WO2001038315A1 - Quinazolines et leur utilisation dans l'inhibition des enzymes kinase dependant de la cycline - Google Patents

Quinazolines et leur utilisation dans l'inhibition des enzymes kinase dependant de la cycline Download PDF

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WO2001038315A1
WO2001038315A1 PCT/US2000/030376 US0030376W WO0138315A1 WO 2001038315 A1 WO2001038315 A1 WO 2001038315A1 US 0030376 W US0030376 W US 0030376W WO 0138315 A1 WO0138315 A1 WO 0138315A1
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quinazolin
phenyl
cyclopentyl
piperazin
methoxy
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PCT/US2000/030376
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English (en)
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Mark Robert Barvian
Yadagiri Bathini
Ellen Myra Dobrusin
James Stanley Kaltenbronn
Ronald George Micetich
Inderjit S. Sidhu
Rajeshwar Singh
Peter Laurence Toogood
Roy Thomas Winters
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Warner-Lambert Company
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Priority to AU14621/01A priority Critical patent/AU1462101A/en
Priority to US10/130,843 priority patent/US6982260B1/en
Priority to MXPA02003140A priority patent/MXPA02003140A/es
Priority to CA002386955A priority patent/CA2386955A1/fr
Priority to EP00976914A priority patent/EP1235815A1/fr
Priority to JP2001540078A priority patent/JP2003514901A/ja
Priority to BR0015718-0A priority patent/BR0015718A/pt
Publication of WO2001038315A1 publication Critical patent/WO2001038315A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to quinazolines that inhibit cyclin-dependent kinase enzymes, and as such are useful to treat cell proliferative diseases and disorders, such as cardiovascular diseases (i.e., atherosclerosis, restenosis), and cancer, infections (i.e, viral and fungal), autoimmune diseases, organ transplant rejections (i.e., inflammation), gout, kidney disease, and also neurodegenerative diseases and disorders.
  • Cyclin-dependent kinases and related serine/threonine protein kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation.
  • the cyclin-dependent kinase catalytic units of which 9 have now been described, are activated by regulatory subunits known as cyclins. At least 16 mammalian cyclins have been identified (Johnson D.G. and Walker
  • Cyclin B/Cdkl Cyclin A/Cdk2, Cyclin E/Cdk2, Cyclin D/Cdk4, Cyclin D/Cdk6, and probably other heterodimers including Cdk3 and Cdk7 are important regulators of cell cycle progression. Additional functions of Cyclin/Cdk heterodimers include regulation of transcription, DNA repair, differentiation and apoptosis (Morgan D.O., Annu.
  • Cdk inhibitors also may have potential applications in the treatment of cardiovascular disorders such as restenosis and atherosclerosis.
  • Vascular smooth muscle proliferation and intimal hyperplasia following balloon angioplasty are inhibited by over-expression of the cyclin- dependent kinase inhibitor protein p21 (Chang M. W. et al., J. Clin. Invest., 1995;96:2260; Yang Z-Y. et al., Proc. Natl. Acad. Sci. (USA) 1996;93:9905.
  • Cdk5 The neuronal Cdc2-like kinase, known as Cdk5, together with its brain specific activator protein p35/p25, phosphorylates the neuron-specific microtubule-associated protein tau (Lew J. and Wang J.H., Trends Biochem. Sci. 1995;20:33-37).
  • Aberrant expression of Cdk5 is proposed to contribute to the neurodegenerative disorder Multiple System Atrophy (Nakamura S. et al., J. Neuropathol. Exp. Neurol. 1998;57:690) and tau hyperphosphorylation has long been associated with the pathogenesis of Alzheimer's Disease (AD) (Spillantini M.G. and Giedert M., Trends Neurosci.
  • AD Alzheimer's Disease
  • NFTs neurofibrillary tangles
  • PHF paired helical filament
  • AD Alzheimer's Disease
  • Cdk5 cyclin-dependent kinase 5 (Cdk5), glycogen synthase kinase-3 ⁇ (GSK-3 ⁇ )), and protein phosphatases (type 2 A and 2B)
  • Cdk5 is an important therapeutic target because its activator protein p35 is specifically localized in central and peripheral neurons (Tsai J.-H. et al., Nature 1984;371:419-423).
  • Alzheimer's disease include the following observations. (1) Increased Cdk5 activity has been found in AD brains (Pei J.J. et al., Brain Res. 1998;797:267-77; Lee K.Y. et al., Neurosci Res. 1999;34:21-9). (2) PHF-Tau found in AD brains has 8 phosphorylation sites that overlap with the sites of cdk5 phosphorylation (Paudel H.K. et al., J. Biol. Chem. 1993;268:23512-23518;
  • Cdk inhibitors could find application include those caused by a variety of infectious agents, including DNA and RNA viruses.
  • cyclin-dependent kinases are required for viral replication following infection by herpes simplex virus (HSV) (Schang L.M. et al., J. Virol. 1998;72:5626). HSV replication was inhibited by the cyclin-dependent kinase inhibitors roscovitine and olomoucine but not by a cell cycle inhibitor that does not inhibit cyclin-dependent kinase activity.
