WO2002047690A1 - 2-aryl-4-arylaminopyrimidines substituees et analogues en tant qu'activateurs de caspases et qu'inducteurs d'apoptose, et utilisation associee - Google Patents

2-aryl-4-arylaminopyrimidines substituees et analogues en tant qu'activateurs de caspases et qu'inducteurs d'apoptose, et utilisation associee Download PDF

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WO2002047690A1
WO2002047690A1 PCT/US2001/047498 US0147498W WO0247690A1 WO 2002047690 A1 WO2002047690 A1 WO 2002047690A1 US 0147498 W US0147498 W US 0147498W WO 0247690 A1 WO0247690 A1 WO 0247690A1
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pyrimidine
pyridinyl
trifluoromethyl
methyl
chloro
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PCT/US2001/047498
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Sui Xiong Cai
John A. Drewe
Bao Nguyen
P Sanjeeva Reddy
Azra Pervin
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Cytovia, Inc.
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Priority to EP01990048A priority Critical patent/EP1351691A4/fr
Priority to AU2002228922A priority patent/AU2002228922A1/en
Publication of WO2002047690A1 publication Critical patent/WO2002047690A1/fr

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    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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

  • This invention is in the field of medicinal chemistry.
  • the invention relates to substituted 2-aryl-4-arylaminopyrimidines and analogs, and the discovery that these compounds are activators of caspases and inducers of apoptosis.
  • the invention also relates to the use of these compounds as therapeuticaUy effective anti-cancer agents.
  • Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-431 (1965); Ellis, et al, Dev. 112:591-603 (1991); Vaux, et al., Cell 76:111-119 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721).
  • Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A.H., in Cell Death in Biology and Pathology, Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34).
  • a cell activates its internally encoded suicide program as a result of either internal or external signals.
  • the suicide program is executed through the activation of a carefully regulated genetic program (Wyllie, et al, Int. Rev. Cyt. 68:251 (1980); Ellis, et al, Ann. Rev. Cell Bio. 7:663 (1991)).
  • Apoptotic cells and bodies are usually recognized and cleared by neighboring cells or macrophages before lysis. Because of this clearance mechanism, inflammation is not induced despite the clearance of great numbers of cells (Orrenius, S., J. Internal Medicine 237:529-536 (1995)).
  • caspase family of cysteine proteases comprises 14 different members, and more may be discovered in the future. All known caspases are synthesized as zymogens that require cleavage at an aspartyl residue prior to forming the active enzyme. Thus, caspases are capable of activating other caspases, in the manner of an amplifying cascade.
  • Apoptosis and caspases are thought to be crucial in the development of cancer ⁇ Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds., Humana Press (1999)).
  • cancer cells while containing caspases, lack parts of the molecular machinery that activates the caspase cascade. This makes the cancer cells lose their capacity to undergo cellular suicide and the cells become cancerous.
  • control points are known to exist that represent points for intervention leading to activation.
  • CED-9-BCL-like and CED-3-ICE-like gene family products are intrinsic proteins regulating the decision of a cell to survive or die and executing part of the cell death process itself, respectively (see, Schmitt, et al, Biochem. Cell. Biol. 75:301- 314 (1997)).
  • BCL-like proteins include BCL-xL and BAX-alpha, which appear to function upstream of caspase activation.
  • BCL-xL appears to prevent activation of the apoptotic protease cascade, whereas BAX-alpha accelerates activation of the apoptotic protease cascade.
  • chemotherapeutic drugs can trigger cancer cells to undergo suicide by activating the dormant caspase cascade. This may be a crucial aspect of the mode of action of most, if not all, known anticancer drugs (Los, et al, Blood P0:3118-3129 (1997); Friesen, et al, Nat. Med. 2:514 (1996)).
  • the mechanism of action of current antineoplastic drugs frequently involves an attack at specific phases of the cell cycle.
  • the cell cycle refers to the stages through which cells normally progress during their lifetimes. Normally, cells exist in a resting phase termed G 0 . During multiplication, cells progress to a stage in which DNA synthesis occurs, termed S.
  • Antineoplastic drugs such as cytosine arabinoside, hydroxyurea, 6-mercaptopurine, and methotrexate are S phase specific, whereas antineoplastic drugs such as vincristine, vinblastine, and paclitaxel are M phase specific.
  • Many slow growing tumors for example colon cancers, exist primarily in the G 0 phase, whereas rapidly proliferating normal tissues, for example bone marrow, exist primarily in the S or M phase.
  • a drug like 6-mercaptopurine can cause bone marrow toxicity while remaining ineffective for a slow growing tumor.
  • Ri is H, alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, alkenyl, alkynyl, cycloalkyalkyl, substituted aminoalkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylmercaptoalkyl or phenoxyphenoxyalkyl, wherein the phenyl-portions are optionally substituted;
  • R 2 , R 3 , R 4 independently are H, alkyl or optionally substituted phenyl;
  • R 5 is H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkoxy, alkylthio, alkoxyalkyl, R 7 R 8 N-, alkylthioalkyl, R 7 R 8 -alkyl, halogen, alkenyl, alkynyl, phenyl, phenoxy, phenylalkyl, phenoxyalkyl, phenylmercaptoalkyl, phenylmercapto, phenylalkoxy or phenylalkylthio, wherein the phenyl- portions are optionally substituted;
  • R ⁇ 5 is H, alkyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio, halogen or optionally substituted phenyl; or R 5 and R are taken together to form a polymethylene group;
  • R 7 and R 8 independently are H, alkyl, alkoxyalkyl, hydroxyalkyl, alkylthioalkyl, alkenyl, substituted aminoalkyl, alkynyl, cycloalkyl, cycloalkylalkyl, which in the cycloalkyl-portion is optionally substituted, formyl, phenyl or phenylalkyl, which in the phenyl-portion is optionally substituted; or
  • R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 5- to 7-member, saturated or unsaturated, heterocycle with 1 or 3 heteroatoms, which are the same or different; and the acid addition salts which are functional as fungicides.
