Substituted aryl or heteroarylamides having retinoid-like biological activity

• US 6,437,129 B1
• Filed: 10/16/2001
• Issued: 08/20/2002
• Est. Priority Date: 11/22/1995
• Status: Expired due to Fees

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan Sales LLC (Abbvie Incorporated)
• Inventors: Teng, Min, Chandraratna, Roshantha A., Duong, Tien T.
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US09/982,362
• Publication Number:
  US 20020091262A1
• Time in Patent Office: 308 Days
• Field of Search: 544/405, 546/283.4
• US Class Current: 544/405
• 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, L, Y, A, B, W, R₁, m, p and r are defined above.

Claims

1. A compound of the formula

wherein X is 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 O or S;

Y is pyrazinyl, 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_1-6alkyl, CO—

C_1-6alkyl, COOR₈, phenyl, phenyl itself substituted with a W group other than with phenyl or substituted phenyl;

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;

with the proviso that if B represents COOH then W is not Cl.

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 W is branch-chained alkyl, F, NO₂, Br, I, CF₃, N₃, or OH.

5. A compound in accordance with claim 4 wherein (W)_p represents two branch-chained alkyl groups.

6. A compound in accordance with claim 4 wherein (W)_r represents one or two fluoro or one or two NO₂ groups.

7. A compound of the formula

wherein X is 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—

where Z is O or S;

Y is furyl, 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_1-6alkyl, CO—

C_1-6alkyl, COOR₈, phenyl, phenyl itself substituted with a W group other than with phenyl or substituted phenyl;

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;

with the proviso that if B represents COOH then W is not Cl.

8. A compound of the formula

wherein X is 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 1-2;

L is —

(C═

Z)—

NH—

or —

NH—

(C═

Z)—

where Z is O or S;

Y is furyl, 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_1-6alkyl, CO—

C_1-6alkyl COOR₈, phenyl, phenyl itself substituted with a W group other than with phenyl or substituted phenyl;

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.

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

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

11. A compound in accordance with claim 9 wherein (W)_r represents one or two fluoro or one or two NO₂ groups.