  • HSV herpes simplex virus
  • Cdk inhibitor protein pi 6 has both been demonstrated to overcome cell cycle suppression and to promote cell immortalization and the transformed phenotype (Mai A. et al., Nature 1996;380:262-265; Suzuki T. et al., EMBOJ. 1996;15: 1607-1614; Parker G.A. et al., Oncogene 1996;13:2541-2549).
  • Cdk2 also has been implicated in the progression of cytomegalovirus infections (Bresnahan W.A. et al., Virology
  • Fungal infections may be expected to be susceptible to Cdk inhibitors on the basis of the known essential roles of Cdk homologs in yeast.
  • autoimmune disorders may succumb to treatment with selective Cdk inhibitors.
  • the chronic inflammatory disease rheumatoid arthritis is characterized by synovial tissue hyperplasia; inhibition of synovial tissue proliferation should minimize inflammation and prevent joint destruction. Consistent with this idea, expression of the Cdk inhibitor protein pl6 in synovial fibroblasts led to growth inhibition (Taniguchi K. et al., Nat. Med. 1999;5:760-767).
  • joint swelling was substantially inhibited by treatment with a pi 6 expressing adeno virus.
  • Cdk inhibitors may be effective against other disorders of cell proliferation including psoriasis (characterized by keratinocyte hyperproliferation) and possibly lupus. Distinct from gene therapy approaches, many research groups are pursuing small molecule inhibitors of cyclin dependent kinases. Small molecule inhibitors of Cdks that have been published to date include purines such as olomoucine (Vesely et al., Eur. J. Biochem. 1994;224:771-786) and roscovitine (Meijer L. et al., Eur. J. Biochem. 1997;243:527-536), butyrolactone, staurosporine and
  • UCN-01 suramin, 9-hydroxyellipticine, and several flavonoids including flavopiridol (Garrett M.D. and Fattaey A., Curr. Opin. Genes & Develop.
  • Flavopiridol is currently in phase II clinical trials for the treatment of metastatic renal cell carcinoma. It is a relatively nonspecific inhibitor of Cdks and produces cell cycle blocks at Gl and G2. Nonetheless, it is a potent inhibitor of several breast and lung cancer cell lines (Sedlacek H.H. et al., Int. J. Oncol.
  • Cdk inhibitors have been extensively studied in vitro, generally displaying most potency against Cdkl, Cdk2 and Cdk5.
  • Analogs of olomoucine have been synthesized by Meijer and coworkers (Legraverand M. et al., Bioor. Med. Chem. 1999;7:1281-1293 and references therein), Schultz and coworkers (Chang Y-T. et al., Chem. & Biol. 1999;6:361-375), Griffin et al.
  • Cdk inhibitors include aminothiazoles developed independently by Agouron (WO 99/21845) and by Bristol-Myers Squibb (WO 99/24416); indolinones, that have been developed by Sugen (WO 98/50356) and by Glaxo (WO 99/24416); benzothiadiazines (WO 98/49146); peptides (WO 97/11 174); pyrazolo[3,4-b]pyridines (WO 99/30710); and phenylaminopyrimidines (Novartis, unpublished results).
  • Several of these structural classes of protein kinase inhibitors have been reviewed by McMahon et al., Curr. Opin. Drug.
  • This invention provides quinazolines that are useful for treating cell proliferative disorders, such as vascular smooth muscle proliferation associated with atherosclerosis, postsurgical vascular stenosis and restenosis, and endometriosis.
  • This invention also provides quinazolines that are useful for treating infections, including viral infections such as DNA viruses like herpes and RNA viruses like HIV, and fungal infections.
  • This invention further provides quinazolines that are useful for treating autoimmune diseases such as psoriasis, inflammation like rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, and glomerulonephritis, organ transplant rejection, including host versus graft disease.
  • autoimmune diseases such as psoriasis, inflammation like rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, and glomerulonephritis, organ transplant rejection, including host versus graft disease.
  • This invention further provides quinazolines that are useful for treating and neurodegenerative disorders such as Alzheimer's disease.
  • This invention further provides quinazolines that are useful for treating cancer.
  • This invention further provides quinazolines that are useful for treating gout.
  • This invention further provides quinazolines that are useful for treating kidney disease, such as polycystic kidney disease.
  • the above-identified methods of treatment are preferably carried out by administering a therapeutically effective amount of a compound of Formulas I and/or II (set forth below) to a subject in need of treatment.
  • a group of 2-arylamino-7-(alkyl)oxy-8-alkylquinazolines and 8- alkyl-2-arylamino-quinazoline 2,7-diamines are potent inhibitors of cyclin-dependent kinases (cdks).
  • cdks cyclin-dependent kinases
  • the compounds of the invention are members of the class of compounds of Formulas I and II, which will be described further below
  • This invention also provides pharmaceutical formulations comprising a compound of Formulas I or II together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
  • Compounds within the scope of the present invention are inhibitors of the cyclin-dependent kinases such as cdkl, cdk2, cdk4, and cdk5.
  • cyclin-dependent kinases A new class of compounds have been discovered that are potent inhibitors of cyclin-dependent kinases (cdks) and are useful agents for treating subjects suffering from diseases caused by abnormal cell proliferation.
  • Compounds within the scope of the present invention are inhibitors of the cyclin-dependent kinases such as cdkl, cdk2, cdk4, and cdk5.