  • WO 0127089 patent application discloses pyrimidine derivatives for the treatment of diseases or medical conditions mediated by cytokines:
  • each R 1 group which may be the same or different, is selected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulphamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (1- 6C)alkylamino, di[(l-6C)alkyl]amino, (l-6C)alkoxy carbonyl, N-(l- 6C)alkycarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2- 6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l -6C)
  • X 1 is a direct bond or is selected from O, S, SO, SO 2 , N(R 4 ),CO, CH(OR 4 ), CON(R 4 ), N(R 4 )CO, SO 2 N(R 4 ), N(R 4 ), N(R 4 )SO 2 , OC(R 4 ) 2 , SC(R 4 ) 2 and N(R 4 )C(R 4 ) 2 , wherein each R 4 is hydrogen or (l-6C)alkyl, and Q 2 is aryl-(l-6C)alkyl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l- 6C)alkyl, or (R ⁇ m is (l-3C)alkylenedioxy, and wherein any aryl, heteroaryl or heterocyclyl group within a substituted on R 1 optionally bears 1, 2 or 3 substituents,
  • R 3 is hydrogen, halogeno or (l-6C)alkyl; n is 0, 1 or 2 and each R 2 group, which may be the same or different is selected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, (l-6C)alkoxycarbonyl, (l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylamino and di[(l-6C)alkyl]amino; p is O, 1, 2, 3, or 4; and
  • Q 1 is aryl or heteroaryl and Q 1 is optionally substituted with 1, 2, or 3 substituents, which may be the same of different, selected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, (1-6C) alkylsulphinyl, (1- 6C)alkylsulphonyl, (l-6C)alkylamino, di[(l-6C)alkyl]amino, (1- 6C)alkoxycarbonyl, N-(l-6C)alkycarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(2-6C)alky
  • X 3 is a direct a bond or is selected from 0 and N(R 8 ), wherein R 8 is hydrogen or (l-6C)alkyl
  • Q 4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)-alkyl, heterocyclyl or heterocyclyl(l-6C)alkyl, and any Q 4 group optionally bears 1 or 2 substituents, which may be the same of different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino.
  • WO 0027824 patent application discloses substituted pyrimidine compositions and methods of use. The compounds are said to have activity as inhibitors of phospholipase A 2 , and are useful in treating disorders mediated by phospholipase A 2 :
  • R t represents a C ⁇ -C 6 alkyl, CpC ⁇ alkoxy or halogen atom.
  • the symbol R 2 represents a phenyl group, substituted phenyl group, benzyl moiety, substituted benzyl moiety, C 3 -C 7 cycloalkyl, or substituted C 3 -C 7 cycloalkyl.
  • the symbol R 3 represents a hydrogen or C ⁇ -C 6 alkyl group.
  • the symbol j represents -H, -OH, -N 3 or -NHCOCH 3 .
  • the symbol R 5 represents H or alkyl, preferably H.
  • R 1 is hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, (C ⁇ -C 6 )-alkyl, (C ⁇ -C 6 )-hydroxyalkyl, (C ⁇ -C 6 )-alkoxy, (C 6 -C ⁇ 2 )-aryl, (C ⁇ -C 6 )-alkoxycarbonyl- (C ⁇ -C 6 )-alkyl, (C 1 -C 6 )-alkyl-S-(C ⁇ -C 6 )-alkyl, (C 1 -C 6 )-alkyl-SO-(C 1 -C 6 )-alkyl, (C ⁇ -C 6 )-alkyl-SO 2 -(C ⁇ -C 6 )-alkyl, dihydroxy- ⁇ C ⁇ -alkyl, aryl, heteroaryl, heteroaryl-(C ⁇ -C 6 )-alkyl, aryl-(C 1 -C 6 )-alkyl, aryl-
  • R 4 and R 5 independently of one another are hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, (C ⁇ -C 6 )-alkyl, (CrC ⁇ -hydroxyalkyl, ( -C ⁇ -alkoxy, (C 6 -C ⁇ 2 )-aryl, naphthyl, furyl, where (C 6 -C 12 )-aryl, naphthyl and furyl can be substituted by one or two substituents selected from the group consisting of chlorine, bromine, trifluoromethyl, (Q-C ⁇ -alkyl, (C ⁇ -C 6 )-alkoxy, -S-(CrC 6 )- alkyl, -SO-(C ⁇ -C 6 )-alkyl, -SO 2 -(C ⁇ -C 6 )-alkyl, hydroxyl; and their physiologically tolerable salts.
  • the present invention is related to the discovery that substituted 2-aryl-
  • 4-arylaminopyrimidines and analogs, as represented in Formula I, are activators of the caspase cascade and inducers of apoptosis.
  • an aspect of the present invention is directed to the use of compounds of Formula I as inducers of apoptosis.
  • Compounds of the present invention are represented by Formula I:
  • Ar AT] and Ar 2 are independently and optionally substituted aryl or heteroaryl;
  • A is N or C-R 2 ;
  • Ri and R are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol; and
  • R 3 is hydrogen, an optionally substituted alkyl or cycloalkyl.
