US20050113398A1 - 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents - Google Patents

2,4-pyrimidinediamine compounds and uses as anti-proliferative agents Download PDF

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US20050113398A1
US20050113398A1 US10/913,270 US91327004A US2005113398A1 US 20050113398 A1 US20050113398 A1 US 20050113398A1 US 91327004 A US91327004 A US 91327004A US 2005113398 A1 US2005113398 A1 US 2005113398A1
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hydrogen
methyl
group
lower alkyl
ome
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Ankush Argade
Rajinder Singh
Hui Li
David Carroll
Susan Catalano
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Rigel Pharmaceuticals Inc
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Rigel Pharmaceuticals Inc
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Priority to US10/913,270 priority Critical patent/US20050113398A1/en
Publication of US20050113398A1 publication Critical patent/US20050113398A1/en
Assigned to RIGEL PHARMACEUTICALS, INC. reassignment RIGEL PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CATALANO, SUSAN, ARGADE, ANKUSH, CARROLL, DAVID, LI, HUI, SINGH, RAJINDER
Priority to US11/567,824 priority patent/US20080009484A1/en
Priority to US11/567,817 priority patent/US20080021020A1/en
Priority to US11/567,820 priority patent/US7884111B2/en
Priority to US12/981,094 priority patent/US8809341B2/en
Priority to US14/324,636 priority patent/US9598432B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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 three or more hetero rings
    • 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
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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to 2,4 pyrimidinediamine compounds that exhibit antiproliferative activity, prodrugs of the compounds, intermediates and methods of synthesis for making the compounds and/or prodrugs, pharmaceutical compositions comprising the compounds and the use of the compounds in a variety of contexts, including for the treatment of proliferative disorders, such as, for example, tumors and cancers.
  • Cancer is a group of varied diseases characterized by uncontrolled growth and spread of abornmal cells. Generally, all types of cancers involve some abnormality in the control of cell growth and division. The pathways regulating cell division and/or cellular communication become altered in cancer cells such that the effects of these regulatory mechanisms in controlling and limiting cell growth fails or is bypassed.
  • a group of abnormal cells generally originating from a single mutant cell, accumulates additional mutations that provide selective growth advantage over other cells, and thus evolves into a cell type that predominates in the cell mass. This process of mutation and natural selection is enhanced by genetic instability displayed by many types of cancer cells, an instability which is gained either from somatic mutations or by inheritance from the germ line.
  • the enhanced mutability of cancerous cells increases the probability of their progression towards formation of malignant cells. As the cancer cells further evolve, some become locally invasive and then metastasize to colonize tissues other than the cancer cell's tissue of origin. This property along with the heterogeneity of the tumor cell population makes cancer a particularly difficult disease to treat and eradicate.
  • Ionizing radiation including ⁇ -rays and x-rays
  • cytotoxic agents such as bleomycin, cis-platin, vinblastine, cyclophosphamide, 5′-fluorouracil, and methotrexate rely upon a generalized damage to DNA and destabilization of chromosomal structure which eventually lead to destruction of cancer cells.
  • These treatments are particularly effective for those types of cancers that have defects in cell cycle checkpoint, which limits the ability of these cells to repair damaged DNA before undergoing cell division.
  • the non-selective nature of these treatments however, often results in severe and debilitating side effects.
  • the systemic use of these drugs may result in damage to normally healthy organs and tissues, and compromise the long term health of the patient.
  • chemotherapeutic treatments have been developed based on knowledge of how cancer cells develop, for example, the anti-estrogen compound tamoxifen, the effectiveness of all chemotherapeutic treatments are subject to development of resistance to the drugs.
  • the increased expression of cell membrane bound transporters, such as MdrI produces a multidrug resistance phenotype characterized by increased efflux of drugs from the cell.
  • MdrI cell membrane bound transporters
  • identification of other chemotherapeutic agents is critical for establishing therapies effective for attacking the heterogeneous nature of proliferative disease and for overcoming any resistance that may develop over the course of therapy with other compounds.
  • use of combinations of chemotherapeutic agents with differing properties and cellular targets increases the effectiveness of chemotherapy and limits the generation of drug resistance.
  • the present invention provides 2,4-pyrimidinediamine compounds that exhibit antiproliferative activity against a variety of different cell types, including a variety of different types of tumor cells.
  • the compounds are generally 2,4-pyrimidinediamine compounds according to structural formula (I):
  • the present invention provides prodrugs of the 2,4-pyrimidinediamine compounds.
  • Such prodrugs may be active in their prodrug form, or may be inactive until converted under physiological or other conditions of use to an active drug form.
  • one or more functional groups of the 2,4-pyrimidinediamine compounds are included in promoieties that cleave from the molecule under the conditions of use, typically by way of hydrolysis, enzymatic cleavage or some other cleavage mechanism, to yield the functional groups.
  • promoieties that cleave from the molecule under the conditions of use, typically by way of hydrolysis, enzymatic cleavage or some other cleavage mechanism, to yield the functional groups.
  • primary or secondary amino groups may be included in an amide promoiety that cleaves under conditions of use to generate the primary or secondary amino group.
  • the prodrugs include special types of protecting groups, termed “progroups,” masking one or more functional groups of the 2,4-pyrimidinediamine compounds that cleave under the conditions of use to yield an active 2,4-pyrimidinediamine drug compound.
  • Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates, etc.
  • promoieties suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs. Specific examples of promoieties that yield primary or secondary amine groups that can be included in the prodrugs include, but are not limited to amides, carbamates, imines, ureas, phosphenyls, phosphoryls and sulfenyls.
  • promoieties that yield sulfanyl groups that can be included in the prodrugs include, but are not limited to, thioethers, for example S-methyl derivatives (monothio, dithio, oxythio, aminothio acetals), silyl thioethers, thioesters, thiocarbonates, thiocarbamates, asymmetrical disulfides, etc.
  • promoieties that cleave to yield hydroxyl groups that can be included in the prodrugs include, but are not limited to, sulfonates, esters and carbonates.
  • promoieties that yield carboxyl groups include, but are not limited to, esters (including silyl esters, oxamic acid esters and thioesters), amides and hydrazides.
  • the present invention provides compositions comprising one or more 2,4-pyrimidinediamine compounds and/or prodrugs and an appropriate carrier, excipient and/or diluent.
  • an appropriate carrier, excipient and/or diluent will depend on the desired use for the composition, and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use.
  • the 2,4-pyrimidinediamine compounds are potent inhibitors of proliferation abnormal cells, such as tumor cell proliferation, in in vitro assays.