  • the compounds of the instant invention are useful in controlling proliferative diseases and disorders, cancer, infections, autoimmune diseases, gout, kidney disease, and neurodegenerative diseases and disorders.
  • the compounds of the invention comprise those of Formula I:
  • R 1 is hydrogen, alkyl, alkyl substituted with at least one of amine, halogen, hydroxy, or alkoxy, cycloalkyl,or heterocycloalkyl;
  • R 2 is OH, alkyloxy, aryloxy, or NR 3 R 4 ;
  • A is N, or CW 3 ;
  • R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, (CH 2 ) n Ar, cycloalkyl, heterocycloalkyl, or heteroaryl, or R 3 and R 4 together with the nitrogen to which they are attached optionally may form a ring having 3 to 7 carbon atoms and said ring optionally contains 1 , 2 or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur including S(O) and S(O) 2 .
  • Said ring also may be additionally substituted with up to 3 groups selected from alkyl, haloalkyl, NR 8 C(O)R 9 , C(O)OR 8 , C(O)R 8 , C(O)NR 8 R 9 , NR 8 R 9 , NR 8 SO 2 R 9 , OR 8 , SO,NR 3 R 4 , or SR 8 ;
  • W and W z are independently selected NTDR3 J TR54 4 R ⁇ X, OR 3 , SR 3 , hydrogen, halogen, haloalkyl, COR 3 , CO 2 R 3 , CONR 3 R 4 , S(O)R 3 ,
  • T is
  • R 5 is hydrogen, or alkyl
  • R 6 is hydrogen, alkyl, halogen, haloalkyl, alkynyl, alkenyl, COR 3 , CO 2 R 3 ,
  • OR 3 or NR 3 R 4 W 3 is NR 3 R 4 , N(O)R 3 R 4 , NR 3 R 4 R 8 X, OH, OR 3 , SH, SR 3 , halogen, COR 3 , CO 2 R 3 ,
  • NR 8 C(O)T(CH 2 ) m QR or T(CH 2 ) m CO 2 R 3 where m and n are independently 1-6, T is O, S, NR 3 , N(O)R 3 , NR 3 R 4 W, or CR 3 R 4 , and Q is O, S, NR 9 , N(O)R 9 or NR 9 R 10 X;
  • R 8 , R 9 , R 10 and R 11 are hydrogen, alkyl, or aryl;
  • X is a halogen; or a pharmaceutically acceptable salt, ester, amide or pro-drug thereof.
  • the compounds of the invention further comprise those of Formula II:
  • R 1 is hydrogen, alkyl, alkyl substituted with at least one of amine, halogen, hydroxy, or alkoxy, cycloalkyl,or heterocycloalkyl;
  • R 2 is OH, alkyloxy, aryloxy, or NR 3 R 4 ;
  • A is N, or CW 3 ;
  • R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, (CH 2 ) n Ar, cycloalkyl, heterocycloalkyl, or heteroaryl, or R 3 and R 4 together with the nitrogen to which they are attached optionally may form a ring having 3 to
  • said ring optionally contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur including S(O) and S(O) 2 .
  • Said ring also may be additionally substituted with up to 3 groups selected from alkyl, haloalkyl, NR 8 C(O)R 9 , C(O)OR 8 , C(O)R 8 , C(O)NR 8 R 9 , NR 8 R 9 , NR 8 SO 2 R 9 , OR 8 ,
  • W 1 and W 2 are independently selected from NR 3 R 4 , N(O)R 3 R 4 , NR 3 R 4 R 8 X, OR 3 , SR 3 , hydrogen, halogen, haloalkyl, COR 3 , CO 2 R 3 , CONR 3 R 4 , S(O)R 3 , SO 2 R 3 , SO 2 NR 3 R 4 , SO 3 R 3 , P(O)(OR ) 2 , aldehyde, nitrile, nitro, alkyl, T(CH 2 ) m QR 8 , C(O)T(CH 2 ) m QR 8 , or T(CH 2 ) m CO 2 R 8 where m is 1 -6, T is O, S, NR 3 , N(O)R 3 , NR 3 R 4 X, or CR 3 R 4 , and Q is O, S, NR 9 , N(O)R 9 or
  • R 5 is hydrogen, or alkyl
  • R 6 is hydrogen, alkyl, halogen, haloalkyl, alkynyl, alkenyl, COR 3 , CO 2 R 3 , CONR 3 R 4 , SO 2 NR 3 R 4 , SO 2 R 3 , SO 3 R 3 , P(O)(OR ) 2 , aldehyde, nitrile, nitro,
  • OR 3 or NR 3 R 4 W 3 is NR 3 R 4 , N(O)R 3 R 4 , NR 3 R 4 R 8 X, OH, OR 3 , SH, SR 3 , halo, COR 3 , CO 2 R 3 ,
  • NR 3 SO 2 R 4 aldehyde, nitrile, nitro, alkyl, T(CH 2 ) m QR 8 , C(O)T(CH 2 ) m QR 8 , NR 8 C(O)T(CH 2 ) m QR' ' , or T(CH 2 ) m CO 2 R 3 where n and m independently are 1-6; T is O, S, NR 3 , N(O)R 3 , NR 3 R 4 W, or CR 3 R 4 ; and Q is O, S, NR 9 ,
  • R 8 , R 9 , R 10 and R 11 are hydrogen, alkyl, or aryl;
  • X is a halogen; or a pharmaceutically acceptable salt, ester, amide or pro-drug thereof.