  • a second aspect of the present invention is to provide a method for treating, preventing or ameliorating neoplasia and cancer by administering a compound of Formula I to a mammal in need of such treatment.
  • a third aspect of the present invention is to provide novel compounds of Formula I, and to also provide for the use of these novel compounds for treating, preventing or ameliorating neoplasia and cancer.
  • a fourth aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the induction of apoptosis, containing an effective amount of a compound of Formula I in admixture with one or more pharmaceutically acceptable carriers or diluents.
  • a fifth aspect of the present invention is directed to methods for the preparation of novel compounds of Formula I.
  • Figs. 1A-B are graphs showing drug induced cell cycle arrest and apoptosis in T47D cells.
  • Fig. 1 A control cells showing most of the cells in GI phase of the cell cycle (M2).
  • Fig. IB cells treated with 200 nM of 4-(3- methoxyamTino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine for 48 h showing a reduction in the GI population (M2), an increase in the G2 M population (M4) and the sub-diploid DNA population of cells (Ml).
  • Fig. 2 is a graph showing inhibition of clonogenic survival of MX-1 and T47D cells treated for 48 h with different concentrations of 4-(3- methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine.
  • Fig. 2 shows increasing inhibition of clonogenicity with increasing drug concentration, with IC50 of about 100 nM and 300 nM for T47D and MX-1 cells, respectively.
  • the present invention arises out of the discovery that substituted 2- aryl-4-arylaminopyrimidines and analogs, as represented in Formula I, are potent and highly efficacious activators of the caspase cascade and inducers of apoptosis. Therefore compounds of Formula I are useful for treating disorders responsive to induction of apoptosis.
  • Arr and Ar 2 are independently and optionally substituted aryl or heteroaryl;
  • A is N or C-R 2 ;
  • Ri and R 2 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol; and R 3 is hydrogen, an optionally substituted alkyl or cycloalkyl.
  • Preferred compounds of Formula I include compounds wherein Ari or
  • Ar 2 is optionally substituted phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, isoquinolyl, thienyl, furyl, or pyrrolyl.
  • Preferred compounds of Formula I also include compounds wherein R 3 is hydrogen.
  • Preferred compounds of Formula I also include compounds wherein A is C- R 2 .
  • Especially preferred compounds of Formula I include compounds wherein Aii is optionally substituted pyridinyl, pyrimidinyl and pyrazinyl.
  • Ar 2 is optionally substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl.
  • Ar 2 are as defined in Formula I;
  • B is N or C-R ⁇
  • D is N or C-R 5 ;
  • E is N or C-R 6 ;
  • F is N or C-R 7 ;
  • G is N or C-R 8 ; and Rj-Rs are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol; provided that not more than three of B, D, E, F and G are N.
  • Preferred compounds falling within the scope of Formula II include compounds wherein Ri is an optionally substituted alkyl, haloalkyl or phenyl. Preferred compounds of Formula II also include compounds wherein Ar 2 is an optionally substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl. Preferred compounds of Formula II also include compounds wherein B is nitrogen, D is C-R 5 , E is C-R 6 , F is C-R , and G is C-R 8 . Preferred compounds of Formula II also include compounds wherein D is nitrogen, B is C-R 4 , E is C-Re, F is C-R , and G is C-R 8 .
  • Preferred compounds of Formula II also include compounds wherein E is nitrogen, D is C-R 5 , B is C-Ri, F is C-R 7 , and G is C-R 8 .
  • Preferred compounds of Formula II also include compounds wherein two of B, D, E, F and G are N.
  • RT-R 3 , and B, D, E, F and G are as defined in Formula I and II;
  • R 9 -R 13 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol.
  • Preferred compounds falling within the scope of Formula III include compounds wherein Ri is an optionally substituted alkyl, haloalkyl. Preferred compounds of Formula III also include compounds wherein R 2 is hydrogen. Preferred compounds of Formula III also include compounds wherein one of the B, D, E, F and G is nitrogen. Preferred compounds of Formula III also include compounds wherein two of the B, D, E, F and G is nitrogen. Preferred compounds of Formula III also include compounds wherein Rio or R ⁇ 2 are not hydrogen. Preferred compounds of Formula III also include compounds wherein R 9 and R ⁇ 2 are not hydrogen. Preferred compounds of Formula III also include compounds wherein Rio and R ⁇ 2 are not hydrogen. Preferred compounds of Formula III also include compounds wherein R 9 , R ⁇ and R ⁇ 2 are not hydrogen. Preferred compounds of Formula III also include compounds wherein R 9 , R ⁇ and R ⁇ 2 are not hydrogen. [0027] Exemplary preferred compounds that may be employed in the method of the invention include, without limitation:
  • Useful alkyl groups include straight-chained and branched Cno alkyl groups, more preferably C ⁇ . 6 alkyl groups.
  • Typical CM O alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups, which may be optionally substituted.
  • Useful alkoxy groups include oxygen substituted by one of the Ci-io alkyl groups mentioned above, which may be optionally substituted.
  • Useful alkylthio groups include sulphur substituted by one of the Ci-io alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
  • Useful amino groups include -NH 2 , -NHR 15 and -NR ⁇ 5 R ⁇ 6 , wherein
  • R ⁇ 5 and R ⁇ 6 are C MO alkyl or cycloalkyl groups, or R ⁇ 5 and R ⁇ 6 are combined with the N to form a ring structure, such as a piperidine, or R ⁇ 5 and R ⁇ 6 are combined with the N and other group to form a ring, such as a piperazine.
  • the alkyl group may be optionally substituted.