  • the present invention provides methods of inhibiting proliferation of abnormal cells, in particular tumor cells.
  • the method generally involves contacting an abnormal cell such as a tumor cells with an amount of a 2,4-pyrimidinediamine compound or prodrug, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to inhibit its proliferation.
  • the method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of proliferative disorders, such as tumorigenic cancers.
  • the present invention provides methods of treating proliferative disorders.
  • the methods may be practiced in animals in veterinary contexts or in humans.
  • the methods generally involve administering to an animal or human subject an amount of a 2,4-pyrimidinediamine compound or prodrug, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to treat the disorder.
  • Proliferative disorders that can be treated according to the methods include, but are not limited to, tumorigenic cancers.
  • Alkyl by itself or as part of another substituent refers to a saturated or unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having the stated number of carbon atoms (i.e., C1-C6 means one to six carbon atoms) that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, buta-1,3-die
  • alkanyl alkenyl
  • alkynyl alkynyl
  • Alkanyl by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.
  • Alkenyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.
  • Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.
  • Alkyldiyl by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group having the stated number of carbon atoms (i.e., C1-C6 means from one to six carbon atoms) derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne.
  • the two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms.
  • Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,2-d
  • alkanyldiyl alkenyldiyl and/or alkynyldiyl
  • alkylidene alkylidene
  • the alkyldiyl groups are saturated acyclic alkanyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and the like (also referred to as alkylenes, defined infra).
  • Alkylene by itself or as part of another substituent refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne.
  • the locant of a double bond or triple bond, if present, in a particular alkylene is indicated in square brackets.
  • Typical alkylene groups include, but are not limited to, methylene (methano); ethylenes such as ethano, etheno, ethyno; propylenes such as propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenes such as butano, but[ ]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used.
  • the alkylene group is (C1-C6) or (C1-C3) alkylene. Also preferred are straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.
  • Cycloalkyl by itself or as part of another substituent refers to a cyclic version of an “alkyl” group.
  • Typical cycloalkyl groups include, but are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl; and the like.
  • “Lower cycloalkyl” refers to a cycloalkyl group having from 3 to 8 ring carbon atoms.
  • Cycloalkylalkyl by itself or as part of another substitutent refers to an alkyl group that comprises a linear or branched portion and a cyclic portion.
  • Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, 1-cycopropyleth-1-yl, 2-cyclopropyleth-1-yl, cyclobutylmethyl, 1-cycobytyleth-1-yl, 2-cyclobutyleth-1-yl, cyclopentylmethyl, 1-cycopentyleth-1-yl, 2-cyclopentyleth-1-yl, cyclohexylmethyl, 1-cycohexyleth-1-yl, 2-cyclohexleth-1-yl, and the like.
  • “Lower cycloalkylalkyl” refers to a cycloalkylalkyl group in which the linear or branched portion contains from 1 to 4 carbon atoms
  • Heteroalkyl by itself or as part of another substituent refers to an alkyl group in which at least one of the carbon atoms is replaced with a heteroatom, for example, a heteroatom selected from O, S and N. In heteroalkyl groups including more than one heteroatom, the heteroatoms may be the same or they may be different. Like an alkyl group, a heteroalkyl can be linear, branched or cyclic in structure, and can be saturated or unsaturated.
  • Typical heteralkyl groups include, but are not limited to, —CH 2 —O—CH 2 —, —CH 2 —S—CH 2 —, —CH 2 —NH—CH 2 —, —CH 2 —N(CH 3 )—CH 2 —, —CH 2 CH 2 —O—CH 2 —, —CH 2 CH 2 —S—CH 2 —, —CH 2 CH 2 —NH—CH 2 —, —CH 2 CH 2 —N(CH 3 )—CH 2 —, —CH 2 CH(CH 3 )—O—CH 2 —, —CH 2 CH(CH 3 )—S—CH 2 —, —CH 2 CH(CH 3 )—NH—CH 2 —, —CH 2 CH(CH 3 )—N(CH 3 )—CH 2 —, —CH ⁇ CH—O—CH 2 —, —CH ⁇ CH—S—CH 2 —, —CH ⁇ CH—NH—CH 2 —
  • heteroalkanyl refers to a heteroalkyl group having from 1 to 8 carbon and heteroatoms.
  • Cycloheteroalkyl by itself or as part of another substituent refers to a cyclic version of a heteroalkyl. Typical examples of cycloheteroalkyl groups include, but are not limited to, and the like. “Lower cycloheteroalkyl” refers to a cycloheteroalkyl group having from 3 to 8 ring atoms.
  • Parent aromatic Ring System refers to an unsaturated cyclic or polycyclic ring system having a conjugated n electron system.
  • parent aromatic ring system fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, tetrahydronaphthalene, etc.
  • Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and the like, as well as
  • Aryl by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon group having the stated number of carbon atoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers
  • Halogen or “Halo” by themselves or as part of another substituent, unless otherwise stated, refer to fluoro, chloro, bromo and iodo.
  • Haloalkyl by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms is replaced with a halogen.
  • haloalkyl is meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.
  • (C1-C2) haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.
  • alkyloxy or “alkoxy” refers to a group of the formula —OR
  • alkylamine refers to a group of the formula —NHR
  • dialkylamine refers to a group of the formula —NRR, where each R is independently an alkyl.
  • haloalkoxy or “haloalkyloxy” refers to a group of the formula —OR′, where R′ is a haloalkyl.
  • Prodrug refers to a derivative of an active 2,4-pyrimidinediamine compound (drug) that may require a transformation under the conditions of use, such as within the body, to release the active 2,4-pyrimidinediamine drug.
  • Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug.
  • Prodrugs are typically obtained by masking a functional group in the 2,4-pyrimidinediamine drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active 2,4-pyrimidinediamine drug.
  • the cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid or base, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature.
  • the agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
  • progroups as well as the resultant promoieties, suitable for masking functional groups in the active 2,4-pyrimidinediamines compounds to yield prodrugs are well-known in the art.
  • a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group.
  • An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group.
  • a carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group.
  • ester including silyl esters and thioesters
  • amide or hydrazide promoiety which may be hydrolyzed in vivo to provide the carboxyl group.
  • suitable progroups and their respective promoieties will be apparent to those of skill in the art.
  • Progroup refers to a type of protecting group that, when used to mask a functional group within an active 2,4-pyrimidinediamine drug to form a promoiety, converts the drug into a prodrug.
  • Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use.