  • W 3 include piperidine; piperidine substituted with up to 2 groups consisting of alkyl, haloalkyl, OR 9 , (CH 2 ) n OR 9 , CO 2 R 9 , CONR 9 R 10 , NR 9 R 10 ; 3-aminopyrrolidine, 3-acylaminopyrrolidine; 3- alkylaminopyrrolidine, 3-aminoalkylpyrrolidine; pyrrolidine substituted with up to 3 groups selected from alkyl, haloalkyl, NR 8 C(O)R 9 , C(O)NR 8 R 9 , NR 8 R 9 , OR 8 ; piperazine; N-acylpiperazine; N-aminoacylpiperazine; piperazine substituted with up to five groups selected from alkyl, haloalkyl, OR 8 , (CH 2 ) n OR 8 , CO 2 R 8 , ⁇ R 8 C(O)R 9 , C(O)NR 8 R 9 , NR
  • Especially preferred groups include N-acetylpiperazine, 3,5-dimethylpiperazine, 3,3,4-trimethylpiperazinyl, N-methylpiperazine, homopiperazine, N- acetylhomopiperazine, N-tert-butylacetylpiperazine, N-pivaloylpiperazine, N- leucylpiperazine, N-isoleucylpiperazine; N-valylpiperazine, N-prolylpiperazine,
  • N-alanylpiperazine and N-glycylpiperazine.
  • a preferred group of compounds of Formulas I and II have the above formulas wherein R 1 is alkyl.
  • Another preferred group of compounds of Formulas I and II have the above formulas wherein R 2 is ⁇ R 3 R 4 .
  • Another preferred group of compounds of Formulas I and II have the above formulas wherein A is CW 3 .
  • Another preferred group of compounds of Formulas I and II have the above formulas wherein R 6 is alkyl.
  • Another preferred group of compounds of Formulas I and II have the above formulas wherein Wl, W ⁇ , and W ⁇ are hydrogen.
  • Another preferred group of compounds of Formulas I and II have the above formulas wherein R ⁇ and R > are hydrogen.
  • a particularly preferred group of compounds of Formulas I and II have the above formulas wherein W ⁇ , W ⁇ , and W ⁇ are hydrogen, and R! is alkyl.
  • Another particularly preferred group of compounds of Formulas I and II have the above formulas wherein W ⁇ , W ⁇ , and W ⁇ are hydrogen, and R! is cycloalkyl.
  • a further particularly preferred group of compounds of Formulas I and II have the above formulas wherein W ⁇ is piperidine or substituted piperidine, and
  • R! is alkyl or cycloalkyl.
  • a further particularly preferred group of compounds of Formulas I and II have the above formulas wherein W ⁇ is pyrrolidine or substituted pyrrolidine, and R! is alkyl or cycloalkyl.
  • a further particularly preferred group of compounds of Formulas I and II have the above formulas wherein W ⁇ is piperazine or substituted piperazine, and R! is alkyl or cycloalkyl.
  • a further particularly preferred group of compounds of Formulas I and II have the above formulas wherein W ⁇ is piperidine or substituted piperidine, R 2 is alkyloxy, and R! is alkyl or cycloalkyl.
  • a further particularly preferred group of compounds of Formulas I and II have the above formulas wherein W ⁇ is pyrrolidine or substituted pyrrolidine, R 2 is alkyloxy, and R! is alkyl or cycloalkyl.
  • a further particularly preferred group of compounds of Formulas I and II have the above formulas wherein W ⁇ is piperazine or substituted piperazine, R 2 is alkyloxy, and R! is alkyl or cycloalkyl.
  • Additional preferred embodiments of the present invention include those in Examples 1-10, 85, 54, and 57, infra.
  • Compounds of Formula I wherein R 2 is alkyl, R ⁇ and R > are hydrogen are especially useful as intermediates leading to compounds that display good inhibitory activity against cyclin-dependent kinases.
  • Other especially useful intermediates leading to compounds that display good inhibitory activity against cyclin-dependent kinases are compounds of Formula III
  • Rl, R 2 , R5. and R° are as defined above and X is oxygen or halogen.
  • Particularly useful intermediates are those wherein R 2 is alkyloxy, R ⁇ is hydrogen or alkyl, R 6 is hydrogen, and R° is oxygen or chlorine or a pharmaceutically acceptable salt, ester, amide, or pro-drug thereof.
  • the present invention also discloses processes for preparing compounds of
  • Alkyl means a straight or branched hydrocarbon radical having from
  • 1 to 10 carbon atoms (unless stated otherwise) and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso- pentyl, n-hexyl, and the like.
  • Hydro includes fluoro, chloro, bromo, and iodo.
  • Alkenyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-l-yl,
  • Alkynyl means straight and branched hydrocarbon radicals having from
  • Cycloalkyl means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, no ⁇ inanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl.
  • groups can be substituted with groups such as hydroxy, keto, and the like.
