Pyrido›2, 3-d!pyrimidines for inhibiting protein tyrosine kinase mediated cellular proliferation

• US 5,733,914 A
• Filed: 04/03/1996
• Issued: 03/31/1998
• Est. Priority Date: 05/03/1995
• Status: Expired due to Term

• Current Assignee: Warner-Lambert Company (Pfizer Inc.)
• Original Assignee: Warner-Lambert Company (Pfizer Inc.)
• Inventors: Boschelli, Diane Harris, Klutchko, Sylvester, Doherty, Annette Marian, Hamby, James Marino, Panek, Robert Lee, Blankley, Clifton John
• Primary Examiner(s): Grumbling, Matthew V.
• Application Number:
  US08/611,279
• Time in Patent Office: 727 Days
• Field of Search: 544/279, 514/258
• US Class Current: 514/264.1
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

6-Aryl pyrido 2,3-d!pyrimidine 7-imines, 7-ones, and 7-thiones are inhibitors of protein tyrosine kinases, and are thus useful in treating cellular proliferation mediated thereby. The compounds are especially useful in treating cancer, atherosclerosis, restenosis, and psoriasis.

Claims

1. A compound of the formula ##STR28## wherein X is NH, N-Acyl, O, or S;

R₁ is SOR₃ or SO₂ R₃,

R₂, R₃, and R₄ independently are hydrogen, (CH₂)_n Ph where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3, heteroaromatic, cycloalkyl, C₁ -C₆ alkanoyl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, or C₂ -C₆ alkynyl, where the alkyl, alkenyl, and alkynyl groups may be substituted by NR₅ R₆, phenyl, substituted phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, or cycloalkyl, and where R₅ and R₆ are independently hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, (CH₂)_n Ph where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3, cycloalkyl, or heteroaromatic, and R₅ and R₆ taken together with the nitrogen to which they are attached can complete a ring having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

R₄ can additionally be --C(═

O)R₃, --C(═

O)OR₃, --SO₂ R₃, --SO₂ NR₅ R₆, --C(═

O)NR₅ R₆, --C(═

S)NR₅ R₆, --C(═

NH)R₃, --C(═

NH)NR₅ R₆, and R₃ and R₄ can be taken together with the nitrogen to which they are attached to complete a ring having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

Ar is phenyl, substituted phenyl, or heteroaromatic;

and the pharmaceutically acceptable salts thereof.

2. A compound of claim 1 having the formula ##STR29## wherein R₇ and R₈ independently are C₁ -C₆ alkoxy and R₁, R₂, and X are as defined above.

3. A compound of claim 2 wherein R₂ is C₁ -C₆ alkyl or substituted C₁ -C₆ alkyl.

4. A compound of claim 2 wherein X is NH.

6. A compound of claim 2 wherein X is O.

8. A compound of claim 2 wherein R₄ is C₁ -C₆ alkyl substituted with NR₅ R₆.

9. A compound of claim 8 wherein R₅ and R₆ both are C₁ -C₆ alkyl.

10. A compound of claim 9 wherein X is NH.

11. A compound of claim 9 wherein X is O.

12. A compound of claim 2 wherein X is S.

13. A compound of claim 2 wherein X is O.

15. A compound of claim 2 wherein X is N-Acyl.

22. A pharmaceutical formulation comprising a compound of claim 1 together with a pharmaceutically acceptable carrier therefor.

23. A formulation of claim 22 employing a compound wherein Ar is phenyl or substituted phenyl.

24. A formulation of claim 23 employing a compound wherein X is NH or N-Acyl.

25. A formulation of claim 23 employing a compound wherein X is O.

26. A formulation of claim 23 employing a compound wherein X is S.

27. A method for treating atherosclerosis comprising administering an effective amount of a compound of claim 1 to a mammal in need of treatment.

28. A method for treating psoriasis comprising administering to a mammal in need of treatment an anti-psoriatic amount of a compound of claim 1.

29. A method for treating restenosis comprising administering to a mammal in need of treatment an effective amount of a compound of claim 1.

5. A compound which is

6-(2,6-Dichlorophenyl)-8-methyl-2- 3-(4-methylpiperazin-1-yl)-propyiamino!-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2-methylamino-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-dimethylaminomethyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-ethylamino-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-(2-hydroxyethylamino)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-isopropylaminomethyl-8H-pyrido 2,3-d!pyrimidin-7-one;

2-Butylamino-6-(2,6-dichlorophenyl)-8-methyl-8 H-pyrido 2,3-d!pyrimidin-7-one;

2-Benzylamino-6-(2,6-dichlorophenyl)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2-(3-morpholin-4-yl-propylamino)-8H-pyrido2,3-d!-pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2- 2-(3,4-dimethoxyphenyl)-ethylamino!-8-methyl-8H-pyrido 2,3-d!-pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2- (pyridinylmethyl)-amino!-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2- (pyridin-3-ylmethyl)-amino!-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2-(2-pyridin-2-yl-ethylamino)-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2- 3- 4-(2-methoxyphenyl)-piperazin-1-yl!-propylamino!-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2- 4-(4-methylpiperazin-1-yl)-butylamino!-8H-pyrido 2,3-d!pyrimidin-7-one;