  • a progroup is that portion of a promoiety that cleaves to release the functional group under the specified conditions of use.
  • an amide promoiety of the formula —NH—C(O)CH 3 comprises the progroup —C(O)CH 3 .
  • Proliferative disorder refers to a disease or disorder characterized by aberrant cell proliferation, for example where cells divide more than their counterpart normal cells.
  • the aberrant proliferation may be caused by any mechanism of action or combination of mechanisms of action.
  • the cell cycle of one or more cells may be affected such that cell(s) divide more frequently than their counterpart normal cells, or alternatively, one or more cells may bypass inhibitory signals which would normally limit their number of divisions.
  • Proliferative diseases include, but are not limited to, slow or fast growing tumors and cancers.
  • Antiproliferative compound refers to a compound that inhibits the proliferation of a cell as compared to an untreated control cell of a similar type.
  • the inhibition can be brought about by any mechanism or combination of mechanisms, and may operate to inhibit proliferation cytostatically or cytotoxically.
  • inhibition as used herein includes, but is not limited to, arrest of cell division, a reduction in the rate of cell division, proliferation and/or growth and/or induction of cell death.
  • “Pharmaceutically effective amount” or “therapeutically effective amount” refers to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder.
  • a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or to decrease the growth rate of the tumor.
  • the antiproliferative compounds are generally 2,4-pyrimidinediamine compounds according to structural formula (I):
  • An important class of compounds of structural formula (I) includes compounds in which L 1 and L 2 are each a covalent bond, such that the compound is a 2,4-pyrimidine diamine according to structural formula (II):
  • An important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R 5 is fluoro.
  • Another important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R 2′ is hydrogen.
  • R 2′ and R 4′ are each, independently of one another, selected from hydrogen and methyl.
  • Another important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R 4′ is methyl.
  • R 9 and R 10 are not both simultaneously lower alkoxy or methoxy. In other embodiments, R 8 , R 9 and R 10 are not each simultaneously lower alkoxy or methoxy. In still other embodiments R 8 , R 9 and R 10 are each methoxy or lower alkoxy.
  • R 8 is selected from hydrogen, lower alkyl, lower alkoxy, —OR a , halo, —CF 3 and —OCF 3 and one of R 9 or R 10 is selected from In a specific embodiment, the other one of R 9 or R 10 is other than In yet other embodiments, R 8 is selected from hydrogen, lower alkyl, —OR a , halo, —CF 3 and —OCF 3 and one of R 9 or R 10 is selected from —OCH 2 C(O)R a , —OCH 2 C(O)OR a , —OCH 2 C(O)NHR a , —OCH 2 C(O)NHR d and —OCH 2 C(O)NR c R c .
  • the other one of R 9 or R 10 is other than —OCH 2 C(O)R a , OCH 2 C(O)OR a , —OCH 2 C(O)NHR a , —OCH 2 C(O)NHR d or —OCH 2 C(O)NR c R c .
  • R 8 and R 9 are each, independently of one another, selected from hydrogen, lower alkyl, —OR a , halo, —CF 3 and —OR a and R 10 is In yet other embodiments R 9 is hydrogen and R 8 and R 10 are each, independently of one another, selected from the group consisting of lower alkyl, methyl, lower alkoxy, methoxy, —CF 3 and —OCF 3 . Specific combinations of R 8 and R 10 when R 9 is hydrogen are as follows:
  • R 9 is hydroxy, methoxy or chloro and R 8 and R 10 are each, independently of one another, selected from the group consisting of lower alkyl, methyl, lower alkoxy, methoxy and chloro.
  • R 8 , R 9 and R 10 are as follows:
  • R 2 and R 4 are each in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments no more than one of R 8 , R 9 and R 10 of the R 4 phenyl is hydrogen unless at least one of R 8 , R 9 or R 10 of the R 2 phenyl is —O(CH 2 ) n —NR c R c , In other embodiments, the substitution patterns of the R 2 and R 4 phenyl rings are different from each other such that the compound is not a N2,N4-bis(3,4,5-substituted phenyl)pyrimidinediamine.
  • the compound is a compound according to structural formula (VI): including the salts, hydrates, solvates and N-oxides thereof, wherein R 4′ , R 8 , R 9 and R 10 are as previously defined for structural formula (I).
  • R 2 and R 4 are each R 8 , R 9 and R 10 are selected such that each R 2 and R 4 phenyl ring is di-substituted. In one specific embodiment, each R 2 and R 4 phenyl ring is substituted with an ethylenedioxy acetal group.
  • R 2 and R 4 when R 2 and R 4 are each R 10 of the R 2 or R 4 ring is other than 1,3-oxazolyl or 1,3-oxazol-5-yl when the R 8 and R 9 of the same ring are each hydrogen.
  • R 8 , R 9 and R 10 are as defined in the preceeding sentence when R 5 is fluoro and L 2 is a lower alkylene.
  • R 2 is other than 3-(1,3-oxazolyl)phenyl or 3-(1,3-oxazol-5-yl)phenyl when R 4 is 2-(trifluoromethyl)benzyl.
  • the compound is other than N2-[3-(1,3-oxazolyl)phenyl]-N-4-[2-trifluoromethy)lbenzyl]-5-fluoro-2,4-pyrimidinediamine.
  • R 10 is an oxazolyl
  • the oxazolyl is not connected at the 5 position.
  • the oxazole is connected at the 2 position.
  • the compound is not any compound described in WO 03/040141, the disclosure of which is incorporated herein by reference.
  • R 9 or R 10 is selected from where R 12 is as previously defined for structural formula (I) and the other one of R 9 or R 10 is other than
  • R 8 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy and halo and one of R 9 or R 10 is —OCH 2 —R b , where R b is selected from —C(O)NR a and —C(O)NHR a , and the other one of R 9 or R 10 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy and halo.
  • R 2 is where R 8 is hydrogen, fluoro or CF 3 .
  • R 2 is
  • R 8 and R 9 are each independently selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo and chloro.
  • R 8 , R 9 and R 13 are each independently selected from halo, lower alkyl, methyl, lower alkoxy, and methoxy.
  • R 2 is selected from
  • R 4 is selected from where D is as previously defined for structural formula (I).
  • R 4 is where Z 1 , Z 2 and R 16 , R 17 , R 18 , R 19 and R 20 are as previously described for structural formula (I).
  • R 12 is methyl.
  • R 12 is —C(O)R a or —C(O)OR a , where R a is lower alkyl, ethyl or methyl.