  • Optional substituents on the alkyl and cycloalkyl groups include one or more halo, hydroxy, carboxyl, amino, nitro, cyano, C ⁇ -C 6 acylamino, C ⁇ -C 6 acyloxy, C ⁇ -C 6 alkoxy, aryloxy, alkylthio, C 6 -C ⁇ o aryl, C 4 -C cycloalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C ⁇ o aryl(C 2 -C 6 )alkenyl, C 6 -C ⁇ o aryl(C 2 - C 6 )alkynyl, saturated and unsaturated heterocyclic or heteroaryl.
  • Optional substituents on the aryl, arylalkyl and heteroaryl groups include one or more halo, C ⁇ -C 6 haloalkyl, C 6 -C ⁇ o aryl, C 4 -C 7 cycloalkyl, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C ⁇ 0 aryl(C ⁇ -C 6 )alkyl, C 6 -C ⁇ 0 aryl(C 2 -C 6 )alkenyl, C 6 -C ⁇ o aryl(C 2 -C 6 )alkynyl, C ⁇ -C 6 hydroxyalkyl, nitro, amino, ureido, cyano, C ⁇ -C 6 acylamino, hydroxy, thiol, C ⁇ -C 6 acyloxy, azido, C ⁇ -C 6 alkoxy or carboxy.
  • aryl as employed herein by itself or as part of another group refers to monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbons in the ring portion.
  • Useful aryl groups include C 6 _ ⁇ 4 aryl, preferably C 6 - ⁇ o aryl. Typical
  • C 6 . ⁇ 4 aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • Useful cycloalkyl groups are C 3 . 8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. [0038] Useful saturated or partially saturated carbocyclic groups are cycloalkyl groups as described above, as well as cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.
  • Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
  • Useful arylalkyl groups include any of the above-mentioned Ci-io alkyl groups substituted by any of the above-mentioned C 6 - ⁇ 4 aryl groups.
  • the arylalkyl group is benzyl, phenylethyl or naphthylmethyl.
  • Useful haloalkyl groups include Ci-io alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.
  • acylamino (acylamido) groups are any C ⁇ - 6 acyl (alkanoyl) attached to an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted C ⁇ . 6 acylamino groups, e.g., benzoylamido, and pentafluorobenzoylamido .
  • Useful acyloxy groups are any C ⁇ . 6 acyl (alkanoyl) attached to an oxy
  • (-O-) group e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.
  • heterocycle is used herein to mean a saturated or partially saturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms ' independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.
  • heteroaryl refers to groups having 5 to
  • Useful heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, ⁇ -carbolinyl
  • heteroaryl group contains a nitrogen atom in a ring
  • nitrogen atom may be in the form of an N-oxide, e.g., a pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
  • Some of the compounds of the present invention may exist as stereoisomers including optical isomers.
  • the invention includes all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
  • Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base addition salts with bases such as sodium hydroxy, Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and N-methyl-glucamine.
  • inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate
  • inorganic and organic base addition salts with bases such as sodium hydroxy, Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and N-methyl-glucamine.
  • prodrugs of the compounds of the invention include the simple esters of carboxylic acid containing compounds (e.g., those obtained by condensation with a C alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g., those obtained by condensation with a Cm carboxylic acid, C 3 . 6 dioic acid or anhydride thereof such as succinic and fumaric anhydrides according to methods known in the art); phosphate of hydroxy containing compounds (e.g. combretastatin A-l phosphate prodrug, see Pettit G. R. and Lippert III, J.
  • carboxylic acid containing compounds e.g., those obtained by condensation with a C alcohol according to methods known in the art
  • esters of hydroxy containing compounds e.g., those obtained by condensation with a Cm carboxylic acid, C 3 . 6 dioic acid or anhydride thereof such as succinic and fumaric anhydrides according to methods known in the art
  • the compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention. Specifically, the compounds of this invention with Formulae I-III may be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of 4- chloro-6-methyl-2-(2-pyridinyl)pyrimidine with aniline gave the product 4- anilino-6-methyl-2-(2-pyridinyl)pyrimidine.
  • the 2-aryl-4-chloro-pyrimidine may be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of pyridine-2-carboxamidine with 4,4,4-trifluoro-but-2-ynoic acid ethyl ester in ethanol in the presence of base such as KOH produced the substituted 4-hydroxy-pyrimidine. Treatment of the hydroxy-pyrimidine with POCI 3 gave the product 4-chloro-2-(2-pyridinyl)- 6-trifluoromethylpyrimidine.
  • the 2-aryl-4-chloro-pyrimidine may be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of pyrimidine-2- carboxamidine with ethyl 4,4,4-trifluoro-acetoacetate in ethanol in the presence of base such as EtONa produced the substituted 4-hydroxy- pyrimidine. Treatment of the hydroxy-pyrimidine with POCI3 gave the product 4-chloro-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidine.
  • An important aspect of the present invention is the discovery that compounds having Formula I-III are activators of caspases and inducers of apoptosis. Therefore, these compounds are useful in a variety of clinical conditions in which there is uncontrolled cell growth and spread of abnormal cells, such as in the case of cancer.
  • Another important aspect of the present invention is the discovery that compounds having Formula I-III are potent and highly efficacious activators of caspases and inducers of apoptosis in drug resistant cancer cells, such as breast cancer cells (Examples 11-14), which enables these compounds to kill these drug resistant cancer cells.
  • drug resistant cancer cells such as breast cancer cells (Examples 11-14)
  • most standard anti-cancer drugs are not effective in killing drug resistant cancer cells under the same conditions. Therefore, compounds of this invention are useful for the treatment of drug resistant cancer such as breast cancer in animals.
