3(5)-amino-pyrazole derivatives, process for their preparation and their use as antitumor agents

• US 6,218,418 B1
• Filed: 09/22/2000
• Issued: 04/17/2001
• Est. Priority Date: 08/12/1999
• Status: Expired due to Fees

• Current Assignee: Pharmacia & Upjohn Company (Pfizer Inc.), Pharmacia & Upjohn LLC (Pfizer Inc.)
• Original Assignee: Pharmacia & Upjohn Company (Pfizer Inc.), Pharmacia & Upjohn LLC (Pfizer Inc.)
• Inventors: Brasca, Maria Gabriella, Varasi, Mario, Pevarello, Paolo, Traquandi, Gabriella, Orsini, Paolo, Warpehoski, Martha A., Fritzen, Edward L., Pierce, Betsy S.
• Primary Examiner(s): Ramsuer, Robert W.
• Application Number:
  US09/667,603
• Time in Patent Office: 207 Days
• Field of Search: 548/372.5, 548/372.1, 514/404
• US Class Current: 514/404
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 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
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 231/16 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 231/40 Acylated on said nitrogen atom
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

Abstract

Compounds which are 3-amino-pyrazole derivatives represented by formula (I):

where

R is a C₃-C₆ cycloalkyl group, which may optionally be substituted by a straight or branched C₁-C₆ alkyl group, and

R₁ is a straight or branched C₁-C₆ alkyl group or a C₂-C₄ alkenyl, cycloalkyl, aryl, arylalkyl, arylcarbonyl, aryloxyalkyl and arylalkenyl, which may be optionally substituted; or a pharmaceutically acceptable salt thereof.

The compounds are useful for the treatment of cancer, cell proliferative disorders, Alzheimer'"'"'s disease, viral infections, auto-immune diseases or neurodegenerative diseases.

Claims

1. A method of treating cell proliferative disorders associated with an altered cell dependent kinase activity, comprising:

administering to a mammal in need thereof an effective amount of a compound represented by formula (I);

wherein

R is a C₃-C₆ cycloalkyl group optionally substituted with a straight or branched C₁-C₆ alkyl group; and

R₁ is a straight or branched C₁-C₆ alkyl, C₂-C₄ alkenyl, cycloalkyl, aryl, arylalkyl, arylcarbonyl, aryloxyalkyl or arylalkenyl group, which is optionally substituted with one or more groups selected from the group consisting of cycloalkyl, hydroxy, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, alkylcarbonyl, alkylsulphonyl, alkoxycarbonyl, carboxy, halogen, nitro, aryloxy, arylthio, arylsulphonyl, N-alkyl-piperazinyl, piperidinyl, 4-morpholinyl, arylamino, cyano, alkyl, aryl, oxo, haloaryl, haloarylalkyl, haloaryloxy, haloarylsulphonyl, aminosulphonyl, aminocarbonyl, arylcabonyl, perfluorinated alkyl, and perfluorinated alkoxy groups;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the cell proliferative disorder is selected from the group consisting of cancer, Alzheimer'"'"'s disease, vial infections, auto-immune diseases and neurodegenerative disorders.

3. The method of claim 2, wherein the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'"'"'s sarcoma.

4. The method of claim 1, wherein the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.

5. The method of claim 1, which provides tumor angiogenesis and metastasis inhibition.

6. The method of claim 1, which provides cell cycle inhibition or cdk/cyclin dependent inhibition.

7. The method of claim 1, further comprising subjecting the mammal in need thereof to a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.

8. The method of claim 1, wherein the mammal in need thereof is a human.

9. The method of claim 1, wherein R is a cycloalkyl group and R₁ is a C₁-C₄ alkyl, phenyl, phenylalkyl, or 5 or 6 membered heteroaryl or heteroarylalkyl group, which is optionally further substituted with said groups.

10. The method of claim 1, wherein R is a cycloalkyl group and R₁ is a C₁-C₄ alkyl, phenyl or phenylalkyl group, which is optionally substituted with hydroxy, halogen, amino, alky, alkoxy, alkoxycarbonyl, phenyl or by an optionally benzocondensed heterocycle.