  • each R 13 is, independently or the other, selected from lower alkyl, methyl, hydroxy, lower alkoxy and methoxy; and/or (ii) R 4 is selected from where Z 1 , Z 2 and R 16 , R 17 , R 18 , R 19 and R 20 are as previously described for structural formula (I).
  • R 4 is where Z 1 is CH, R 16 is hydrogen, R 17 and R 18 are taken together to form an oxo ( ⁇ O) group and R 19 and R 20 are each hydrogen or methyl; and R 2 is where each R 13 is, independently of the other, selected from lower alkyl, methyl, hydroxy, lower alkoxy and methoxy.
  • R 4 is where D is as previously defined for structural formula (I).
  • R 11 is selected from the group consisting of hydroxy, methoxy, ethoxy, —NHCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH(OH)CH 2 OH, —NHCH 2 CH(OH)(CH 3 ) 2 , —N(CH 3 )CH 2 CH 2 OH and —N(CH 3 )C(CH 3 ) 2 CH 2 OH and Y is as previously defined.
  • R 2 is in the compounds described herein, such as the compounds of structural formulae (I)-(V), in some embodiments the ring is connected to the remainder of the molecule at the 5-position ( ). In other embodiments, it is connected to the remainder of the molecule at the 6-position ( ).
  • R 16 is selected from lower n-alkanyl, lower branched alkanyl, lower cycloalkanyl and lower cycloalkanylmethyl.
  • R 4 is selected from
  • R 4 is selected from lower cycloalkyl and lower cycloheteroalkyl optionally substituted at one or more ring carbon or heteroatoms with an R a or an R b group.
  • R 4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, where R e and R f are selected from (C1-C3) alkanyl and methyl and R g is benzyl.
  • each R e is methyl.
  • R f is ethyl.
  • R 4 is selected from lower alkyl, isopropyl, t-butyl, lower cycloalkyl, in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments R 2 is selected from where R 8 , R 9 , R 10 and R 13 are as previously defined for structural formula (I). In a specific embodiment, R 2 is selected from any of the above-described embodiments of these substituted phenyls. In other embodiments, R 2 is where R 8 and R 9 are a prevsiously defined for structural formula (I).
  • R 4 is where R 15 is lower branched alkyl or t-butyl, and R 2 is in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments at least one of R 8 or R 10 is other than hydrogen. In other embodiments, at least two of R 8 , R 9 and R 10 are other than hydrogen. In still other embodiments, at least two of R 8 , R 9 and R 13 are other than hydrogen.
  • R 9 is and R 10 is other than or (ii) R 10 is and R 9 is other than In a specific embodiment of alternative (i), R 10 is hydrogen. In a specific embodiment of alternative (ii), R 9 is hydrogen.
  • R 10 when R 2 is where R 8 and R 9 are each hydrogen, then R 10 is other than lower branched alkyl, t-butyl or O(CH 2 ) n R b , where n is as previously defined for structural formula (I) and R b is selected from —NR c R c , —C(O)OR a , —C(O)NR c R c and —C(O)NR a R d .
  • R 8 is other than —O(CH 2 ) n R b , where n is as previously defined for structural formula (I) and R b is —NR c R c .
  • the compound is not any compound described in WO 01/64656, WO 03/026665 or WO 03/026666, the disclosures of which are incorporated herein by reference.
  • R 4 is ——(CH 2 ) n —R b in the compounds described herein, such as, for example, the compounds of structural formulae (II)-(V), in some embodiments R b is selected from the group consisting of —OR, —NR c R c , —C(O)R a and —C(O)NR c R c , where each R c is independently selected from hydrogen and lower alkyl.
  • R 2 is where R 9 is selected from the group consisting of —OR a , methoxy, isopropoxy, —OCH 2 C(O)OR a , —OCH 2 C(O)NHR a , —OCH 2 C(O)NR a R a and —OCH 2 CH 2 NR a R a ; and R 8 and R 10 are as previously defined for structural formual (I).
  • R 8 and R 10 are selected from one of the following combinations:
  • R 4 is selected from lower alkyl optionally monosubstituted with an R b group, a lower cycloalkyl optionally monosubstituted with an R b group and —C(R a R a ) n —R b , where, R a and R b are as previously defined for structural formula (I), and/or L 2 is a lower alkylene linker in the compounds described herein, in some embodiments, R 2 is other than mono-substituted phenyl, 3-hydroxyphenyl, 3-halophenyl, 3-chlorophenyl, 3-bromophenyl, 4-halophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-dihalophenyl, 3,4-dichlorophenyl or 3,4-dichlorophenyl.
  • R 2 is other than these defined groups in compounds in which R 5 is —CF 3 .
  • the compound is not any compound described in US 2003/0171359 and/or WO 03/032997, the disclosures of which are incorporated herein by reference.
  • R 9 and R 9 are non-bulky substitutents.
  • R 9 is other than and R 10 is other than
  • R 8 , R 9 and R 10 are each, independently of one another, selected from hydrogen lower alkyl, methyl hydroxy, lower alkoxy, methoxy, halo, fluoro and chloro.
  • R 8 is selected from hydrogen, lower alkyl, methyl, lower alkoxy and methoxy
  • R 9 is selected from hyrogen
  • R 10 is selected from lower alkyl, methyl, lower alkoxy, methoxy, halo, fluoro and
  • R 4 is in some embodiments D is selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —, —CF 2 —CF 2 — and —CH 2 —CH 2 —CH 2 —.
  • the lower alkyl substituent or group is a saturated straight-chained, branched or cyclic alkyl (i.e., an alkanyl).
