically with the daily dose being administered on multiple consecutive days.
• the compounds of the present invention include novel compounds of the invention, novel prodrug thereof, and novel prodrugs of known compounds.
• a therapeutically or prophylactically effective dose of a compound and/or a prodrug of the invention can be administered daily or once every other day or once a week to the patient. Controlled and sustained release formulations of the analogs can be used. Generally, multiple administrations of the compound and/or prodrug of the invention are employed. For optimum treatment benefit, the administration of the prophylactically effective dose can be continued for multiple days, such as for at least five consecutive days, and often for at least a week and often for several weeks or more.
• the compound and/or prodrug of the invention is administered once (qday), twice (bid), three times (tid), or four times (qid) a day or once every other day (qod) or once a week (qweek), and treatment is continued for a period ranging from three days to two weeks or longer.
• the present invention provides a method for treating cancer or other hyperproliferative diseases by administering to a patient in need of therapy thereof a therapeutically effective dose of a compound or prodrug compound of the invention. In one embodiment, the present invention provides a method for treating cancer or other hyperproliferative diseases by administering about 0.1 to about 500 mg/Kg of a compound or a prodrug compound of the invention to a patient in need of therapy thereof.
• a compound and/or a prodrug of the invention is administered in a daily dose in the range of about 0.5 mg to about 400 mg/Kg; about 1.0 mg to about 300 mg/Kg; about 1.5 mg to about 250 mg/Kg; about 2.0 mg to about 200 mg/Kg; about 2.5 mg to about 150 mg/Kg; about 5 to about 100 mg/Kg; about 10 to about 50 mg/Kg; and about 10 to about 70 mg per kg of body weight of the patient to be treated.
• the present invention provides a unit dosage form of about 1 to about 200 mg of a compound or prodrug compound of the invention to a patient in need of therapy thereof.
• Combretastatin A-4 phosphate CA4P
• a tubulin-binding compound is reported to have a maximum tolerated daily dose of 60 - 68 mg/m 2 , and has, for example, been administered to patients in clinical trials in daily doses of 27 and 36 mg/m 2 , by a 10-minute infusion, once every 21 days (Young et al., 2004 , Expert Opin. Investig. Drugs, 13(9):1171-82 and Bilenker ef a/., 2005, Clin. Cancer Res., 11(4): 1527-33).
• a compound of the present invention can be administered in a therapeutically affective daily dose of about 0.3 to about 3 mg/kg, about 0.6 to about 2.4 mg/kg, about 0.9 to about 2.1 mg/kg, about 1.2 to about 1.8 mg/kg, and about 1.4 to about 1.6 mg/kg to treat cancer.
• a drug "cocktail" in which several anti-cancer drugs are contemporaneously administered to a cancer patient.
• the novel compounds of the present invention and the prodrug compounds of the invention can be used in such therapies either in addition to or in substitution of one or more of the co- administered drugs.
• cancer cells in a patient that are normoxic and located adjacent to a hypoxic region of a tumor there may be cancer cells in a patient that are normoxic and located adjacent to a hypoxic region of a tumor, one can, in one embodiment of the invention, co-administering a prodrug of the invention with one or more other drugs that target normoxic cells.
• a compound and/or a prodrug compound of the invention can be co-administered in combination with other anti-cancer agents ("anticancer agent").
• anticancer agent an anti-cancer agent
• co-administration can in some cases provide one or more of several advantages over known cancer therapies, such as, for example co-administration of a compound and/or a prodrug compound of the invention and the anticancer agent has a synergistic effect on induction of cancer cell death.
• Co-administration provides a better therapeutic result than administration of the anticancer agent alone, e.g., greater alleviation or amelioration of one or more symptoms of the cancer, diminishment of extent of disease, delay or slowing of disease progression, amelioration, palliation or stabilization of the disease state, partial or complete remission, prolonged survival or other beneficial therapeutic results.
• a compound and/or a prodrug compound of the invention is "co-administered" with another anticancer agent (also referred to herein as, "Agent") wherein a compound and/or a prodrug compound of the invention and Agent are administered as part of the same course of therapy.
• Agent another anticancer agent
• a compound and/or a prodrug compound of the invention is first administered prior to administration of the Agent, (i.e., the initiation of the other cancer therapy), and treatment with the compound and/or prodrug compound of the invention is continued throughout the course of administration of the Agent (i.e., the course of the other therapy).