  • the present invention includes a therapeutic method useful to modulate in vivo apoptosis or in vivo neoplastic disease, comprising administering to a subject in need of such treatment an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis.
  • the present invention also includes a therapeutic method comprising administering to an animal an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I- III, wherein said therapeutic method is useful to treat cancer, which is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells.
  • Such diseases include, but are not limited to, Hodgkin's disease, non- Hodgkin's lymphomas, acute lymphatic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinomas, ovarian carcinomas, lung carcinomas, Wilms' tumor, cervical carcinomas, testicular carcinomas, soft-tissue sarcomas, primary macroglobulinemia, bladder carcinomas, chronic granulocytic leukemia, primary brain carcinomas, malignant melanoma, small-cell lung carcinomas, stomach carcinomas, colon carcinomas, malignant pancreatic insulinoma, malignant carcinoid carcinomas, malignant melanomas, choriocarcinomas, mycosis fungoides, head or neck carcinomas, osteogenic sarcoma, pancreatic carcinomas, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's
  • compositions containing therapeuticaUy effective concentrations of the compounds formulated for oral, intravenous, local and topical application, for the treatment of neoplastic diseases and other diseases in which caspase cascade mediated physiological responses are implicated are administered to an individual exhibiting the symptoms of one or more of these disorders.
  • the amounts are effective to ameliorate or eliminate one or more symptoms of the disorders.
  • An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce, the symptoms associated with the disease.
  • Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • the amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms
  • a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt of said compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis in combination with a pharmaceutically acceptable vehicle is provided.
  • Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I- III, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.
  • cancer chemotherapeutic agents which may be used for combination therapy include, but not are limited to alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents such as colchicine, vinblastine, paclitaxel, and docetaxel; topo I inhibitors such as camptothecin and topotecan; topo II inhibitors such as doxorubicin and etoposide; RNA/DNA antimetabolites such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; antibodies such as Herceptin® and Rituxan®.
  • alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin
  • antimitotic agents such as colchicine, vinblastine, paclitaxel, and docetaxel
  • cancer chemotherapeutic agents which may be used for combination therapy include melphalan, chlorambucil, cyclophosphamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen and alanosine.
  • the compound of the invention may be administered together with at least one known chemotherapeutic agent as part of a unitary pharmaceutical composition.
  • the compound of the invention may be administered apart from at least one known cancer chemotherapeutic agent.
  • the compound of the invention and at least one known cancer chemotherapeutic agent are administered substantially simultaneously, i.e. the compounds are administered at the same time or one after the other, so long as the compounds reach therapeutic levels in vivo at the same time.
  • the compound of the invention and at least one known cancer chemotherapeutic agent are administered according to their individual dose schedule, so long as the compounds reach therapeutic levels in vivo.
  • Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a bioconjugates of said compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis, in bioconjugation with at least one known therapeuticaUy useful antibody, such as Herceptin® or Rituxan®, growth factors such as EGF, NGF, cytokines such as IL-2, IL-4, or any molecule that binds to the cell surface.
  • the antibodies and other molecules will deliver the compound of Formulae I-III to its targets and make it an effective anticancer agent.
  • the bioconjugates could also enhance the anticancer effect of therapeuticaUy useful antibodies, such as Herceptin® or Rituxan®.
  • another embodiment of the present invention is directed to a composition effective in inhibiting neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I- III, which functions as a caspase cascade activator and inducer of apoptosis, in combination with radiation therapy.
  • the compound of the invention may be administered at the same time as the radiation therapy is administered or at a different time.
  • Yet another embodiment of the present invention is directed to a composition effective for post-surgical treatment of cancer, comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis.
  • the invention also relates to a method of treating cancer by surgically removing the cancer and then treating the animal with one of the pharmaceutical compositions described herein.
  • a wide range of immune mechanisms operate rapidly following exposure to an infectious agent. Depending on the type of infection, rapid clonal expansion of the T and B lymphocytes occurs to combat the infection. The elimination of the effector cells following an infection is one of the major mechanisms for maintaining immune homeostasis.
  • autoimmune diseases have lately been determined to occur as a consequence of deregulated cell death.
  • the immune system directs its powerful cytotoxic effector mechanisms against specialized cells such as oligodendrocytes in multiple sclerosis, the beta cells of the pancreas in diabetes mellitus, and thyrocytes in Hashimoto's thyroiditis (Ohsako, S. & Elkon, K.B., Cell Death Differ. 6:13-21 (1999)).
  • lymphocyte apoptosis receptor Fas/APO-l/CD95 are reported to be associated with defective lymphocyte apoptosis and autoimmune lymphoproliferative syndrome (ALPS), which is characterized by chronic, histologically benign splenomegaly, generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation.
  • APS autoimmune lymphoproliferative syndrome
  • Fas-Fas ligand (FasL) interaction is known to be required for the maintenance of immune homeostasis.
  • Experimental autoimmune thyroiditis (EAT) characterized by autoreactive T and B cell responses and a marked lymphocytic infiltration of the thyroid, is a good model to study the therapeutic effects of FasL. Batteux, F., et al, (J. Immunol.
  • FasL expression on thyrocytes may have a curative effect on ongoing EAT by inducing death of pathogenic autoreactive infiltrating T lymphocytes.
  • Bisindolylmaleimide VIII is known to potentiate Fas-mediated apoptosis in human astrocytoma 1321N1 cells and in Molt-4T cells; both of which were resistant to apoptosis induced by anti-Fas antibody in the absence of bisindolylmaleimide VIII. Potentiation of Fas-mediated apoptosis by bisindolylmaleimide VIII was reported to be selective for activated, rather than non-activated, T cells, and was Fas-dependent. Zhou T., et al, (Nat. Med.