  • heterocyclyl which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, orNR2, examples being substituted or unsubstituted oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, piperazinyl, acylpiperazinyl, pyrrolidinyl, and mo ⁇ holine.
  • Alkoxy refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.
  • alkoxy refers to polyethers such as -O-(CH2)2" -CH3, and the like.
  • Alkanoyl groups are alkyl linked through a carbonyl, ie, Ci -C5-C(O)-.
  • Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
  • acyl means an alkyl or aryl (Ar) group bonded through a carbonyl group, ie, R-C(O)-.
  • acyl includes a Cj-Cg alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 O ⁇ a carboxylic or heterocyclic group.
  • Typical acyl groups include acetyl, benzoyl, and the like.
  • alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5 ; phenyl, substituted phenyl, thio C j -Cg alkyl, C ⁇ -Cg alkoxy, hydroxy, carboxy, C ⁇ -C5 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur.
  • "Substituted nitrogen” means nitrogen bearing Cj-Cg alkyl or (CH2) n Ph where n is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced.
  • substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-mo ⁇ holinopropyl, piperazinylmethyl, and
  • substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-(l-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like.
  • Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
  • substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-l-yl,
  • heteroaryl refers to unsubstituted and substituted aromatic groups.
  • Heteroaryl groups have from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N.
  • Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring.
  • Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl.
  • Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, pyrrole, pyrazole, imidazole, thiazole, and the like.
  • Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, hydroxy, -COOR 7 , amino of the formula -NR 4 R 5 , and T(CH2) m QR 4 or T(CH 2 ) m CO 2 R 4 wherein m is 1 to 6, T is O, S, NR 4 , N(O)R 4 , NR 4 R 6 Y, or
  • CR 4 R 5 , Q is O, S, NR 5 , N(O)R 5 , or NR 5 R6 ⁇ wherein R 4 and R 5 are as described above, and R 7 is alkyl or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like.
  • R 7 is alkyl or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like.
  • the alkyl and alkoxy groups can be substituted as defined above.
  • typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl.
  • patient means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
  • the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • the compounds of Formulas I, II, and III are capable of further forming both pharmaceutically acceptable formulations comprising salts, esters, amides, and prodrugs.
  • pharmaceutically acceptable salts, esters, amides, and prodrugs refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed and including, but not limited to, acid addition and/or base salts, solvents and N-oxides of a compound of Formulas I, II, and III.
  • This invention also provides pharmaceutical formulations comprising a compound of Formulas I, II, or III together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All of these forms are within the present invention.
  • Formulas I, II and III include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge, et al., "Pharmaceutical Salts,” J. of Pharmaceutical Science, 1977;66:1-19.
  • the acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for pu ⁇ oses of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • Suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge, et al., supra.
  • the base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for pu ⁇ oses of the present invention.
  • esters of the compounds of this invention examples include Cj-Cgalkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include Cf-C cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C]-C4alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary
  • the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
  • Amides derived from ammonia, Ci -C alkyl primary amines, and Ci -C2dialkyl secondary amines are preferred.
  • Amides of the compounds of the invention may be prepared according to conventional methods.
  • the term "pro-drug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American
  • a therapeutically effective amount is an amount of a compound of Formulas I, II, or III, that when administered to a patient, ameliorates a symptom of the disease.
  • cardiovascular disorders and diseases includes, but is not limited to atherosclerosis, psoriasis, and restenosis.
  • Those skilled in the art are easily able to identify patients having atherosclerosis, psoriasis, restenosis, or at risk of having atherosclerosis or restenosis.
  • patients who are at risk of having restenosis include, but are not limited to, patients having undergone balloon angioplasty or other surgical vascular procedures.
  • cancer includes, but is not limited to, the following cancers: breast; ovary; cervix; prostate; testis; esophagus; glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma; bone; colon, adenocarcinoma, adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colon-rectum, large intestine, rectum; brain and central nervous system; and leukemia.
  • autoimmune disease includes, but is not limited to inflammation, such as rheumatoid arthritis, and organ graft rejections.
  • kidney disease includes, but is not limited to kidney disease, such as polycystic kidney disease.
  • Compounds within the scope of the present invention effectively inhibit vascular smooth muscle cell proliferation and migration.
  • the method entails inhibiting vascular smooth muscle proliferation, and/or migration by administering an effective amount of a compound of Formulas I, II, or III to a subject in need of treatment.
  • the compounds of the present invention are useful for treating cancer (for example, leukemia and cancer of the lung, breast, prostate, and skin such as melanoma), cardiovascular disorders and diseases, infections, autoimmune diseases, gout, kidney diseases, and neurodegenerative diseases and disorders.
  • cancer for example, leukemia and cancer of the lung, breast, prostate, and skin such as melanoma
  • cardiovascular disorders and diseases infections, autoimmune diseases, gout, kidney diseases, and neurodegenerative diseases and disorders.
  • a patient having the indication is administered a therapeutically effective amount of a pharmaceutically acceptable composition comprising an invention compound.
  • the term "neurological disease and disorders" includes, but is not limited to, Alzheimer's disease.
  • Compounds within the scope of the present invention effectively inhibit the degradation of neurons.
  • the method entails inhibiting neural degeneration by administering an effective amount of a compound of Formulas I, II, or III to a subject in need of treatment.