• a compound and/or a prodrug compound of the invention is administered after the initiation or completion of the other cancer therapy.
• a compound and/or a prodrug compound of the invention is first administered contemporaneously with the initiation of the other cancer therapy.
• a compound and/or a prodrug compound of the invention is first administered prior to administration of the Agent, and treatment with the compound and/or prodrug compound of the invention is continued after the cessation of administration of the Agent.
• a compound and/or a prodrug compound of the invention is first administered prior to administration of the Agent, and treatment with the compound and/or prodrug compound of the invention is continued during part of the period of administration of the Agent.
• administration of a compound and/or a prodrug compound of the invention can be initiated and completed prior to the administration of the second drug.
• the present invention provides a method wherein a compound and/or a prodrug compound of the invention administered in combination with a chemoprotective agent or a chemoprotectant.
• a chemoprotective agent protect healthy tissue from the toxic effects of anticancer drugs.
• the chemoprotective agent is a thiol or a disulfide.
• the chemoprotectant can reduce superoxide.
• the chemoprotectant can react with the "Michael-receptor" generated from a hypoxia activated prodrug of the invention and prevent "Michael-receptor” from reacting with proteins and nucleic acid.
• Anticancer drug therapy today typically involves multiple rounds, or
• the compound and/or prodrug compound of the invention and additional therapy can be administered at the same time or can be administered separately.
• the two agents can be administered simultaneously or can be administered sequentially with some time between administrations.
• One of skill in the art will understand methods of administering the agents simultaneously and sequentially and possible time periods between administrations.
• the Agents can be administered as the same or different formulations and can be administered via the same or different routes.
• Chemotherapeutic agents that can be used in combination with the compound of the invention include, but are not limited to, busulfan, improsulfan, piposulfan, benzodepa, carboquone, 2-deoxy-D-glucose, lonidamine and analogs thereof (refrence apps), glufosfamide, meturedepa, uredepa, altretamine, imatinib, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlomaphazine, estramustine, ifosfamide, gefitinib, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, nimustine, ranimustine, dacarba
• a compound and/or a prodrug compound of the invention is administered with an anti-cancer agent that acts, either directly or indirectly, to inhibit the epidermal growth factor or EGFR receptor.
• EGFR inhibitors suitable for coadministration with a compound of the invention include gefitinib and erlotonib.
• a compound and/or a prodrug compound of the invention is administered with an anti-cancer agent that acts, either directly or indirectly, to inhibit hypoxia-inducible factor 1 alpha (HIFIa) or to inhibit a protein or enzyme, such as a glucose transporter or VEGF, whose expression or activity is increased upon increased HIFIa levels.
• an anti-cancer agent that acts, either directly or indirectly, to inhibit hypoxia-inducible factor 1 alpha (HIFIa) or to inhibit a protein or enzyme, such as a glucose transporter or VEGF, whose expression or activity is increased upon increased HIFIa levels.
• HIFI a inhibitors suitable for use in this version of the methods and compositions described herein include P13 kinase inhibitors; LY294002; rapamycin; histone deacetylase inhibitors such as [(E)-(1 S,4S,10S,21 R)-7-[(Z)-ethylidene]-4,21 ⁇ diisopropyl-2- oxa-12,13-dithia-5,8,20,23-tetraazabicyclo-[8,7,6]-tricos-16-ene-3,6,9,19,22- pentanone (FR901228, depsipeptide); heat shock protein 90 (Hsp90) inhibitors such as geldanamycin, 17-allylamino-geldanamycin (17-AAG), and other geldanamycin analogs, and radicicol and radicicol derivatives such as KF58333; genistein; indanone; staurosporin; protein kinase-1
• angiogenesis inhibitors for purposes of the combination therapies provided by the present methods and compositions described herein include Cox-2 inhibitors like celecoxib (Celebrex), diclofenac (Voltaren), etodolac (Lodine), fenoprofen (Nalfon), indomethacin (Indocin), ketoprofen (Orudis, Oruvail), ketoralac (Toradol), oxaprozin (Daypro), nabumetone (Relafen), sulindac (Clinoril), tolmetin (Tolectin), rofecoxib (Vioxx), ibuprofen (Advil), naproxen (Aleve, Naprosyn), aspirin, and acetaminophen (Tylenol).