  • Type A Type B No. Type R 21 R 22 R 23 R 4′ A549 H1299 178 A H H H + + 179 A H H H + + 180 A H Cl H + + 181 A H Me H + + 182 A H CF 3 H + + 183 B H — H + + 184 B Me — H + + +
  • Type A Type B No. Type R 21 R 22 R 23 R 4′ A549 H1299 185 A H H H + + 186 A H H H + + 187 A H Cl H + + 188 A H Me H + + 189 A H CF 3 H + + 190 B H — H + +
  • Type A Type B No. Type R 21 R 22 R 23 R 4′ A549 H1299 191 A H H H 192 A H H H 193 A H H H 194 A H H H 195 A H H H 196 A H H H 197 A H H H 198 A H H H H
  • Type A Type B No. Type R 4 R 21 R 22 R 23 A549 H1299 215 A i-propyl H H + + 216 A i-propyl H Cl + + 217 A i-propyl H Me + + 218 A i-propyl H CF 3 + + 219 A i-propyl H H + + 220 A t-butyl H H + + 221 A t-butyl H H + + 222 A t-butyl H Cl + + 223 A t-butyl H Me + + + 224 A t-butyl H CF 3 + + 225 B i-propyl H — + + 226 B t-butyl H — + + 227 B i-propyl Me — + + + + +
  • Type A Type B No. Type R 4′ R 4 Y R 11 A549 HTC116 H1299 617 A H NH OEt ⁇ 618 A H NH OEt + 619 A H O OMe ⁇ 620 A H O OMe 621 A H NH OH ⁇ 622 A H O OH ⁇ 623 A H O OMe ⁇ 624 A H O ⁇ 625 A H O + + 626 A H O ⁇ /+ + 627 A H O NHMe ⁇ 628 A H O NHMe ⁇ 629 A H O NHMe + + 630 A H O NH(CH 2 ) 2 OH ⁇ 631 A H O NH(CH 2 ) 2 OH + + 632 A H O + + 633 A H O + + 634 A H O + ⁇ 635 A H O + 636 A H O OMe + ⁇ 637 A H NH OEt 638 A H O OMe ⁇ 639 A H O OH ⁇ 640 A H O O
  • Type A Type B Type C Type D No. Type R 16 R 31 R 32 R 33 A549 H1299 1066 B ethyl H OMe Cl 1067 B ethyl H Cl Cl 1068 B ethyl ⁇ ⁇ ⁇ 1069 B ethyl H F OMe 1070 A ethyl H OMe Cl 1071 A ethyl H Cl Cl 1072 C ethyl ⁇ ⁇ ⁇ 1073 A ethyl H F OMe 1074 B n-propyl H OMe Cl + + 1075 B n-propyl H Cl Cl ⁇ ⁇ 1076 D n-propyl ⁇ ⁇ + + 1077 A n-propyl H F OMe + + 1078 B n-propyl H OMe Cl + + 1079 B n-propyl H Cl Cl + + 1080 C n-propyl ⁇ ⁇ ⁇ + + 1081 A n-propyl H F OM
  • the 2,4-pyrimidinediamine compounds described herein may include functional groups that can be masked with progroups to create prodrugs.
  • prodrugs are usually, but need not be, pharmacologically inactive until converted into their active drug form.
  • ester groups commonly undergo acid-catalyzed hydrolysis to yield the parent carboxylic acid when exposed to the acidic conditions of the stomach, or base-catalyzed hydrolysis when exposed to the basic conditions of the intestine or blood.
  • 2,4-pyrimidinediamines that include ester moieties may be considered prodrugs of their corresponding carboxylic acid, regardless of whether the ester form is pharmacologically active.
  • any available functional moiety may be masked with a progroup to yield a prodrug.
  • Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.
  • Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs of the invention.
  • the prodrugs are compounds according to structural formulae (I)-(VI) in which R a , R b and R c may be, in addition to their previously-defined alternatives, a progroup.
  • the prodrugs are compounds according to structural formulae (I)-(VI) in which R 2′ and R 4′ are each, independently of one another, a progroup.
  • Specific examples of progroups according to this embodiment of the invention include, but are not limited to, —C(O)CH 3 , —C(O)NHR h and —S(O) 2 R h , where R h is selected from the group consisting of lower alkyl, (C5-C15) aryl and (C3-C8) cycloalkyl.
  • the compounds and prodrugs described herein, as well as the various compound species specifically described and/or illustrated herein, may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism.
  • the compounds and prodrugs may include one or more chiral centers and/or double bonds and as a consequence may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers and diasteromers and mixtures thereof, such as racemic mixtures.
  • the compounds and prodrugs may exist in several tautomeric forms, including the enol form, the keto form and mixtures thereof.
  • the 2,4-pyrimidinediamine compounds and prodrugs may be in the form of salts.
  • Such salts include salts suitable for pharmaceutical uses (“pharmaceutically-acceptable salts”), salts suitable for veterinary uses, etc.
  • Such salts may be derived from acids or bases, as is well-known in the art.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans.
  • Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids.
  • Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenes
  • Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion or an aluminum ion) or coordinates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.).
  • a metal ion e.g., an alkali metal ion, an alkaline earth metal ion or an aluminum ion
  • organic base e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.
  • the 2,4-pyrimidinediamine compounds and prodrugs, as well as the salts thereof, may also be in the form of hydrates, solvates and N-oxides, as are well-known in the art.
  • the 2,4-pyrimidinediamine compounds and prodrugs may be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods. Suitable exemplary methods that may be routinely adapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugs are found in U.S. Pat. No. 5,958,935, the disclosure of which is incorporated herein by reference. Specific examples describing the synthesis of numerous 2,4-pyrimidinediamine compounds and prodrugs, as well as intermediates therefor, are described in copending U.S. application Ser. No. 10/355,543, filed Jan. 31, 2003 (U.S. 2004-0029902 published Feb. 12, 2004), WO 03/63794, copending U.S.
  • the compounds can be synthesized from substituted or unsubstituted uracils or thiouracils as illustrated in Scheme (I), below:
  • R 2 , R 4 , R 5 , R 6 , L 1 and L 2 are as previously defined for structural formulae (I),
  • X is a halogen (e.g., F, Cl, Br or I) and G and G′ are each, independently of one another, selected from the group consisting of O and S.
  • uracil or thiouracil 2 is dihalogenated at the 2- and 4-positions using standard halogenating agent POX 3 (or other standard halogenating agent) under standard conditions to yield 2,4-bishalo pyrimidine 4.
  • the halide at the C4 position is more reactive towards nucleophiles than the halide at the C2 position.
  • This differential reactivity can be exploited to synthesize 2,4-pyrimidinediamines according structural formulae (I) by first reacting 2,4-bishalopyrimidine 4 with one equivalent of amine 10, yielding 4N-substituted-2-halo-4-pyrimidineamine 8, followed by amine 6 to yield a 2,4-pyrimidinediamine according structural formulae (I).
  • 2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be obtained by reacting 2,4-bishalopyrimidine 4 with excess 6 or 10, respectively.
  • the C4 halide is more reactive towards nucleophiles, as illustrated in the Scheme.
  • the identity of the R 5 substituent may alter this reactivity. For example, when R 5 is trifluoromethyl, a 50:50 mixture of 4N-substituted-4-pyrimidineamine 8 and the corresponding 2N-substituted-2-pyrimidineamine is obtained. Regardless of the identity of the R 5 substituent, the regioselectivity of the reaction can be controlled by adjusting the solvent and other synthetic conditions (such as temperature), as is well-known in the art.