  • Psoriasis is a chronic skin disease that is characterized by scaly red patches.
  • Psoralen plus ultraviolet A (PUVA) is a widely used and effective treatment for psoriasis vulgaris and Coven, et al, Photodermatol. Photoimmunol Photomed. 15:22-21 (1999), reported that lymphocytes treated with psoralen 8-MOP or TMP and UVA, displayed DNA degradation patterns typical of apoptotic cell death.
  • Ozawa, et al, J. Exp. Med. 189:111-118 (1999) reported that induction of T cell apoptosis could be the main mechanism by which 312-nm UVB resolves psoriasis skin lesions.
  • methotrexate Low doses of methotrexate may be used to treat psoriasis to restore a clinically normal skin. Heenen, et al, Arch. Dermatol Res. 290:240-245 (1998), reported that low doses of methotrexate may induce apoptosis and that this mode of action could explain the reduction in epidermal hyperplasia during treatment of psoriasis with methotrexate. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis, should be an effective treatment for psoriasis.
  • Synovial cell hyperplasia is a characteristic of patients with rheumatoid arthritis (RA). It is believed that excessive proliferation of RA synovial cells, as well as defects in synovial cell death, may be responsible for synovial cell hyperplasia. Wakisaka, et al, Clin. Exp. Immunol. 77 :119-128 (1998), found that although RA synovial cells could die via apoptosis through a Fas/FasL pathway, apoptosis of synovial cells was inhibited by proinflammatory cytokines present within the synovium.
  • an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis should be an effective treatment for rheumatoid arthritis.
  • an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis, should be an effective treatment for inflammation.
  • compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the compounds may be administered to animals, e.g., mammals, orally at a dose of 0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a mammal being treated for apoptosis-mediated disorders.
  • a dose 0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a mammal being treated for apoptosis-mediated disorders.
  • about 0.01 to about 10 mg/kg of body weight is orally administered to treat or prevent such disorders.
  • the dose is generally about one-half of the oral dose.
  • a suitable intramuscular dose would be about 0.0025 to about 25 mg/kg of body weight, and most preferably, from about 0.01 to about 5 mg/kg of body weight.
  • a known cancer chemotherapeutic agent is also administered, it is administered in an amount that is effective to achieve its intended purpose.
  • the amounts of such known cancer chemotherapeutic agents effective for cancer are well known to those of skill in the art.
  • the unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg of the compound of the invention.
  • the unit dose may be administered one or more times daily as one or more tablets each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.
  • the compound in a topical formulation, may be present at a concentration of about 0.01 to 100 mg per gram of carrier.
  • the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which may be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which may be used pharmaceutically.
  • the preparations particularly those preparations which may be administered orally and which may be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which may be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s), together with the excipient.
  • non- toxic pharmaceutically acceptable salts of the compounds of the present invention are included within the scope of the present invention.
  • Acid addition salts are formed by mixing a solution of the particular apoptosis inducers of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
  • Basic salts are formed by mixing a solution of the particular apoptosis inducers of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl-glucamine and the like.
  • a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl-glucamine and the like.
  • compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention.
  • animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be so limited.
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which may be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules may contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which may be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400) or cremophor, or cyclodextrins.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • compounds of the invention are employed in topical and parenteral formulations and are used for the treatment of skin cancer.
  • the topical compositions of this invention are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers.
  • Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C ⁇ 2 ).
  • the preferred carriers are those in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers are found in U.S. Patent Nos. 3,989,816 and 4,444,762.
  • Creams are preferably formulated from a mixture of mineral oil, self- emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil such as almond oil, is admixed.
  • a typical example of such a cream is one which includes about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool.
  • a vegetable oil such as almond oil
  • a typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight.
  • the title compound was prepared from 4-chloro-6-methyl-2-(3- methylphenyl)pyrimidine (100 mg, 0.457 mmol) and N,N-dimethyl-l,3- phenylene-diamine dihydrochloride (96 mg, 0.457 mmol) similar to Example 13 as a yellow oil (9 mg, 6%).
  • the title compound was prepared from 4-chloro-6-methyl-2-(2- pyridinyl)pyrimidine (100 mg, 0.486 mmol) and m-phenetidine (65 ⁇ l, 0.486 mmol) similar to Example 11 and isolated as a light tan solid (116 mg, 78%).
  • the title compound was prepared from a mixture of 4-chloro-6- methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-isopropylaniline (33 ⁇ l, 0.243 mmol) similar to Example 13 and isolated as a gray oil (70 mg, 95%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (100 mg, 0.385 mmol) and 2,5- dimethoxyaniline (59 mg, 0.385 mmol) similar to Example 13 and isolated as a greenish-yellow solid (24 mg, 17%).
  • the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5- dimethoxyaniline (32 mg, 0.193 mmol) similar to Example 13 and isolated as a light tan solid (15 mg, 21%).
  • the title compound was prepared from a mixture of 4-chloro-5- methoxy-2-(2-pyridinyl)pyrimidine (50 mg, 0.226 mmol) and 2,5- dimethoxyaniline (35 mg, 0.226 mmol) similar to Example 11 and isolated as a gray solid (46 mg, 61%).
  • the title compound was prepared from a mixture of 4-(6-chloro-2- phenyl-4-pyrimidyl)morpholine (50 mg, 0.181 mmol) and 2,5- dimethoxyaniline (28 mg, 0.181 mmol) similar to Example 46 and isolated as a brown oil (6 mg, 8%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5- methoxy aniline (37 mg, 0.193 mmol) similar to Example 13 and isolated as a white solid (10 mg, 14%).
