Aryl-and heteroarylcyclohexenyl substituted alkenes having retinoid agonist, antagonist or inverse agonist type biological activity

• US 5,760,276 A
• Filed: 03/06/1997
• Issued: 06/02/1998
• Est. Priority Date: 03/06/1997
• Status: Expired due to Fees

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan SPA (Abbvie Incorporated)
• Inventors: Beard, Richard L., Johnson, Alan T., Teng, Min, Chandraratna, Roshantha A., Vuligonda, Vidyasagar
• Primary Examiner(s): Killos, Paul J.
• Application Number:
  US08/810,826
• Time in Patent Office: 453 Days
• Field of Search: 560/102, 562/492
• US Class Current: 560/102
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 309/65 of a saturated carbon skeleton
• CPC Class Codes: C07C 403/02 having side-chains containing only carbon and hydrogen atoms
• CPC Class Codes: C07C 69/76 Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring

Abstract

Compounds of the formula ##STR1## wherein the symbols have the meaning defined in the specification, have retinoid-like, retinoid antagonist or retinoid inverse agonist-like biological activity.

Claims

1. A compound of the formula ##STR13## wherein one of the dashed lines respectively designated α

and β

represents a bond and the other represents absence of a bond, the dashed line designated γ

represents absence of a bond when β

represents a bond, and wherein the dashed line designated γ

represents absence of a bond or a bond when α

represents a bond;

the cyclohexene ring is unsubstituted or substituted with 1 to 7 R₁ groups where R₁ is independently selected from the group consisting of alkyl of 1 to 6 carbons, F, Cl, Br and I;

R₃ is H, alkyl of 1 to 6 carbons, F, Cl, Br or I;

R₄ is phenyl, naphthyl, or heteroaryl where the heteroaryl group is 5-membered or 6-membered and has 1 to 3 heteroatoms selected from the group consisting of O, S and N, and where the R₄ group is unsubstituted or substituted with 1 to 5 R₅ groups where R₅ is independently selected from the group consisting of F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈ CON(R₈)₂, OH, OCOR₈, OR₈, CN, COOH, COOR₈ an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons;

##STR14## Y is phenyl or naphthyl, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with one or two R₂ groups, where R₂ is independently selected from the group consisting of lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, and alkylthio of 1 to 6 carbons;

alternatively when Z is --(CR₁ ═

CR₁)_n'"'"' -- and n'"'"' is 2, 3, 4 or 5 then Y may represent a direct valence bond between said (CR₂ ═

CR₂)_n'"'"' group and B;

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 hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃ O, --COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, or Si(C_1-6 alkyl)₃, 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 (trimethylsilyl)alkyl 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.

2. A compound of claim 1 where Y is phenyl, naphthyl, pyridyl, thienyl or furyl.

3. A compound of claim 2 where Y is phenyl and the phenyl group is substituted in the 1 and 4 (para) positions by the Z and A--B groups.

4. A compound of claim 1 where the A--B group is (CH₂)_q COOH or (CH₂)_q --COOR₈.

5. A compound of claim 1 where the Z group is selected from the group consisting of --C.tbd.C--, --CH═

CH--, --CONH--, --COO--, --COS--, --CSNH--, --(CR₁ ═

CR₁)_n'"'"' -- where n'"'"' is 3, and --(CR₁ ═

CR₁)_n'"'"' -- where n'"'"' is 0.

6. A compound of claim 1 where Z is --(CR₁ ═

CR₁)_n'"'"' --, --CO-- NR₁ --, or COO.

7. A compound of claim 1 where R₄ is phenyl, R₅ -substituted phenyl, pyridyl, R₅ -substituted pyridyl, thienyl, R₅ -substituted thienyl, furyl or R₅ -substituted furyl.

8. A compound of claim 7 where R₄ is phenyl, 4-alkylphenyl, 3-pyridyl, 6-methyl-3-pyridyl, 2-thienyl and 5-methyl-2-thienyl, 2-furyl and 5-methyl-2-furyl.

9. A compound of claim 1 where the line designated β

represents a bond.