  • the compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. It will be recognized to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formulas I, II, or III or a corresponding pharmaceutically acceptable salt or solvate of a compound of Formulas I, II, or III.
  • a further embodiment of this invention is a pharmaceutical formulation comprising a compound of Formulas I, II, or III together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
  • pharmacuetically acceptable carriers can be either a solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the formulations of this invention preferably contain from about 5% to about 70% or more of the active compound.
  • Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • capsules which include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogenously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient size molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions such as water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution, isotonic saline, 5% aqueous glucose, and the like.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water and mixing with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • Such liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Waxes, polymers, microparticles ⁇ and the like can be utilized to prepare sustained-release dosage forms.
  • osmotic pumps can be employed to deliver the active compound uniformally over a prolonged period.
  • the pharmaceutical preparations of the invention are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the therapeutically effective dose of a compound of Formulas I, II, or III will generally be from about 1 mg to about 100 mg/kg of body weight per day. Typical adult doses will be about 50 mg to about 800 mg per day.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 500 mg, preferably about 0.5 mg to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • a subject in need of treatment with a compound of Formulas I, II, or III is administered a dosage of about 1 to about 500 mg per day, either singly or in multiple doses over a 24-hour period.
  • the compounds of the present invention are capable of binding to and inhibiting the activity of proteins having the ability to phosphorylate other proteins, such as cdks. Cdks form complexes with cyclins, and these complexes phosphorylate key proteins allowing cells to proceed through the cell cycle (Meijer L., Progress in Cell Cycle Research, 1995;1 :351-363).
  • the compounds of this invention inhibit this phosphorylation and therefore can be used as anti- proliferative agents for the treatment of cancer and/or restenosis and other proliferative diseases, and as anti-neural degenerative agents for the treatment of neural degenerative disorders such as Alzheimer's disease.
  • the compounds of the present invention are also useful research tools for studying the mechanism of action of those kinases, both in vitro and in vivo. While the forms of the invention herein constitute presently preferred embodiments, many others are possible. It is not intended herein to mention all of the possible equivalent forms or ramifications of the invention. It is understood that the terms used herein are merely descriptive rather than limiting, and those skilled in the art will realize that various changes may be made without departing from the spirit or scope of the invention.
  • Scheme 1 describes a typical method for the preparation of the quinazoline compounds of the invention.
  • BocN ⁇ NHBoc (ref Bernatowivz et al
  • EXAMPLE 5 6-Hydroxymethylene-2-isopropyl-3-methoxy-cyclohex-2-enone To a suspension of sodium hydride (3.6 g, 60% suspension, 90 mmol) in benzene (100 mL), a mixture of ethyl formate (12.5 g) and 2-isopropyl-3 -methoxy- cyclohex-2-enone (5 g, 29.7 mmol) in benzene was added dropwise at 5°C. The reaction mixture was stirred at ice temperature for 1 hour, and at room temperature for 18 hours. The reaction mixture was cooled in an ice bath, and 10%) sodium hydrogen phosphate solution (200 mL) was added dropwise.
  • EXAMPLE 6 8-Isopropyl-7-methoxy-quinazolin-2-ylamine A mixture of 6-hydroxymethylene-2-isopropyl-3-methoxy-cyclohex-2-enone (3.5 g) and guanidine carbonate (7 g) in DMF (40 mL) was heated at 150°C for
  • the dihydroquinazoline was aromatized to the title compound by heating in nitrobenzene at 150°C in the ' presence of 10%> Pd-C.
  • nitrobenzene 20 mL
  • 200 mg of 10% Pd-C was added, and the reaction mixture was heated at 150°C for 3 days.
  • the Pd-C was removed by filtration.
  • the filtrate was concentrated, and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as an off-white solid (1 g, 50% yield), mp
  • the compounds of this invention are potent inhibitors of cyclin-dependent kinases, and accordingly, are useful in treating and preventing neurodegenerative disorders, atherosclerosis, and other cell proliferative disorders like cancer.
  • the compounds have exhibited excellent inhibitory activity against a wide variety of cyclin-dependent kinases, all in assay systems routinely utilized to measure such activity.
  • a typical assay measures inhibitory activity against the cyclin D dependent kinase 4 enzyme (cdk4/D).
  • the invention compounds of Formula I exhibited IC50 values ranging generally from 0.011 ⁇ iM to 1.75 ⁇ M.
  • the cdk4 assay was carried out as follows. Cyclin-Dependent Kinase 4 (cdk4) Assay
  • Enzyme assays for IC50 determinations (Table 1 above) and kinetic evaluation were performed in 96 well filter plates (Millipore MADVN6550). The total volume was 0.1 mL containing a final concentration of 20 mM TRIS (tris[hydroxymethyl]aminomethane), at pH 7.4, 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl2, 25 ⁇ M ATP containing 0.25 ⁇ Ci of [ 32 P]ATP,
  • cdk4 20 ng of cdk4, 1 ⁇ g of retinoblastoma, and appropriate dilutions of a compound of the present invention. All components except the ATP were added to the wells, and the plate was placed on a plate mixer for 2 minutes. The reaction was started by adding [32p]ATP and the plate was incubated at 25 °C for 15 minutes. The reaction was terminated by addition of 0.1 mL of 20% trichloroacetic acid (TCA). The plate was kept at 4°C for at least 1 hour to allow the substrate to precipitate.