• Cox-2 inhibitors like celecoxib (Celebrex), diclofenac (Voltaren), etodolac (Lodine), fenoprofen
• pyruvate mimics and glycolytic inhibitors like halopyruvates, including bromopyruvate can be used in combination with an anti-angiogenic compound and a compound and/or a prodrug compound of the invention to treat cancer.
• a compound and/or a prodrug compound of the invention is administered with an anti-angiogenic agent and another anti ⁇ cancer agent, including but not limited to a cytotoxic agent selected from the group consisting of alkylators, Cisplatin, Carboplatin, and inhibitors of microtubule assembly, to treat cancer.
• the present methods and compositions described herein provides a variety of synergistic combinations of the compound and/or prodrug compound of the invention and other anti-cancer drugs.
• Those of skill in the art can readily determine the anti- cancer drugs that act "synergistically" with a compound and/or a prodrug compound of the invention as described herein.
• Such “low dose” therapies can involve, for example, administering an anti-cancer drug, including but not limited to paclitaxel, docetaxel, doxorubicin, cisplatin, or carboplatin, at a lower than approved dose and for a longer period of time together with a compound and/or a prodrug compound of the invention administered in accordance with the methods described herein.
• an anti-cancer drug including but not limited to paclitaxel, docetaxel, doxorubicin, cisplatin, or carboplatin
• the other anti-cancer agent or agents will be administered at the same dose levels used when a compound and/or a prodrug compound of the invention is not co-administered.
• the additional anti-cancer agent(s) is dosed using either the standard dosages employed for those Agents when used without the compound and/or prodrug compound of the invention or are less than those standard dosages.
• a compound and/or a prodrug compound of the invention in accordance with the methods described herein can therefore allow the physician to treat cancer with existing (or later approved) drugs at lower doses (than currently used), thus ameliorating some or all of the toxic side effects of such drugs.
• the exact dosage for a given patient varies from patient to patient, depending on a number of factors including the drug combination employed, the particular disease being treated, and the condition and prior history of the patient, but can be determined using only the skill of the ordinarily skilled artisan in view of the teachings herein.
• chemotherapeutic agents or antineoplastic agents i.e., the recommended effective dose
• physicians are given, for example, in the product descriptions found in the Physician's Desk Reference 2003, (Physicians' Desk Reference, 57th Ed) Medical Economics Company, Inc., Oradell, NJ and/or are available from the Federal Drug Administration.
• Illustrative dosage regimens for certain anti-cancer drugs are also provided below.
• Cancer drugs can be classified generally as alkylators, anthracyclines, antibiotics, aromatase inhibitors, bisphosphonates, cyclo- oxygenase inhibitors, estrogen receptor modulators, folate antagonists, inorganic aresenates, microtubule inhibitors, modifiers, nitrosoureas, nucleoside analogs, osteoclast inhibitors, platinum containing compounds, retinoids, topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, and tyrosine kinase inhibitors.
• a compound and/or a prodrug compound of the invention can be co ⁇ administered with any anti-cancer drug from any of these classes or can be administered prior to or after treatment with any such drug or combination of such drugs.
• a compound and/or a prodrug compound of the invention can be administered in combination with a biologic therapy (e.g., treatment with interferons, interleukins, colony stimulating factors and monoclonal antibodies).
• a biologic therapy e.g., treatment with interferons, interleukins, colony stimulating factors and monoclonal antibodies.
• Biologies used for treatment of cancer are known in the art and include, for example, trastuzumab (Herceptin), tositumomab and 131 I Tositumomab (Bexxar), rituximab (Rituxan).
• Alkylators useful in the practice of the methods described herein include but are not limited to busulfan (Myleran, Busulfex), chlorambucil (Leukeran), ifosfamide (with or without MESNA), cyclophosphamide (Cytoxan, Neosar), glufosfamide, melphalan, L-PAM (Alkeran), dacarbazine (DTIC- Dome), and temozolamide (Temodar).
• busulfan Myleran, Busulfex
• chlorambucil Leukeran
• ifosfamide with or without MESNA
• cyclophosphamide Cytoxan, Neosar
• glufosfamide glufosfamide
• melphalan L-PAM (Alkeran)
• dacarbazine DTIC- Dome
• temozolamide Temodar
• the cancer is chronic myelogenous leukemia, multiple myeloma, or anaplastic astrocytoma.