  • the uracil or thiouracil 2 starting materials may be purchased from commercial sources or prepared using standard techniques of organic chemistry.
  • Commercially available uracils and thiouracils that can be used as starting materials in Scheme (I) include, by way of example and not limitation, uracil (Aldrich #13,078-8; CAS Registry 66-22-8); 2-thio-uracil (Aldrich #11,558-4; CAS Registry 141-90-2); 2,4-dithiouracil (Aldrich #15,846-1; CAS Registry 2001-93-6); 5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7; 5-fluorouracil (Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry 696-07-1); 5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5); 5-(trifluoromethyl)
  • Additional 5-substituted uracils and/or thiouracils are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • Amines 6 and 10 may be purchased from commercial sources or, alternatively, may be synthesized utilizing standard techniques. For example, suitable amines may be synthesized from nitro precursors using standard chemistry. Specific exemplary reactions are provided in the Examples section. See also Vogel, 1989, Practical Organic Chemistry , Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.
  • amines 6 and 10 and/or substituents R 5 and/or R 6 on uracil or thiouracil 2 may include functional groups that require protection during synthesis.
  • the exact identity of any protecting group(s) used will depend upon the identity of the functional group being protected, and will be apparent to these of skill in the art.
  • Guidance for selecting appropriate protecting groups, as well as synthetic strategies for their attachment and removal, may be found, for example, in Greene & Wuts, Protective Groups in Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New York (1999) and the references cited therein (hereinafter “Greene & Wuts”).
  • Scheme (I) A specific embodiment of Scheme (I) utilizing 5-fluorouracil (Aldrich #32,937-1) as a starting material is illustrated in Scheme (II), below:
  • non-bis-2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may be obtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with one equivalent of amine 10 (to yield 2-chloro-N-4-substituted-5-fluoro-4-pyrimidineamine 7) followed by one or more equivalents of amine 6.
  • 2,4-pyrimidinediamine compounds of the invention may be synthesized from substituted or unsubstituted cytosines as illustrated in Schemes (IIa) and (IIb), below:
  • Protected cytosine 22 is halogenated at the C2 position using a standard halogenation reagent under standard conditions to yield 2-chloro-4N-protected-4-pyrimidineamine 24. Reaction with amine 6 followed by deprotection of the C4 exocyclic amine and reaction with amine 10 yields a 2,4-pyrimidinediamine according to structural formulae (I).
  • cytosine 20 may be reacted with amine 10 or protected amine 21 to yield N4-substituted cytosine 23 or 27, respectively.
  • substituted cytosines may then be halogenated as previously described, deprotected (in the case of N4-substituted cytosine 27) and reacted with amine 6 to yield a 2,4-pyrimidinediamine according to structural formulae (I).
  • cytosines that may be used as starting materials in Schemes (IIa) and (IIb) include, but are not limited to, cytosine (Aldrich #14,201-8; CAS Registry 71-30-7); N4-acetylcytosine (Aldrich #37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich #27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine.
  • suitable cytosines useful as starting materials in Schemes (IIa) are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • the 2,4-pyrimidinediamine compounds may be synthesized from substituted or unsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III), below:
  • Suitable commercially-available 2-amino-4-pyrimidinols 30 that can be used as starting materials in Scheme (III) are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • 2,4-pyrimidinediamine compounds may be prepared from substituted or unsubstituted 4-amino-2-pyrimidinols as illustrated in Scheme (IV), below:
  • R 2 , R 4 , R 5 , R 6 , L 1 and L 2 are as previously defined for Scheme (I) and Z represents a leaving group.
  • Z represents a leaving group.
  • the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towards nucleophiles than the C4-amino such that reaction with amine 6 yields N2-substituted-2,4-pyrimidinediamine 42.
  • Subsequent reaction with compound 44, which includes a good leaving group Z, or amine 10 yields a 2,4-pyrimidinediamine according to structural formulae (I).
  • Compound 44 may include virtually any leaving group that can be displaced by the C4-amino of N2-substituted-2,4-pyrimidinediamine 42.
  • Suitable leaving groups Z include, but are not limited to, halogens, methanesulfonyloxy (mesyloxy; “OMs”), trifluoromethanesulfonyloxy (“OTf”) and p-toluenesulfonyloxy (tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”) and metanitro benzene sulfonyloxy (“nosylate”).
  • halogens methanesulfonyloxy
  • OTf trifluoromethanesulfonyloxy
  • OTs p-toluenesulfonyloxy
  • besylate benzene sulfonyloxy
  • Substituted 4-amino-2-pyrimidinol starting materials may be obtained commercially or synthesized using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • the 2,4-pyrimidinediamine compounds can be prepared from 2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines as illustrated in Scheme (V), below:
  • pyrimidines 50 and 54 suitable for use as starting materials in Scheme (V) are commercially available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • 4-chloro-2-pyrimidineamines 50 may be prepared as illustrated in Scheme (Va):
  • R 5 and R 6 are as previously defined for structural formulae (I).
  • dicarbonyl 53 is reacted with guanidine to yield 2-pyrimidineamine 51.
  • Reaction with peracids like m-chloroperbenzoic acid, trifluoroperacetic acid or urea hydrogen peroxide complex yields N-oxide 55, which is then halogenated to give 4-chloro-2-pyrimidineamine 50.
  • the corresponding 4-halo-2-pyrimidineamines may be obtained by using suitable halogenation reagents.
  • the 2,4-pyrimidinediamine compounds can be prepared from substituted or unsubstituted uridines as illustrated in Scheme (VI), below:
  • R 2 , R 4 , R 5 , R 6 , L 1 , L 2 and X are as previously defined for Scheme (I) and the superscript PG represents a protecting group, as discussed in connection with Scheme (IIb).
  • uridine 60 has a C4 reactive center such that reaction with amine 10 or protected amine 21 yields N4-substituted cytidine 62 or 64, respectively.
  • N4-substituted 62 or 64 Acid-catalyzed deprotection of N4-substituted 62 or 64 (when “PG” represents an acid-labile protecting group) yields N4-substituted cytosine 28, which may be subsequently halogenated at the C2-position and reacted with amine 6 to yield a 2,4-pyrimidinediamine according to structural formulae (I).
  • uridines and cytidines useful as starting materials in Schemes (VI) and (VII) are known in the art, and include, by way of example and not limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem. Sources #ABCR F07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem.
  • R 4 , R 5 , R 6 , L 2 , Y, R a and R c are as previously defined for structural formulae (I).