  • TCA trichloroacetic acid
  • IC50 values were determined using enzyme assays performed in a total volume of 0.1 mL of a solution comprising 25 mM Hepes, pH 7.4, 5 mM MgCL2, 2 mM MnCL2, 50 ⁇ M sodium vanadate, 5 to 10 ng of cdk4, and 200 ⁇ M of a substrate peptide Ala-Glu-Gly-Ser-Ala-Tyr472.Qiu.Qiu_Yai.NH2, derived from the amino acid [Try4 ' h as Deen shown to be 1 of 4 tyrosines in PLC- ⁇ that are phosphorylated by the EGF receptor tyrosine kinase (Wahl M.I., et al., J Biol.
  • the reaction was terminated by the addition of 2 mL of 75 mM phosphoric acid, and the contents of the reaction passed through a 2.5 cm phosphocellulose filter disc to bind the peptide.
  • the filter was washed five times with 75 mM phosphoric acid, placed in a vial along with 5 mL of scintillation fluid (Ready gel, Beckman), and counted on a scintillation counter.
  • the compounds of Formula I have also exhibited good inhibitor activity against other cyclin-dependent kinase enzymes such as cdk2/cyclinE, cdk2/cyclinA, and cdk 1 /cyclinB .
  • the invention compounds When measured against cdk2/E. the invention compounds exhibited IC50 values ranging generally from about 0.004 to greater than 5 ⁇ M. Against cdk2/A, the compounds exhibited IC50 values ranging from about 0.028 to greater than
  • Source of enzyme recombinant baculovirus-infected insect cell sf9 - expressed recombinant Cdk5-p25 complex
  • Pu ⁇ ose To evaluate the ability of test agents to inhibit Cdk5/p25 phosphorylation of Histone HI.
  • Method Baculovirus-insect cell His-tagged Cdk5/Glu-tagged p25 (or GST-p25) enzyme complex is diluted to a concentration of 50 ng/20 ⁇ L in Enzyme Dilution Buffer (EDB - 50 mM Tris-HCl [pH 8.0], 10 mM NaCl, 10 mM MgCl , and
  • test agent 1 mM DTT
  • 20 ⁇ L sample of test agent diluted in EDB
  • 20 ⁇ L of the of the final Cdk5/p25 enzyme preparation is then combined with 20 ⁇ L of the of the final Cdk5/p25 enzyme preparation and allowed to stand for 5 minutes at room temperature.
  • Twenty-five microliters of substrate solution containing 115 ⁇ L/mL Histone HI, 30 ⁇ M ATP (vanadate-free), and 30 ⁇ iCi/mL ⁇ .33p ATP (Amersham) in EDB is then added to the test agent/enzyme preparation and shaken at 30°C for 45 minutes.
  • a 50 ⁇ L sample of the final preparation is added to 100 mL of 150 mM phosphoric acid on ice for 30 minutes to facilitate precipitation.
  • the precipitate is then filtered through a 96 well phosphocellucose filter plate and subsequently rinsed 3 times with 75 mM phosphoric acid. Each well then receives 20 ⁇ L of scintillation cocktail, and the plates are counted for beta emissions using a Trilux Counter ( 33 p filter protocol). Test samples are compared to Control (no test agent present; as 0% inhibition) and
  • Baseline level no enzyme, no test agent; as 100% inhibition beta emissions to determine the percent inhibition of Histone HI phosphorylation.
  • the invention compounds can be formulated in conventional manners to provide convenient dosage forms for delivery to mammals by various routes, including oral, parenteral (i.e., subcutaneous, intravenous, and intramuscular), transdermal, e.g. slow release skin patch or cream, as well as by slow release delivery devices such as osmotic pumps, suppositories, and buccal seals.
  • parenteral i.e., subcutaneous, intravenous, and intramuscular
  • transdermal e.g. slow release skin patch or cream
  • slow release delivery devices such as osmotic pumps, suppositories, and buccal seals.
  • magnesium stearate (1 20 g
  • the quinazoline, lactose, and corn starch (for mix) are blended to uniformity.
  • the corn starch (for paste) is suspended in 600 mL of water and heated with stirring to form a paste. This paste is used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 hand screen and dried at 80°C.
  • the dry granules are then passed through a No. 16 screen.
  • the mixture is lubricated with 1 % magnesium stearate and compressed into tablets in a conventional tableting machine.
  • the tablets are useful for treating cancers such as breast, prostate, lung, ovarian, colon, pancreatic, melanoma, esophageal, brain,
  • Kaposi's sarcoma and lymphomas, or neurodegenerative disorders such as Alzheimer's.
  • Example 20 In a solution of 700 mL of propylene glycol and 200 mL of water for injection is suspended 20.0 g of Example 20 with stirring. After suspension is complete, the pH is adjusted to 5.5 with hydrochloric acid, and the volume is made up to 1000 mL with water for injection. The formulation is sterilized, filled into 5.0 mL ampoules, each containing 2.0 mL (representing 40 mg of invention compound) and sealed under nitrogen.