• the present invention provides a method of treating cancer treatable by administering a compound and/or a prodrug compound of the invention alone or in combination with at least another alkylator or a prodrug thereof.
• the present invention provides a method of treating cancer by administering a compound and/or a prodrug compound of the invention with a cancer treatment regimen using at least the alkylator Glufosfamide.
• Glufosfamide is in the clinic for the treatment of pancreatic cancer or Gemzar resistant pancreatic cancer.
• Glufosfamide can be used for treating breast cancer, Morbus Hodgkin, gastrointestinal tract cancer, or as part of the GCE (Glufosfamide, Carboplatin, and Etoposide) or RGCE (Rituxan and GCE) regimen, for treating lymphomas.
• GCE Glufosfamide, Carboplatin, and Etoposide
• RGCE Renuxan and GCE
• Additional examples of Agents include Terciva, Iressa, Cytarabine and Erbitux.
• Cisplatin with Bleomycin, Etoposide, and Vinblastine is used to treat advanced testicular cancer; and with one of Paclitaxel, Cyclophosphamide, or Doxorubicin to treat ovarian carcinoma.
• Anthracyclines useful in the practice of the methods described herein include but are not limited to, doxorubicin (Adriamycin, Doxil, Rubex), mitoxantrone (Novantrone), idarubicin (Idamycin), valrubicin (Valstar), and epirubicin (Ellence).
• a compound and/or a prodrug compound of the invention is co-administered with an anthracycline to treat cancer.
• the cancer is acute nonlymphocytic leukemia, Kaposi's sarcoma, prostate cancer, bladder cancer, metastatic carcinoma of the ovary, and breast cancer.
• Doxorubicin has been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, lymphomas of both Hodgkin and non-Hodgkin types, bronchogenic carcinoma, and gastric carcinoma.
• Doxorubicin is typically administered in a dose in the range of 30- 75 mg/m 2 as a single intravenous injection administered at 21 -day intervals; weekly intravenous injection at doses of 20 mg/m 2 ; or 30 mg/m 2 doses on each of three successive days repeated every four weeks.
• a compound and/or a prodrug compound of the invention is co-administered starting prior to and continuing after the administration of doxorubicin at such doses (or at lower doses).
• Cyclic Anthracycline cytotoxin prodrugs useful in the practice of the methods described herein are provided by the reference Matteuci et a/., PCT Patent Aplication No. US05/08161.
• Antibiotics useful in the practice of the methods described herein include but are not limited to dactinomycin, actinomycin D (Cosmegen), bleomycin (Blenoxane), daunorubicin, and daunomycin (Cerubidine, DanuoXome).
• a compound and/or a prodrug compound of the invention is co-administered with an antibiotic to treat cancer.
• the cancer is a cancer selected from the group consisting of acute lymphocytic leukemia, other leukemias, and Kaposi's sarcoma.
• Aromatase inhibitors useful in the practice of the methods described herein include but are not limited to anastrozole (Arimidex) and letroazole (Femara).
• a compound and/or a prodrug compound of the invention is co-administered with an aromatase inhibitor to treat cancer.
• the cancer is breast cancer.
• Cyclo-oxygenase inhibitors useful in the practice of the methods described herein include but are not limited to celecoxib (Celebrex).
• a compound and/or a prodrug compound of the invention is co-administered with a cyclo-oxygenase inhibitor to treat cancer.
• the cancer is colon cancer or a pre-cancerous condition known as familial adenomatous polyposis.
• Estrogen receptor modulators useful in the practice of the methods described herein include but are not limited to tamoxifen (Nolvadex) and fulvestrant (Faslodex).
• a compound and/or a prodrug compound of the invention is co-administered with an estrogen receptor modulator to treat cancer.
• the cancer is breast cancer or the treatment is administered to prevent the occurrence or reoccurrence of breast cancer.
• Folate antagonists useful in the practice of the methods described herein include but are not limited to methotrexate and tremetrexate.
• a compound and/or a prodrug compound of the invention is co-administered with a folate antagonist to treat cancer.
• the cancer is osteosarcoma.
• the cancer is ovarian cancer, breast cancer, non-small cell lung cancer, Kaposi's sarcoma, and metastatic cancer of breast or ovary origin.
