Substituted aryl or heteroarylamides having retinoid-like biological activity

• US 20020091262A1
• Filed: 10/16/2001
• Published: 07/11/2002
• Est. Priority Date: 11/22/1995
• Status: Active Grant

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan SPA (Abbvie Incorporated)
• Inventors: Teng, Min, Chandraratna, Roshantha A., Duong, Tien T.
• Granted Patent: US 6,437,129 B1
• Time in Patent Office: Days
• US Class Current: 544/238
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 233/81 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07D 213/82 in position 3

Abstract

Compounds of the formula

wherein X is CH or N; R₁ is independently H or alkyl of 1 to 6 carbons; m is an integer having the value of 0-5; p is an integer having the value of 0-2; r is an integer having the value 0-2; L is —(C═Z)—NH— or —NH—(C═Z)— where Z is 0 or S; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one or two R₁ groups; W is a substituent selected from the group consisting of F, Br, Cl, I, C_1-6alkyl, fluoro substituted C_1-6 alkyl, NO₂, N₃, OH, OCH₂OCH₃, OC_1-10alkyl, tetrazol, CN, SO₂C_1-6-alkyl, SO₂C_1-6-alkyl, SO₂C_1-6-fluoro substituted alkyl, SO—C_1-6 alkyl, CO—C_1-6alkyl, COOR₈, phenyl, phenyl itself substituted with a W group other than with phenyl or substituted phenyl with the proviso that when X is CH and r is 0 then p is not 0 and at least one W group is not alkyl; A is (CH₂)_q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is COOH or a pharmaceutically acceptable salt thereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons, have retinoid-like biological activity.

Claims

1. A compound of the formula

2. A compound in accordance with claim 1 wherein L is —

(C═

Z)—

NH—

.

3. A compound in accordance with claim 1 wherein L is —

NH—

(C═

Z)—

.

4. A compound in accordance with claim 1 wherein X is CH.

5. A compound in accordance with claim 1 wherein X is N.

6. A compound in accordance with claim 1 wherein Y is selected from the group consisting of phenyl, pyridyl, 2-thiazolyl, thienyl and furyl.

7. A compound in accordance with claim 6 wherein Y is phenyl.

8. A compound in accordance with claim 1 wherein W is branch-chained alkyl, F, NO₂, Br, I, CF₃, N₃, or OH.

9. A compound in accordance with claim 8 wherein (W)_p represents two branch-chained alkyl groups.

10. A compound in accordance with claim 8 wherein (W)_r represents one or two fluoro or one or two NO₂ groups.

11. A compound of the formula

12. A compound in accordance with claim 11 wherein X is CH.

13. A compound in accordance with claim 12 wherein Z is 0.

14. A compound in accordance with claim 13 wherein A is (CH₂)_q, and B is COOH or a pharmaceutically acceptable salt thereof, COOR₈ or CONR₉R₁₀.

15. A compound in accordance with claim 14 wherein (W)_p represents two branch-chained alkyl groups and (W)_r represents one or two fluoro or one or two NO₂ groups.

16. A compound in accordance with claim 15 wherein the phenyl ring is 1,4-substituted by the (C═

Z)NH— and

—

A—

B—

groups.

18. A compound in accordance with claim 17 wherein X is N.

19. A compound in accordance with claim 18 wherein W₂ is F and W₃ is H.

20. A compound in accordance with claim 19 which is:

ethyl 2-fluoro-4-[(2′

,6′

-di-t-butylpyrid-4′

-yl)carbamoyl]benzoate, or

2-fluoro-4-[(2′

,6′

-di-t-butylpyrid-4′

-yl)carbamoyl]benzoic acid.

21. A compound in accordance with claim 18 where in W₂ is F and W₃ is F.

22. A compound in accordance with claim 21 which is:

methyl 2,6-difluoro-4-[(2′

,6′

-di-t-butylpyrid-4′

yl)carbamoyl]benzoate, or

2,6-difluoro-4-[(2′

,6′

-di-t-butylpyrid-4′

yl)carbamoyl]benzoic acid.

23. A compound in accordance with claim 18 wherein W₂ is NO₂.

24. A compound in accordance with claim 23 which is:

methyl 2-nitro-4-[(2′

,6′

-di-t-butylpyrid-4′

-yl)carbamoyl]benzoate, or

2-nitro-4-[(2′

,6′

-di-t-butylpyrid-4′

-yl)carbamoyl]benzoic acid.

25. A compound in accordance with claim 18 wherein W₁, W₂ and W₃ are all hydrogen.

26. A compound in accordance with claim 25 which is:

ethyl 4-[(2′

,6′

-di-t-butylpyrid-4′

-yl)carbamoyl]benzoate, or

4-[(2′

,6′

-di-t-butylpyrid-4′

-yl)carbamoyl]benzoic acid.

27. A compound in accordance with claim 17 wherein X is CH.

28. A compound in accordance with claim 27 wherein W₂ is F and W₃ is H.

29. A compound in accordance with claim 28 which is:

ethyl 2-fluoro-4-[(3′

,5′

-di-t-butylphenyl)carbamoyl]benzoate, or

2-fluoro-4-[(3′

,5′

-di-t-butyl)phenylcarbamoyl]benzoic acid.

30. A compound in accordance with claim 27 wherein W₂ is F and W₃ is F.

31. A compound in accordance with claim 30 which is:

methyl 2,6-difluoro-4-[(3′

,5′

-di-t-butylphenyl)carbamoyl]benzoate, or

2,6-difluoro-4-[(3′

,5′

-di-t-butylphenyl)carbamoyl]benzoic acid.

32. A compound in accordance with claim 27 wherein w is OH.

33. A compound in accordance with claim 32 which is:

ethyl 2-fluoro-4-[(2′

-hydroxy-3′

,5′

-di-t-butylphenyl)carbamoyl]benzoate, or

2-lfuoro-4-[(2′

-hydroxy-3′

,5′

-di-t-butyl)phenyl-carbamoyl]benzoic acid.

17. A compound of the formula