11. A 3-amino-pyrazole derivative represented by formula (I):

wherein

R is a C₃-C₅ cycloalkyl group optionally substituted by a straight or branched C₁-C₆ alkyl group;

R₁ is a straight or branched C₁-C₆ alkyl group, C₂-C₄ alkenyl, cycloalkyl, aryl, arylalkyl, arylcarbonyl, aryloxyalkyl or arylalkenyl group, which is optionally substituted with one or more groups selected from the group consisting of cycloalkyl, hydroxy, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, alkylcarbonyl, alkylsulphonyl, alkoxycarbonyl, carboxy, halogen, nitro, aryloxy, arylthio, arylsulphonyl, N-alkyl-piperazinyl, piperidinyl, 4-morpholinyl, arylamino, cyano, alkyl, aryl, oxo, haloaryl, haloarylalkyl, haloaryloxy, haloarylsulphonyl, aminosulphonyl, aminocarbonyl, arylcarbonyl, perfluorinated alkyl, and perfluorinated alkoxy groups;

or a pharmaceutically acceptable salt thereof.

12. The 3-amino-pyrazole derivative of claim 11, wherein the aryl group is a phenyl, 1-naphtyl, 2-naphthyl, indanyl, indenyl, biphenyl, benzocycloalkyl, benzoheterocyclyl, quinoxalyl, indolyl or optionally benzocondensed pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl or pyrimidyl group.

13. The 3-amino-pyrazole derivative of claim 11, wherein R is a cycloalkyl group and R₁ is a C₁-C₄ alkyl, phenyl, phenylalkyl, or 5 or 6 membered heteroaryl or heteroarylalkyl group, which is optionally further substituted with said groups.

14. The 3-amino-pyrazole derivative of claim 11, wherein R is a cycloalkyl group and R₁ is a C₁-C₄ alkyl, phenyl or phenylalkyl group, which is optionally substituted with hydroxy, halogen, amino, alky, alkoxy, alkoxycarbonyl, phenyl or by an optionally benzocondensed heterocycle.

15. The 3-amino-pyrazole derivative of claim 14, wherein the optionally benzocondensed heterocycle is pyridine, pyrrole, thiophene, thiazole, isoxazole, furan, piperidine or morpholine.

16. The 3-amino-pyrazole derivative of claim 14, which is selected from the group consisting of:

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2,2-diphenylacetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(4-nitrophenyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-4-methoxybenzamide,

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(3-methoxyphenyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-[4-(dimethylamino)phenyl]acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-1-phenylcyclopropancarboxamide;

2-(1,3-benzodioxol-5-yl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(4-methoxyphenyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-phenylpropanamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(3,4-dimethoxyphenyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(1H-indol-3-yl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(5-methoxy-1H-indol-3-yl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;

2-(5-chloro-1-benzothiophen-3-yl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)acetamide;

2-(1-benzothiophen-3-yl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-3-cyclopentylpropanamide;

2-(4-chlorophenyl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-4-oxo-4-phenylbutanamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(2,3-diydro-1H-inden-5-yl)acetamide;

3-(2-chlorophenoxy)-N-(3-cyclopropyl-1H-pyrazol-5-yl)propanamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-oxo-2-phenylacetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(4-methylphenyl)acetamide;

2-[1,1′

-biphenyl]-4-yl-N-(3-cyclopropyl-1H-pyrazol-5-yl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(3-chlorophenyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(1-naphtyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(2-fluorophenyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(2-chlorophenyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(4-fluorophenyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(4-trifluoromethylphenyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-methoxy-2-phenylacetamide;

N-(3-cyclopropyl-1H˜

pyrazol-5-yl)-3-oxo-1-indanecarboxamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(3-thienyl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)bicyclo[4.2.0]octa-1.3,5-triene-7-carboxamide;

N-(3-cyclopropy-1H-pyrazol-5-yl)-4-phenyl-3-butenamide;

5-[(4-chlorophenyl)sulphonyl]-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-methyl-2-thiophenecarboxamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-4-phenoxybenzamide;

4-bromo-N-(5-cyclobutyl-1H-pyrazol-3-yl)benzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,5-bis(trifluoromethyl)benzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-4-bromobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,3-dimethylbutanamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-4-iodobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-1-napthamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-cyanobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-1,3-benzadioxole-5-carboxamide;