• the compound 22-oxo-vincaleukobIastine also commonly known as vincristine, is an alkaloid obtained from the common periwinkle plant (Vinca rosea, Linn.) and is useful in the treatment of acute leukemia. It has also been shown to be useful in combination with other oncolytic agents in the treatment of Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, rhabdomyosarcoma, neuroblastoma, and Wilm's tumor.
• N- hydroxyurea has been reported to enhance the ability of a cell to take up 2- deoxyglucose (see the reference Smith et al., 1999, Cancer Letters 141: 85, incorporated herein by reference), and administration of N-hydroxyurea at levels reported to increase 2-deoxyglucose uptake or to treat leukemia together with administration of 2-deoxyglucose and a compound of the invention is one version of the therapeutic methods provided herein.
• a compound and/or prodrug compound of the invention is co-administered with nitric oxide or a nitric oxide precursor, such as an organic nitrite or a spermineNONOate, to treat cancer, as the latter compounds stimulate the uptake of glucose.
• Nitrosoureas useful in the practice of the methods described herein include but are not limited to procarbazine (Matulane), lomustine, CCNU (CeeBU), carmustine (BCNU, BiCNU, Gliadel Wafer), and estramustine (Emcyt).
• a compound and/or prodrug compound and/or prodrug compound of the invention is co ⁇ administered with a nitrosourea to treat cancer.
• the cancer is prostate cancer or glioblastoma, including recurrent glioblastoma multiforme.
• the compound 5-fluoro-2,4(1 H,3H)-pyrimidinedione is an antimetabolite nucleoside analog effective in the palliative management of carcinoma of the colon, rectum, breast, stomach, and pancreas in patients who are considered incurable by surgical or other means.
• 5-Fluorouracil is administered in initial therapy in doses of 12 mg/m 2 given intravenously once daily for 4 successive days with the daily dose not exceeding 800 mg. If no toxicity is observed at any time during the course of the therapy, 6 mg/kg are given intravenously on the 6th, 8th, 10th, and 12th days. No therapy is given on the 5th, 7th, 9th, or 11th days.
• a daily dose of 6 mg/kg is administered for three days, with the daily dose not exceeding 400 mg. If no toxicity is observed at any time during the treatment, 3 mg/kg can be given on the 5th, 7th, and 9th days. No therapy is given on the 4th, 6th, or 8th days. A sequence of injections on either schedule constitutes a course of therapy.
• a compound and/or prodrug compound of the invention is co-administered with 5-FU administered at such doses or with the prodrug form Xeloda with correspondingly adjusted doses.
• the compound 2- amino-1 ,7-dihydro-6H-purine-6-thione is a nucleoside analog effective in the therapy of acute non- pymphocytic leukemias.
• 6-Thioguanine is orally administered in doses of about 2 mg/kg of body weight per day. The total daily dose can be given at one time. If after four weeks of dosage at this level there is no improvement, the dosage can be cautiously increased to 3 mg/kg/day.
• a compound and/or prodrug compound of the invention is co-administered with 6-TG administered at such doses (or at lower doses).
• Osteoclast inhibitors useful in the practice of the methods described herein include but are not limited to pamidronate (Aredia).
• a compound and/or prodrug compound of the invention is co-administered with an osteoclast inhibitor to treat cancer.
• the cancer is osteolytic bone metastases of breast cancer, and one or more additional anti-cancer agents are also co-administered with a compound and/or prodrug compound of the invention.
• Platinum compounds useful in the practice of the methods described herein include but are not limited to cisplatin (Platinol) and carboplatin
• a compound and/or prodrug compound of the invention is co-administered with a platinum compound to treat cancer.
• the cancer is metastatic testicular cancer, metastatic ovarian cancer, ovarian carcinoma, and transitional cell bladder cancer.
• the compound cis-Diaminedichloroplatinum (II) commonly known as cisplatin, is useful in the palliative treatment of metastatic testicular and ovarian tumors, and for the treatment of transitional cell bladder cancer which is not amenable to surgery or radiotherapy.
• Cisplatin when used for advanced bladder cancer, is administered in intravenous injections of doses of 50-70 mg/m 2 once every three to four weeks.
• a compound and/or prodrug compound of the invention is co-administered with cisplatin administered at these doses (or at lower doses).
• One or more additional anti ⁇ cancer agents can be co-administered with the platinum compound and a compound and/or prodrug compound of the invention.