  • EXAMPLE 54 Suppositories A mixture of 400 mg of Example 20, and 600 mg of theobroma oil is stirred at 60°C to uniformity. The mixture is cooled and allowed to harden in a tapered mold to provide a 1 g suppository.
  • Example 55 Slow Release Formulation Five hundred milligrams of Example 20 is converted to a hydrochloride salt and placed into an Oros osmotic pump for controlled release for treatment of atherosclerosis.
  • Example 56 Skin Patch Formulation Fifty milligrams of Example 20 is admixed with 50 mg of propylene glycol monolaurate in a polydimethylsiloxane adhesive. The mixture is layered onto an elastic film made with an adhesive formulation of polybutene, polyisobutylene, and propylene glycol monolaurate. The layers are placed between 2 layers of polyurethane film. A release liner is attached to the adhesive surface, and is removed prior to application to a skin surface. The propylene glycol monolaurate serves as a permeation-enhancing agent.

Abstract

Cette invention porte sur des quinazolines qui sont utiles pour traiter des pathologies et états induisant la prolifération cellulaire tels que les maladies cardio-vasculaires, les infections, les cancers, les maladies auto-immunes, la goutte, les maladies du foie et les maladies et états dégénératifs tels que la maladie d'Alzheimer. Nous avons maintenant découvert un groupe de 2-arylamino- quinazolines (I) et (II) qui sont de puissants inhibiteurs des kinases dépendant de la cycline (cdks). Les composés sont facilement synthétisés et peuvent être administrés de différentes manières, y compris par voie orale, et ont une biodisponibilité suffisante. Cette invention porte également sur des formulations pharmaceutiques comprenant au moins un des composés de quinazoline et un support acceptable d'un point de vue pharmaceutique, un diluant ou un excipient de celui-ci. L'invention porte en outre sur des intermédiaires utiles générés au cours de la production des composés de quinalozine.
PCT/US2000/030376 1999-11-22 2000-11-03 Quinazolines et leur utilisation dans l'inhibition des enzymes kinase dependant de la cycline WO2001038315A1 (fr)

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AU14621/01A AU1462101A (en) 1999-11-22 2000-11-03 Quinazolines and their use for inhibiting cyclin-dependent kinase enzymes
US10/130,843 US6982260B1 (en) 1999-11-22 2000-11-03 Quinazolines and their use for inhibiting cyclin-dependent kinase enzymes
MXPA02003140A MXPA02003140A (es) 1999-11-22 2000-11-03 Quinazolinas y su uso para la inhibicion de las enzimas cinasa dependientes del ciclin.
CA002386955A CA2386955A1 (fr) 1999-11-22 2000-11-03 Quinazolines et leur utilisation dans l'inhibition des enzymes kinase dependant de la cycline
EP00976914A EP1235815A1 (fr) 1999-11-22 2000-11-03 Quinazolines et leur utilisation dans l'inhibition des enzymes kinase dependant de la cycline
JP2001540078A JP2003514901A (ja) 1999-11-22 2000-11-03 キナゾリン類およびシクリン依存性キナーゼ酵素を阻害するためのその使用
BR0015718-0A BR0015718A (pt) 1999-11-22 2000-11-03 Quinazolinas e seu uso para inibição de enzimas de cinase dependente de ciclina

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WO2004092144A2 (fr) * 2003-04-16 2004-10-28 F. Hoffmann-La Roche Ag Composes de quinazoline
US6982260B1 (en) 1999-11-22 2006-01-03 Warner-Lambert Company Quinazolines and their use for inhibiting cyclin-dependent kinase enzymes
WO2006017844A1 (fr) 2004-08-06 2006-02-16 Janssen Pharmaceutica, N.V. Nouveaux derives de 2-amino-quinazoline utiles en tant qu'inhibiteurs de la $g(b)-secretase (bace)
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WO2011161159A1 (fr) 2010-06-22 2011-12-29 Fovea Pharmaceuticals Composés hétérocycliques, leur préparation et leur application thérapeutique
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US8802697B2 (en) 2012-07-11 2014-08-12 Blueprint Medicines Corporation Inhibitors of the fibroblast growth factor receptor
WO2015086523A1 (fr) * 2013-12-09 2015-06-18 Ucb Biopharma Sprl Dérivés hétéroaromatiques bicycliques condensés comme modulateurs de l'activité du tnf
US9434700B2 (en) 2013-10-25 2016-09-06 Neil Bifulco, JR. Inhibitors of the fibroblast growth factor receptor
US9624195B2 (en) 2014-12-24 2017-04-18 Gilead Sciences, Inc. Isoquinoline compounds
US9695165B2 (en) 2014-01-15 2017-07-04 Blueprint Medicines Corporation Inhibitors of the fibroblast growth factor receptor
US9701677B2 (en) 2014-12-24 2017-07-11 Gilead Sciences, Inc. Fused pyrimidine compounds
US9730936B2 (en) 2014-12-24 2017-08-15 Gilead Sciences, Inc. Quinazoline compounds
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US7906522B2 (en) 2005-04-28 2011-03-15 Kyowa Hakko Kirin Co., Ltd 2-aminoquinazoline derivatives
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MXPA02003140A (es) 2002-09-30
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