3-(2-chlorophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-propenamide;

2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-thiophenecarboxamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(propylsulfanyl)nicotinamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2,2,5,7-tetraethyl-1-oxo-4-indanecarboxamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-pyridinecarboxamide;

N-(5-cyclopropy-1H-pyrazol-3-yl)-2-adamantanecarboxamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-4-methylbenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2,3,4,5,6-pentafluorobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenoxyacetamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylacetamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)cyclopentancarboxamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-thienyl)acetamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,5-dichlorobenzamide;

2-chloro-N-(5-cyclopropy-1H-pyrazol-3-yl)-6-methylisonicotinamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-isoxazolecarboxamide;

2,4-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluorobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2,4-difluorobenzemide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-chlorobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2,4-dichlorobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2,6-dichlorobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-methoxybenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-methylbenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-fluorobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-chlorobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,5-dimethoxybenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-methylbenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-4-fluorobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-4-trifluoromethylbenzamide;

Methyl 4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-oxobutanoate;

N-(5-cyclopropyl-1H-pyrazol-3-yl)cyclopropanecarboxamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-4-cyanobenzamide,

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-napthamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-thiophenecarboxamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-quinoxalinecarboxamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,4-difluorobenzarmide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,5-difluorobenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,5-dimethoxybenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,5-dimethoxyphenyl)acetamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-ethoxybenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,4-dimethoxybenzamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylbutanamide;

N-(5-cyclopropyl-1H-pyrazol-3-yl)-4-(trifluoromethoxy)benzamide;

3-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1-benzothiophene-2-carboxamide;

2-(4-chlorophenoxy)-N-(5-cyclopropyl-1H-pyrazol-3-yl)nicotinamide;

3-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-thiophenecarboxamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)acetamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)benzamide;

4-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)benzamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-1-benzothiophene-2-carboxamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)[1,1′

-biphenyl]-4-carboxamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-3-phenylpropanamide;

Methyl 4-{[(3-cyclopropyl-1H-pyrazol-5-yl)amino]carbonyl}benzoate;

4-([(3-cyclopropyl-1H-pyrazol-5-yl)amino]carbonyl}benzoic acid;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-3-bromobenzamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-3,4-dichlorobenzamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-bromobenzamide;

N-(3 -cyclopropyl-1H-pyrazol-5-yl)-3-methoxybenzamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-3-trifluoromethylbenzamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-4-methoxybenzamide;

4-butoxy-N-(3-cyclopropyl-1H-pyrazol-5-yl)benzamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-1H-indole-2-carboxamide;

N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-[5-(2,6-difluorobenzyl)-2-methoxyphenyl]acetamide;

and

N¹-(3-cyclopropyl-1H-pyrazol-5-yl)terephthalamide;

or a pharmaceutically acceptable salt thereof.

17. A process for preparing the 3-amino-pyrazole derivative of claim 11, or the pharmaceutically acceptable salt thereof, comprising:

(a) reacting a compound represented by formula (II);

18. The process of claim 17, further comprising converting the 3-amino-pyrazole derivative represented by formula (I) into another derivative represented by formula (I), and/or into a salt thereof.

20. A process for preparing the 3-amino-pyrazole derivative of claim 11, or the pharmaceutically acceptable salt thereof, comprising:

(a) reacting a compound represented by formula (IV);

with a compound represented by formula (VII);

21. A pharmaceutical composition, comprising the (5)-amino-pyrazole derivative of claim 11 and at least one pharmaceutically acceptable carrier and/or diluent.

22. The method of claim 11, wherein R is a C₃-C₄ cycloalkyl group optionally substituted by a straight or branched C₁-C₆ alkyl group.

23. The method of claim 22, wherein R is unsubstituted.

24. The method of claim 11, wherein R is a cyclopropyl group optionally substituted by a straight or branched C₁-C₆ alkyl group.

25. The method of claim 24, wherein R is unsubstituted.

19. A compound represented by formula (V):

wherein R is a C₃-C₆ cycloalkyl group optionally substituted with a straight or branched C₁-C₆ alkyl group.