10. A compound of claim 1 where the line designated α

represents a bond.

11. A compound of claim 1 where the line designated α

represents a bond and the line designated γ

also represents a bond.

12. A compound of the formula ##STR15## wherein one of the dashed lines respectively designated α

and β

represents a bond and the other represents absence of a bond, the dashed line designated γ

represents absence of a bond when β

represents a bond, and wherein the dashed line designated γ

represents absence of a bond or a bond when a represents a bond;

the cyclohexene ring is unsubstituted or substituted with 1 to 7 R₁ groups where

R₁ is independently selected from the group consisting of alkyl of 1 to 6 carbons, F, Cl, Br and I;

R₃ is H, alkyl of 1 to 6 carbons, F, Cl, Br or I;

R₄ is phenyl, naphthyl, or heteroaryl where the heteroaryl group is 5-membered or 6-membered and has 1 to 3 heteroatoms selected from the group consisting of O, S and N, and where the R₄ group is unsubstituted or substituted with 1 to 5 R₅ groups where R₅ is independently selected from the group consisting of F, Cl, Br, I, NO₂, N(R₈)₂, N(R₈)COR₈, NR₈ CON(R₈)₂, OH, OCOR₈, OR₈, CN, COOH, COOR₈ an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons;

Y is phenyl or naphthyl, or heteroaryl selected from a group consisting of pyridyl, thienyl, and furyl, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with one or two R₂ groups, where R₂ is independently selected from the group consisting of lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, and alkylthio of 1 to 6 carbons;

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 hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃ O, --COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, or Si(C_1-6 alkyl)₃, 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 (trimethylsilyl)alkyl 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.

13. A compound of claim 12 where R₃ is H or lower alkyl.

14. A compound of claim 12 where the dashed line designated γ

represents absence of a bond and where the cyclohexene ring has two R₁ substituents which occupy the position adjacent to the ethenyl function.

15. A compound of claim 12 where the dashed line designated γ

represents a bond and where the cyclohexene ring has two R₁ substituents which occupy a position removed by one ring carbon from the ethenyl function.

16. A compound of claim 12 where the Y group is substituted only with the ethynyl and the A--B groups.

17. A compound of claim 12 where R₄ is phenyl or R₅ -substituted phenyl.

18. A compound of claim 12 where Y is phenyl.

19. A compound of the formula ##STR16## wherein one of the dashed lines respectively designated α

and β

represents a bond and the other represents absence of a bond, thus forming a single double bond in the six-membered ring;

R₅ is H or an alkyl group having 1 to 6 carbons;

R₈ is H, or an alkyl group of 1 to 6 carbons, or a pharmaceutically acceptable salt thereof.

20. A compound of claim 19 where the line designated α

represents a bond.

21. A compound of claim 20 where R₅ is methyl.

22. A compound of claim 21 where R₈ is H, methyl or ethyl, or a pharmaceutically acceptable salt thereof.

23. A compound of claim 19 where the line designated β

represents a bond.

24. A compound of claim 23 where R₅ is methyl.

25. A compound of claim 24 where R₈ is R₈ methyl or ethyl, or a pharmaceutically acceptable salt thereof.

26. A compound of claim 23 where R₅ is ethyl.

27. A compound of claim 26 where R₈ is H, methyl or ethyl, or a pharmaceutically acceptable salt thereof.

28. A compound of claim 23 where R₅ is tertiary-butyl.

29. A compound of claim 28 where R₈ is H, methyl or ethyl, or a pharmaceutically acceptable salt thereof.

30. A compound of the formula ##STR17## where R₅ is H or an alkyl group having 1 to 6 carbons;

R₈ is H, or an alkyl group of 1 to 6 carbons, or a pharmaceutically acceptable salt thereof.

31. A compound of claim 30 where R₅ is methyl.

32. A compound of claim 31 where R₈ is H, methyl or ethyl, or a pharmaceutically acceptable salt thereof.

33. A compound of claim 30 where R₅ is tertiary-butyl.

34. A compound of claim 33 where R₈ is H, methyl or ethyl, or a pharmaceutically acceptable salt thereof.