  • Each R a′ is independently an R a , and may be the same or different from the illustrated R a .
  • carboxylic acid or ester 100 may be converted to amide 104 by reaction with amine 102.
  • R a′ may be the same or different than R a of acid or ester 100.
  • carbonate ester 106 may be converted to carbamate 108.
  • Prodrugs as described herein may be prepared by routine modification of the above-described methods.
  • such prodrugs may be prepared by reacting a suitably protected 2,4-pyrimidinediamine of structural formula (I), (II), (III), (IV) and/or (V) with a suitable progroup.
  • Conditions for carrying out such reactions and for deprotecting the product to yield a prodrugs as described herein are well-known.
  • Active 2,4-pyrimidinediamine compounds typically inhibit proliferation of desired cells, such as tumor cells, with an IC 50 in the range of about 1 mM or less, as measured in a standard in vitro cellular proliferation assay.
  • desired cells such as tumor cells
  • IC 50 in the range of about 1 mM or less, as measured in a standard in vitro cellular proliferation assay.
  • compounds which exhibit lower IC 50 s for example on the order of 100 ⁇ M, 20 ⁇ M, 10 ⁇ M, 1 ⁇ M, 100 nM, 10 nM, 1 nM, or even lower, may be particularly useful in therapeutic applications.
  • the antiprolierative activity may be cytostatic or it may be cytotoxic.
  • the compound may be assayed for activity with the desired cell type and counter-screened for a lack of activity against other cell types.
  • the desired degree of “inactivity” in such counter screens, or the desired ratio of activity vs. inactivity may vary for different situations, and may be selected by the user.
  • the antiproliferative 2,4-pyrimidinediamine compounds may be used to inhibit cell proliferation in a variety of contexts.
  • a cell or population of cells is contacted with an amount of such a compound effective to inhibit proliferation of the cell or cell population.
  • the compound may act cytotoxically to kill the cell, or cytostatically to inhibit proliferation without killing the cell.
  • the methods may be practiced as a therapeutic approach towards the treatment of proliferative disorders.
  • the 2,4-pyrimidinediamine compounds may be used to treat proliferative disorders in animal subjects, including humans.
  • the method generally comprises administering to the subject an amount of a compound of the invention, or a salt, prodrug, hydrate or N-oxide thereof, effective to treat the disorder.
  • the subject is a mammal, including, but not limited to, bovine, horse, feline, canine, rodent, or primate.
  • the subject is a human.
  • a variety of cellular proliferative disorders may be treated with the compounds of the present invention.
  • the compounds are used to treat various cancers in afflicted subjects. Cancers are traditionally classified based on the tissue and cell type from which the cancer cells originate. Carcinomas are considered cancers arising from epithelial cells while sarcomas are considered cancers arising from connective tissues or muscle. Other cancer types include leukemias, which arise from hematopoietic cells, and cancers of nervous system cells, which arise from neural tissue. For non-invasive tumors, adenomas are considered benign epithelial tumors with glandular organization while chondomas are benign tumor arising from cartilage. In the present invention, the described compounds may be used to treat proliferative disorders encompassed by carcinomas, sarcomas, leukemias, neural cell tumors, and non-invasive tumors.
  • the compounds are used to treat solid tumors arising from various tissue types, including, but not limited to, cancers of the bone, breast, respiratory tract (e.g., bladder), brain reproductive organs, digestive tract, urinary tract, eye, liver, skin, head, neck, thyroid, parathyroid, and mestastatic forms thereof.
  • various tissue types including, but not limited to, cancers of the bone, breast, respiratory tract (e.g., bladder), brain reproductive organs, digestive tract, urinary tract, eye, liver, skin, head, neck, thyroid, parathyroid, and mestastatic forms thereof.
  • proliferative disorders include the following: a) proliferative disorders of the breast include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma, lobular carcinoma in situ, and metastatic breast cancer; b) proliferative disorders of the skin include, but are not limited to, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, and Karposi's sarcoma; c) proliferative disorders of the respiratory tract include, but are not limited to, small cell and non-small cell lung carcinoma, bronchial adema, pleuropulmonary blastoma, and malignant mesothelioma; d) proliferative disorders of the brain include, but are not limited to, brain stem and hyptothalamic glioma, cerebellar and cerebral astrocytoma, medullablastoma, ependymal tumors, oligodendroglial, meningiomas, and neuroecto
  • proliferative disorders is not limited to the conditions described above, but encompasses other disorders characterized by uncontrolled growth and malignancy. It is further understood that proliferative disorders include various metastatic forms of the tumor and cancer types described herein. The compounds of the present invention may be tested for effectiveness against the disorders described herein, and a therapeutically effective regimen established. Effectiveness, as further described below, includes reduction or remission of the tumor, decreases in the rate of cell proliferation, or cytostatic or cytotoxic effect on cell growth.
  • the compounds of the present invention may be used alone, in combination with one another, or as an adjunct to, or in conjunction with, other established antiproliferative therapies.
  • the compounds of the present invention may be used with traditional cancer therapies, such as ionization radiation in the form of ⁇ -rays and x-rays, delivered externally or internally by implantation of radioactive compounds, and as a follow-up to surgical removal of tumors.
  • the compounds of the present invention may be used with other chemotherapeutic agents useful for the disorder or condition being treated. These compounds may be administered simultaneously, sequentially, by the same route of administration, or by a different route.
  • the present compounds may be used with other anti-cancer or cytotoxic agents.
  • Various classes of anti-cancer and anti-neoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, substituted ureas, tyrosine kinase inhibitors, hormones and hormone antagonists.
  • Exemplary alkylating agents include, by way of example and not limitation, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (e.g., busulfan), and carmustine.
  • Exemplary antimetabolites include, by way of example and not limitation, folic acid analog methotrexate; pyrmidine analog fluorouracil, cytosine arbinoside; purine analogs mecaptopurine, thioguanine, and azathioprine.
  • Exemplary vinca alkyloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine.
  • Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin.
  • An exemplary enzyme effective as anti-neoplastic agents include L-asparaginase.
  • Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin.
  • hormones and hormone related compounds include, by way of example and not limitation, adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitors amino glutethimide, formestane, and anastrozole; progestin compounds hydroxyprogesteron caproate, medroxyprogesterone; and anti-estrogen compound tamoxifen.
  • Addtional anti-proliferative compounds useful in combination with the compounds of the present invention include, by way of example and not limitation, antibodies directed against growth factor receptors (e.g., anti-Her2); antibodies for activating T cells (e.g., anti-CTLA-4 antibodies); and cytokines such as interferon- ⁇ and interferon- ⁇ , interleukin-2, and GM-CSF.