  • the title compound was prepared from a mixture of 4-chloro-6- methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 2-chloro-5- methoxyaniline (47 mg, 0.243 mmol) similar to Example 13 and isolated as a tan oil (35 mg, 44%).
  • the title compound was prepared from a mixture of 4-chloro-6- methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 5-methoxy-2- methylaniline (33 mg, 0.243 mmol) similar to Example 13 and isolated as a tan oil (45 mg, 60%).
  • the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5- methoxyaniline (38 mg, 0.193 mmol) similar to Example 13 and isolated as a pink solid (18 mg, 25%).
  • the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5- methoxy-2-methylaniline (27 mg, 0.193 mmol) similar to Example 13 and isolated as a pink solid (23 mg, 33%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-(3- aminophenyl)-2-methylpyrimidine (71 mg, 0.386 mmol) similar to Example 58.
  • the mixture was extracted with ethyl acetate (50 ml), washed with water (1x25 ml) and with aqueous 2N HCl (1x25 ml).
  • the acidic aqueous solution was basified with aqueous 2N NaOH to pH 10-12.
  • the resulting precipitate was filtered, washed with water and isolated as a light tan solid (18 mg, 23%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3- aminobiphenyl (65 mg, 0.386 mmol) similar to Example 58.
  • the mixture was basified with aqueous 2N NaOH to pH 10-12.
  • the resulting precipitate was collected by filtration, washed with excess wate ⁇ ethanol (1:1) and isolated as a light brown solid (64 mg, 85%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino- 3'-nitrobiphenyl (83 mg, 0.386 mmol) similar to Example 58 and isolated as a light tan solid (65 mg, 77%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3- (2,3,4,5,6-pentafluorophenoxy)aniline (106 mg, 0.386 mmol) similar to Example 58 and isolated as a yellow solid (65 mg, 68%).
  • the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5- dimethoxyaniline (59 mg, 0.386 mmol) similar to Example 58 and isolated as a light brown solid (36 mg, 50%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-(3- aminophenyl)-2-ethyl-l-phenyl-3-pyrazolin-5-one (54 mg, 0.193 mmol) similar to Example 58 and isolated as a dark yellow solid (52 mg, 54%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3- aminodiphenylsulfone (90 mg, 0.386 mmol) similar to Example 58 and isolated as a yellow solid (44 mg, 50%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3- aminobenzanilide (41 mg, 0.193 mmol) similar to Example 58 and isolated as a dark pink solid (41 mg, 49%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5- dimethylaniline (48 ⁇ l, 0.386 mmol) similar to Example 58 and isolated as a light tan solid ( 14mg, 21%).
  • the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (89 mg, 0.344 mmol) and 3- aminophenol (30 mg, 0.275 mmol) similar to Example 58 and isolated as a yellow solid (61 mg, 67%).
  • the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4- methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a purple solid (24 mg, 35%).
  • the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4- methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a dark brown solid (47 mg, 68%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl) ⁇ yrimidine (50 mg, 0.193 mmol) and 3,4- methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a light brown solid (37 mg, 53%).
  • 6-(trifluoromethyl)pyrimidine 50 mg, 0.193 mmol
  • 3,4-dimethoxyaniline 44 mg, 0.290 mmol
  • the mixture was extracted with ethyl acetate (75 ml), washed with water (2 x 25 ml), washed with aqueous saturated NaCl (1 x 25 ml), and dried over anhydrous sodium sulfate.
  • the ethyl acetate solution was rotary evaporated to dryness. The residual was purified by column chromatography and isolated as a yellow oil (35 mg, 48%).
  • the title compound was prepared from a mixture of 4-chloro-2-(2- pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol), 3,4- dimethoxyaniline (44 mg, 0.288 mmol) similar to Example 76 and isolated as a yellow solid (52 mg, 72%).
  • the title compound was prepared from a mixture of 4-chloro-2-(2- pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol) and 2-chloro- 5-methoxyaniline hydrochloride (56 mg, 0.288 mmol) similar to Example 76 and isolated as a tan solid (41 mg, 56%).
  • the title compound was prepared from a mixture of 4-chloro-2-(2- pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol) and 3,4- methylenedioxyaniline (39 mg, 0.288 mmol) similar to Example 76 and isolated as a pink solid (21 mg, 30%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2- methoxy-5-phenoxyaniline (62 mg, 0.290 mmol) similar to Example 58 and isolated as a tan solid (46 mg, 54%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-4- methylbenzoate (48 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (2 mg, 3%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2- methoxy-5-methylaniline (40 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (41 mg, 59%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-fluoro-2- methylaniline (36 mg, 0.290 mmol) similar to Example 58 and isolated as a tan solid (4 mg, 6%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-4- methoxybenzotrifluoride (55 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (56 mg, 70%).
  • the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 3- ethylaniline (18 ⁇ l, 0.144 mmol) similar to Example 92 and isolated as a yellow oil (12 mg, 36%).
  • the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 5- methoxy-2-methylaniline (20 mg, 0.144 mmol) similar to Example 92 and isolated as a yellow solid (18 mg, 52%).
  • the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 2-chloro-5- methoxyaniline (23 mg, 0.144 mmol) similar to Example 92 and isolated as a white solid (11 mg, 48%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 3- aminophenol (32 mg, 0.290 mmol), and 2N HCl (150 ⁇ l) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and the resulting crystals was filtered, washed with water, with water:ethanol (2:1) and dried to give a tan crystals (22 mg, 30%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-4- methoxybenzoic acid (48 mg, 0.290 mmol) similar to Example 92 and isolated as a white solid (50 mg, 64%).