• Platinol, Blenoxane, and Velbam can be co-administered with a compound and/or a prodrug compound of the invention.
• Platinol and Adriamycin can be co-administered with a compound and/or a prodrug compound of the invention.
• Retinoids useful in the practice of the methods described herein include but are not limited to tretinoin, ATRA (Vesanoid), alitretinoin (Panretin), and bexarotene (Targretin).
• a compound and/or a prodrug compound of the invention is co-administered with a retinoid to treat cancer.
• the cancer is a cancer selected from the group consisting of APL, Kaposi's sarcoma, and T- cell lymphoma.
• Topoisomerase 2 inhibitors useful in the practice of the methods described herein include but are not limited to etoposide, VP-16 (Vepesid), teniposide, VM-26 (Vumon), and etoposide phosphate (Etopophos).
• a compound and/or prodrug compound of the invention is co-administered with a topoisomerase 2 inhibitor to treat cancer.
• the cancer is a cancer selected from the group consisting of refractory testicular tumors, refractory acute lymphoblastic leukemia (ALL), and small cell lung cancer.
• ALL refractory acute lymphoblastic leukemia
• small cell lung cancer small cell lung cancer.
• Tyrosine kinase inhibitors useful in the practice of the methods described herein include but are not limited to imatinib (Gleevec).
• a compound and/or a prodrug compound of the invention is co-administered with a tyrosine kinase inhibitor to treat cancer.
• the cancer is CML or a metastatic or unresectable malignant gastrointestinal stromal tumor.
• a compound and/or a prodrug compound of the invention or a pharmaceutically acceptable salt thereof and one or more additional anti-cancer agents are administered to a patient.
• additional anti-cancer agents include without limitation 5-methyl-6-[[(3,4,5-trimethoxyphenyl)amino]-methyl]- 2,4-quinazolinediamine or a pharmaceutically acceptable salt thereof, (8S,10S)-10-(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-8- glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12- naphthacenedione or a pharmaceutically acceptable salt thereof; 5-fluoro- 2,4(1 H,3H)-pyrimidinedione or a pharmaceutically acceptable salt thereof; 2- amino-1 ,7-dihydro-6H-purine-6-thione
• Compound 4 can also be prepared by a similar procedure from compound 7 (100 mg, 0.56 mmol), 157 mg 5-iodo-1 ,2,3-trimethoxybenzene (0.53 mmol), PdCI 2 (PPh 3 )2 (19 mg, 5.0 mol %), and CuI (5.1 mg, 5.0 mol %) in TEA (8 ml_).
• N - NO 2 compounds 12 and 13 by reacting compound 9 with Br ⁇ - N instead of CH 3 I.
• Example 11 provides methods for synthesizing Compound 22 starting from compound 9.
• Example 12 provides methods for synthesizing Compound 30 starting from compound 22.
• Example 15 provides a method of synthesizing compound 56.
• Example 16 provides a method of synthesizing compound 57.
• Example 19 provides a method of synthesizing compound 61.
• Example 20 provides a method of synthesizing compound 62-64.
• Example 21 provides a method of synthesizing compounds 66-71.
• Example 22 provides a method of synthesizing compounds 73 and 74.
• Example 26 provides a method of synthesizing Compound 78.
• Example 27 provides a method of synthesizing Compound 79.
• Example 18 provides method for synthesis of novel a prodrug compound of the invention derived from a novel compound of the invention.
• Example 30 provides method for synthesis of prodrug compounds of the invention employing as starting material a known tubulin binding compounds.
• R 1 H,r Me, aryl, or heteroaryl
• Example 31 provides method for synthesis of prodrug compounds of the invention employing as starting material a known tubulin binding compounds.
• the antiproliferative activity of these compounds was tested in a multi-well Alamar Blue based assay (at 2 h and 3 days). Cell growth in the presence and absence of the test compound as tabulated in Table 1 was compared, as measured by a fluorescence plate reader at excitation 550 nm and emission 590 nm (see Biosource International Inc., Tech Application Notes, Use of Alamar Blue in the measurement of Cell Viability and Toxicity, Determining IC 50 ).
• H460 cells ATCC HTB-177 (NCI-H40), 4,000 cells/well/200 ⁇ l
• LNCap cells ATCC CRL-1740, 6,000 cells/well/200 ⁇ l
• a test compound was added to each plate in the treatment groups (2h and 3 day) at a concentration as tabulated in Table 1 (in 50 ⁇ l of medium).