  • growth factor receptors e.g., anti-Her2
  • antibodies for activating T cells e.g., anti-CTLA-4 antibodies
  • cytokines such as interferon- ⁇ and interferon- ⁇ , interleukin-2, and GM-CSF.
  • the active compounds When used to treat or prevent such diseases, the active compounds may be administered singly, as mixtures of one or more active compounds or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases.
  • the active compounds may also be administered in mixture or in combination with agents useful to treat other disorders or maladies, such as steroids, membrane stablizers.
  • the active compounds or prodrugs may be administered per se, or as pharmaceutical compositions, comprising an active compound or prodrug.
  • compositions comprising the active compounds of the invention (or prodrugs thereof) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping or lyophilization processes.
  • the compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically (see Remingtons's Pharmaceutical Sciences, 15 th Ed., Hoover, J. E. ed., Mack Publishing Co. (2003)
  • the active compound or prodrug may be formulated in the pharmaceutical compositions per se, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt, as previously described.
  • such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed.
  • compositions of the invention may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.
  • the active compound(s) or prodrug(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
  • Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles.
  • the compositions may also contain formulating agents, such as suspending, stabilizing and/or dispersing agent.
  • the formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.
  • the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use.
  • a suitable vehicle including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc.
  • the active compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are known in the art.
  • the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate, lecithin).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophoreTM or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound or prodrug, as is well known.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compound(s) or prodrug(s) can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the active compound(s) or prodrug(s) may be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye.
  • a variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Pat. No. 6,261,547; U.S. Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807; U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No. 5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat. No. 4,882,150; and U.S. Pat. No. 4,738,851.
  • the active compound(s) or prodrug(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection.
  • the active ingredient may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
  • transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases the active compound(s) for percutaneous absorption may be used.
  • permeation enhancers may be used to facilitate transdermal penetration of the active compound(s). Suitable transdermal patches are described in for example, U.S. Pat. No.
  • Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver active compound(s) or prodrug(s).
  • Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed, although usually at the cost of greater toxicity.
  • DMSO dimethylsulfoxide
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s).
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the active compound(s) or prodrug(s) of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated.
  • the compound(s) may be administered therapeutically to achieve therapeutic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.
  • the amount of compound administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art.
  • Effective dosages may be estimated initially from in vitro assays.
  • an initial dosage for use in animals may be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC 50 of the particular compound as measured in an in vitro assay, such as the in vitro assays described in the Examples section.
  • Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans.
  • the reader is referred to Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics , Chapter 1, pp. 1-46, latest edition, Pagamonon Press, and the references cited therein.
  • Initial dosages may also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well-known in the art. Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration and various factors discussed above. Dosage amount and interval may be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect.
  • the compounds may be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician.
  • the effective local concentration of active compound(s) may not be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • the compound(s) will provide therapeutic or prophylactic benefit without causing substantial toxicity.
  • Toxicity of the compound(s) may be determined using standard pharmaceutical procedures.
  • the dose ratio between toxic and therapeutic (or prophylactic) LD 50 /ED 50 effect is the therapeutic index (LD 50 is the dose lethal to 50% of the population and ED 50 is the dose therapeutically effective in 50% of the population).
  • Compounds(s) that exhibit high therapeutic indices are preferred.
  • kits The compounds and/or prodrugs described herein may be assembled in the form of kits.
  • the kit provides the compound(s) and reagents to prepare a composition for administration.
  • the composition may be in a dry or lyophilized form, or in a solution, particularly a sterile solution.
  • the reagent may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation.
  • the kit may contain a device for administration or for dispensing the compositions, including, but not limited to syringe, pipette, transdermal patch, or inhalant.
  • kits may include other therapeutic compounds for use in conjunction with the compounds described herein.
  • the therapeutic agents are other anti-cancer and anti-neoplastic compounds. These compounds may be provided in a separate form, or mixed with the compounds of the present invention.
  • kits will include appropriate instructions for preparation and administration of the composition, side effects of the compositions, and any other relevant information.
  • the instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, or optical disc.
  • the IC 50 values of various compounds against a various different tumor cell lines were determined using standard in vitro antiproliferation assays.
  • the tumor cell lines tested were as follows: A549 (lung); H1299 (lung), ACHN (kidney/p53 wt), CAKI (renal cell carcinoma), NCI-H460 (lung); HCT116 (colon/p53 wt); HELA (cervix/p53 wt), HUH7 (liver/p53 wt), HUVEC (primary endothelial), LNCAP (prostate), HT-29 (colon); MCF-7 (breast); MCF-7 (breast/ER positive), MDA MB435S (breast); MDA MB231 (breast/ER negative), DU145 (prostate); BxPC-3 (pancreatic); SKOV-3 (ovarian); HepG2 (hepatic), NDHF primary normal human dermal fibroblast), SKMEL28 (breas
  • a “+” indicates an IC 50 of 20 ⁇ M or less
  • a “ ⁇ ” indicates an IC 50 of >20 ⁇ M.
  • a value of “ ⁇ /+” indicates that the specific compound exhibited an IC 50 of >20 ⁇ M in a 3-point assay, but exhibited an IC 50 of ⁇ 20 ⁇ M in a higher-point (e.g., 6-point) assay.
  • a value of “+/ ⁇ ” indicates that the specific compound exhibited an IC 50 of ⁇ 20 ⁇ M in a 3-point assay, but exhibited an IC 50 of >20 ⁇ M in a higher-point (e.g., 6-point) assay.
  • a blank indicates the specified compound was not tested against the specified cell line. Many of the compounds tested exhibited IC50s against A549 and/or H1299 cells in the nanomolar range.
  • tumor size 107 A549 25 mg/kg and Bid daily 16% Cremophor/ Compound No significant 50 mg/kg And 16% EtOH/ crashed out of reduction in Bid 4 days w/8 68% Saline solution when tumor size seen days rest saline was with either added dose 858 A549 25 mg/kg Bid, daily 5% EtOH/ No No significant 15% Cremophor/ precipitation reduction in 80% Saline was noted tumor size seen 164, 211 A549 25 mg/kg R563-5 days bid 100% DMSO No 23.2% with 2 days of precipitation reduction in rest was noted tumor size in R565-bid, daily mice treated with 211. Compound 164 showed no significant reduction in tumor size.

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US8809341B2 (en) 2014-08-19
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