  • the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5- hydroxyaniline (42 mg, 0.290 mmol) similar to Example 108 and isolated as a brown solid (3 mg, 4%).
  • the title compound was prepared from a mixture 4-chloro-2,6-di(2- pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2,5-dimethoxyaniline (21 mg, 0.140 mmol) similar to Example 111 and isolated as a yellow oil (2 mg, 6%).
  • the title compound was prepared from a mixture 4-chloro-2,6-di(2- pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 5-methoxy-2-methylaniline (19 mg, 0.140 mmol) similar to Example 111 and isolated as a white solid (21 mg, 61%).
  • the title compound was prepared from a mixture of 4-chloro-2,6-di(2- pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2-chloro-5-methoxyaniline (27 mg, 0.140 mmol) similar to Example 111 and isolated as a white solid (20 mg, 55%).
  • the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2- methoxy-5-methylaniline (40 mg, 0.290 mmol) similar to Example 115 and isolated as a white solid (48 mg, 69%).
  • the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-hydroxy- 2-methylaniline (36 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (19 mg, 28%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methyl- 5-(trifluoromethyl)aniline (51 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (60 mg, 78%).
  • the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-chloro-2- hydroxyaniline (42 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (38 mg, 54%).

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Abstract

La présente invention concerne la 2-aryl-4-arylamino-pyrimidine substituée et des analogues de celle-ci, de formule générale I: A, Ar1, Ar2, R1 et R3 étant définis dans la présente invention. La présente invention se rapporte également à la découverte selon laquelle des composés de formule I constituent des activateurs de caspases et des inducteurs d'apoptose. Les composés de cette invention peuvent être utilisés pour induire la mort cellulaire dans diverses conditions cliniques dans lesquelles se produisent une croissance incontrôlée et un développement cellulaire anormal.
PCT/US2001/047498 2000-12-12 2001-12-12 2-aryl-4-arylaminopyrimidines substituees et analogues en tant qu'activateurs de caspases et qu'inducteurs d'apoptose, et utilisation associee WO2002047690A1 (fr)

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EP01990048A EP1351691A4 (fr) 2000-12-12 2001-12-12 2-aryl-4-arylaminopyrimidines substituees et analogues en tant qu'activateurs de caspases et qu'inducteurs d'apoptose, et utilisation associee
AU2002228922A AU2002228922A1 (en) 2000-12-12 2001-12-12 Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof

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JP2015525775A (ja) * 2012-07-23 2015-09-07 メルク パテント ゲーエムベーハー リガンドおよびその製造方法
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US6660731B2 (en) * 2000-09-15 2003-12-09 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7691853B2 (en) 2000-09-15 2010-04-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7951820B2 (en) 2000-09-15 2011-05-31 Vertex Pharmaceuticals Incorporated Triazole compounds useful as protein kinase inhibitors
US7226927B2 (en) 2000-12-12 2007-06-05 Cytovia, Inc. Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US8304414B2 (en) 2000-12-21 2012-11-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US7115617B2 (en) 2001-08-22 2006-10-03 Amgen Inc. Amino-substituted pyrimidinyl derivatives and methods of use
US6939874B2 (en) 2001-08-22 2005-09-06 Amgen Inc. Substituted pyrimidinyl derivatives and methods of use
EP1575506A4 (fr) * 2002-07-25 2008-04-23 Scios Inc Methodes pour ameliorer la fonction respiratoire au moyen d'inhibiteurs du tgf-beta
EP1575506A2 (fr) * 2002-07-25 2005-09-21 Scios, Inc. Methodes pour ameliorer la fonction respiratoire au moyen d'inhibiteurs du tgf-beta
US7872129B2 (en) 2002-08-02 2011-01-18 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of GSK-3
US8569305B2 (en) 2002-09-05 2013-10-29 Emory University Treatment of tuberous sclerosis associated neoplasms
EP1549316A4 (fr) * 2002-09-10 2008-04-09 Scios Inc Inhibiteurs de tgf-$g(b)
EP1549316A1 (fr) * 2002-09-10 2005-07-06 Scios Inc. Inhibiteurs de tgf-$g(b)
JP2006503043A (ja) * 2002-09-10 2006-01-26 サイオス インク． ＴＧＦβ阻害剤
WO2004024159A1 (fr) * 2002-09-10 2004-03-25 Scios Inc. Inhibiteurs de tgf-$g(b)
JP2006522143A (ja) * 2003-04-04 2006-09-28 アイアールエム・リミテッド・ライアビリティ・カンパニー プロテインキナーゼ阻害剤としての新規化合物および組成物
EP1610774A2 (fr) * 2003-04-09 2006-01-04 Exelixis, Inc. Modulateurs de tie-2 et procedes d'utilisation
EP1610774A4 (fr) * 2003-04-09 2008-07-16 Exelixis Inc Modulateurs de tie-2 et procedes d'utilisation
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
WO2005003100A3 (fr) * 2003-07-03 2005-05-12 Myriad Genetics Inc Composes et leur utilisation therapeutique
WO2005003100A2 (fr) 2003-07-03 2005-01-13 Myriad Genetics, Inc. Composes et leur utilisation therapeutique
US9751893B2 (en) 2003-07-30 2017-09-05 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US6818631B1 (en) 2003-08-15 2004-11-16 Nippon Soda Co. Ltd. Fungicidal pyrimidine derivatives
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