• the cells were rinsed to remove the test compound and incubated for 3 days, followed by staining with AlamarBlue.
• the cells in the 3-day treatment group were incubated for 3 days, followed by staining with AlamarBlue.
• AlamarBlue was added to the plate at (i) day 0 and (ii) day 3 and measured to establish the control reading.
• the capacity of the cells to proliferate was measured 6 hours after addition of AlamarBlue by a fluorescence plate reader at excitation 550 nm and emission 590 nm. The results of the assay are tabulated in Tables 1A and 1 B.
• H460 cells (2 x 10 5 cells/ml/well) were seeded in a 24 well plate. After 24 h, compound was added at various concentrations as tabulated in Table 3. The culture media were removed after 24 h, the cells were trypsinized and centrifuged. The cell pellets were resuspended in 100 ⁇ l PBS buffer, after which 300 ⁇ l of ice-cold ethanol (96%) added dropwise, and the cells were incubated at 4 0 C for at least 24 hr. The cells were centrifuged and the supernatant was discarded.
• the cell cycle staining reagent (Guava Technologies, Hayward, CA, USA, 200 ⁇ l) was added to each well. The cells were shielded from light and incubated at room temperature for 30 min. The samples were analyzed (Guava PCA-96 instrument, Cytosoft software, Guava Technologies, 25801 Industrial Boulevard, Hayward CA 94545-2991 , USA) to show M phase cell cycle arrest as tabulated below in Table 2.
• a sample of cell free tubulin polymerizes and the sample's fluorescence emission increases.
• Inhibition of tubulin polymerization by a tubulin binding compounds of the present invention was measured by the dose dependence of cell free tubulin fluorescence.
• concentration of compound that reduced tubulin fluorescence by 50% compared to untreated tubulin are tabulated below in Table 3:
• Example 36 For an assessment of plasma stability of compounds, commercially available mouse plasma (Bioreclamation, Hicksville, NY) was added to a DMSO solution of a compound, to a concentration of 5 ⁇ M. The reaction mixture (50 ⁇ l) was withdrawn immediately and after 30 minutes at 37 0 C, proteins were precipitated with acetonitrile. The clear supernatant was analyzed by reversed phase LC-MS/MS and the amount the compound reamining quantified as ahown in table 4.
• Example 28 describes the usefulness of a compound of this invention in treating cancer as demonstrated employing a H460 xenograft mouse model.
• mice Female CB17/SCID mice (purchased from Taconic, Oxnard, CA), 7-8 weeks of age, were allowed to acclimatize for at least three days, and handled under pathogen-free conditions.
• Human non-small cell lung cancer cell line NCI-H60 was obtained from the American Type Culture Collection. The cell lines were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum. Cells were maintained in a 37 0 C incubator with 5% CO 2 . The H460 cells were harvested from culture and inoculated at 1 x 10 6 cells/ animal in the peritoneal subcutaneous space.
• each group of mice (ten per group) was administered for five days, vehicle alone (the vehicle group), compound 30 alone at a daily dose of 5, 20, and 50 mg/kg (treatment group), and compound 30 alone at a daily dose of 5, and 20 mg/kg in combination with Taxol® at a daily dose of 10 mg/kg (combination group). Taxol was administered approximately 2-3 hours before that of compound 30.
• Compound 30, administered at doses greater than 5 mg/kg were toxic and caused lethality in both treatment and combination groups perhaps indicating that the maximum tolerated dose of compound 30 was between 5 and 20 mg/kg.
• the results from the experiment employing a daily dose compound 30 (5 mg/kg) are shown graphically in Figures 1 and 2 below.
• the body weight of each mouse was recorded twice per week ( Figure 1 ).
• the treatment group administered a daily dose of 5 mg/kg exhibited a weight pattern similar to that of the vehicle group with a mean weight loss of 8% on day 22 from the start of treatment on day 8.
• Animals in the combination group displayed a weight loss of 13%.
• One animal in the treatment group was found dead on day 18, and two were found dead on day 22 in the combination group.
• the T/C for day 21 was 56%.
• the xenograft data for compound 30 demonstrates that compared to the known anticancer agent taxol, compound 30 can show in vivo anti tumor activity both as a single agent and in combination with taxol.

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