6- 6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-ylamino!-hexanoic acid, tert-butyl ester;

6- 6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-ylamino!-hexanoic acid;

6-(2,6-Dichlorophenyl)-8-ethyl-2- 3-(4-methyl-piperazin-1-yl)-propylamino!-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2- 5-(4-methylpiperazin-1-yl)-pentylamino!-8H-pyrido 2,3-d!pyrimidin-7-one;

4-{4- 6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido 2,3-d!pyrimidin-2-ylamino!-phenyl}-butyric acid, ethyl ester;

or

4-{4- 6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido 2,3-d!pyrimidin-2-ylamino!-phenyl}-butyric acid.

7. The compound which is

2-Amino-6-(2,6-dichlorophenyl)-8-propyl-8H-pyrido 2,3-d!pyrimidin-7-one;

2-Amino-8-butyl-6-(2,6-dichlorophenyl)-8H-pyrido 2,3-d!pyrimidin-7-one;

2-Amino-6-(2,6-dichlorophenyl)-8-isobutyl-8H-pyrido 2,3-d!pyrimidin-7-one;

2-Amino-6-(2,6-dichlorophenyl)-8-(3-dimethylaminopropyl)-8H-pyrido 2,3-d!pyrimidin-7-one;

2-Amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido 2,3-d!pyrimidin-8-yl!-acetic acid methyl ester;

2-Amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido 2,3-d!pyrimidin-8-yl!-acetic acid tert-butyl ester;

2-Amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido 2,3-d!pyrimidin-8-yl!-acetic acid;

2-Amino-8-benzyl-6-(2,6-dichlorophenyl)-8H-pyrido 2,3-d!pyrimidin-7-one;

2-Amino-8-(3-bromobenzyl)-6-(2,6-dichlorophenyl)-8H-pyrido 2,3-d!pyrimidin-7-one;

4- 2-Amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido 2,3-d!pyrimidin-8-ylmethyl!-benzoic acid methyl ester;

2-Amino-8-(2,6-dichlorobenzyl)-6-(2,6-dichlorophenyl)-8H-pyrido 2,3-d!pyrimidin-7-one;

2-Amino-6-(2,6-dichlorophenyl)-8-(4-methoxybenzyl)-8H-pyrido 2,3-d!pyrimidin-7-one;

2-Amino-6-(2,6-dichlorophenyl)-8-pyridin-4-ylmethyl-8H-pyrido 2,3-d!pyrimidin-7-one;

or

2-Amino-6-(2,6-dichlorophenyl)-8-(3-phenylpropyl)-8H-pyrido 2,3-d!pyrimidin-7-one.

14. The compound which is

6-(2,6-Dichlorophenyl)-2-methanesulfinyl-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido 2,3-d!pyrimidin-7-one;

or

6-(2,6-Dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido 2,3-d!pyrimidin-7-one.

16. The compound which is

N- 6-(2,6-Dichlorophenyl)-8-ethyl-2-methylsulfanyl-8H-pyrido 2,3-d!pyrimidin-7-ylidene!-acetamide.

17. A compound of the formula ##STR30## wherein:

X is NH, N-Acyl, O, or S;

R₂ is (CH₂)_n Ph where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3, heteroaromatic, cycloalkyl, C₁ -C₆ alkanoyl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, and C₂ -C₆ alkynyl, where the alkyl, alkenyl, and alkynyl groups may be substituted by NR₅ R₆, phenyl, substituted phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and where R₅ and R₆ are independently hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, (CH₂)_n Ph where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3, cycloalkyl, heteroaromatic, and R₅ and R₆ taken together with the nitrogen to which they are attached can complete a ring having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur,

R₄ is hydrogen, (CH₂)_n Ph where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3, heteroaromatic, cycloalkyl, C₁ -C₆ alkanoyl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, and C₂ -C₆ alkynyl, where the alkyl, alkenyl, and alkynyl groups may be substituted by NR₅ R₆, phenyl, substituted phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and where R₅ and R₆ are independently hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, (CH₂)_n Ph where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3, cycloalkyl, heteroaromatic, and R₅ and R₆ taken together with the nitrogen to which they are attached can complete a ring having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur,

R₄ can additionally be --C(═

O)R₃, --C(═

O)OR₃, --SO₂ R₃, --SO₂ NR₅ R₆, --C(═

O)NR₅ R₆, --C(═

S)NR₅ R₆, --C(═

NH)R₃, --C(═

NH)NR₅ R₆, and R₃ and R₄ can be taken together with the nitrogen to which they are attached to complete a ring having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur;

Ar is phenyl, substituted phenyl, or heteroaromatic;

and the pharmaceutically acceptable salts thereof.

18. A method for treating cancer selected from small-cell lung carcinoma, human breast cancer, low grade human bladder carcinoma and human colorectal cancer comprising administering an anti-cancer amount of a compound of claim 17.

30. A compound of claim 17 having the formula ##STR32## wherein R₂ is C₁ -C₆ alkyl or substituted C₁ -C₆ alkyl, X is O or NH, and Ar is phenyl, substituted phenyl, pyridyl or substituted pyridyl.

31. A compound of claim 30 which is

6-(2,6-Dichlorophenyl)-8-methyl-2-phenylamino-8H-pyrido 2,3-d!pyrimidin-7-one;

2-(3-Bromophenylamino)-6-(2,6-dichlorophenyl)-8-methyl-8H-pyrido 2,3-d!-pyrimidin-7-one;

2-(4-Chlorophenylamino)-6-(2,6-dichlorophenyl)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

2-(Benzo 1,3!dioxol-5-ylamino)-6-(2,6-dichlorophenyl)-8-methyl-8H-pyrido 2,3-d!-pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2-(pyridinylamino)-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2-p-tolylamino-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-(4-methoxyphenylamino)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-ethyl-2-phenylamino-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-(2-methoxyphenylamino)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-(3-methoxyphenylamino)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-(4-methoxy-3-methylphenylamino)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-ethyl-2-(4-methoxyphenylamino)-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-ethyl-2-(4-hydroxyphenylamino)-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-(4-ethoxyphenylamino)-8-ethyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-(3,4-dimethoxyphenylamino)-8-ethyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-ethyl-2-(3,4,5-trimethoxyphenylamino)-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-8-methyl-2-(pyridinylamino)-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2- 4-(2-diethylaminoethoxy)-phenylamino!-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-(3-hydroxymethylphenylamino)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

6-(2,6-Dichlorophenyl)-2-(3,5-dimethoxyphenylamino)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

{4- 6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido 2,3-d!pyrimidin-2-ylamino!-phenyl}-acetic acid, methyl ester;

6-(2,6-Dichlorophenyl)-2-(6-methoxypyridinylamino)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

{4- 6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido 2,3-d!pyrimidin-2-ylamino!-phenyl}-acetic acid;

6-(2,6-Dichlorophenyl)-2-(3-hydroxyphenylamino)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one;

4- 6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-ylamino!-benzoic acid, ethyl ester;

3- 6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-ylamino!-benzoic acid, ethyl ester;

3- 6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-ylamino!-benzoic acid;

6-(2,6-Dichlorophenyl)-8-ethyl-2-(pyridin-4-ylamino)-8H-pyrido 2,3-d!pyrimidin-7-one;

(6-(2-Bromo-6-chlorophenyl)-8-ethyl-7-imino-7,8-dihydro-pyrido 2,3-d!pyrimidin-8-yl!-phenylamine;

6-(2-Bromo-6-chlorophenyl)-8-ethyl-2-phenylamino-8H-pyrido 2,3-d!pyrimidin-7-one;

(8-Ethyl-7-imino-6-phenyl-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-yl)-2-phenylamine;

8-Ethyl-6-phenyl-2-phenylamino-8H-pyrido 2,3-d!pyrimidin-7-one;

(6-(3,5-Dimethylphenyl)-8-ethyl-7-imino-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-yl)-2-phenylamine;

or

6-(3,5-Dimethylphenyl)-8-ethyl-2-phenylamino-8H-pyrido 2,3-d!pyrimidin-7-one.

19. A compound having the formula ##STR31## where R₂ is C₁ -C₆ alkyl or substituted C₁ -C₆ alkyl, X is NH or O, and R₄ is phenyl or substituted phenyl.

20. A compound of claim 19 which is

8-Ethyl-2-phenylamino-6-thiophen-3-yl-8H-pyrido 2,3-d!pyrimidin-7-one;

8-Ethyl-7-imino-6-thiophen-2-yl-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-yl)-phenylamine;

8-Ethyl-2-phenylamino-6-thiophen-2-yl-8H-pyrido 2,3-d!pyrimidin-7-one;

(8-Ethyl-7-imino-6-pyridin-4-yl-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-yl)-2-phenylamine;

8-Ethyl-2-phenylamino-6-pyridin-4-yl-8H-pyrido 2,3-d!pyrimidin-7-one;

(8-Ethyl-7-imino-6-naphthalen-2-yl-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-yl)-phenylamine;

8-Ethyl-6-naphthalen-2-yl-2-phenylamino-8H-pyrido 2,3-d!pyrimidin-7-one;

(6-Biphenyl-4-yl-8-ethyl-7-imino-7,8-dihydro-pyrido 2,3-d!pyrimidin-2-yl)-phenylamine;

or

6-Biphenyl-4-yl-8-ethyl-2-phenylamino-8-H-pyrido 2,3-d!pyrimidin-7-one.

21. A compound which is 2-Cyclohexylamino-6-(2,6-dichlorophenyl)-8-methyl-8H-pyrido 2,3-d!pyrimidin-7-one.