Tetrahydronaphthalene derivatives substituted in the 8 position with alkyhidene groups having retinoid and/or retinoid antagonist-like biological activity

• US 5,763,635 A
• Filed: 06/21/1996
• Issued: 06/09/1998
• Est. Priority Date: 06/21/1996
• Status: Expired due to Fees

• Current Assignee: Allergan SPA (Abbvie Incorporated)
• Original Assignee: Allergan SPA (Abbvie Incorporated)
• Inventors: Beard, Richard L., Lin, Yuan, Johnson, Alan T., Teng, Min, Chandraratna, Roshantha A., Duong, Tien T., Vuligonda, Vidyasagar
• Primary Examiner(s): Gupta, Yogendra N.
• Application Number:
  US08/667,665
• Time in Patent Office: 718 Days
• Field of Search: 556/400, 556/413, 556/419, 556/442, 560/34, 560/35, 560/45, 560/48, 560/56, 562/439, 562/440, 562/452, 562/455, 562/466, 564/75, 564/163, 564/180
• US Class Current: 556/442
• 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: C07C 245/10 with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems
• CPC Class Codes: C07C 251/44 with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 309/65 of a saturated carbon skeleton
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/55 the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 69/587 Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
• 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
• CPC Class Codes: C07D 277/30 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 309/12 only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• CPC Class Codes: C07D 317/20 Free hydroxyl or mercaptan
• CPC Class Codes: C07D 317/24 esterified
• CPC Class Codes: C07D 317/26 Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
• CPC Class Codes: C07D 333/24 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 339/08 Six-membered rings
• CPC Class Codes: C07D 409/10 linked by a carbon chain containing aromatic rings

Abstract

Compounds of the formula ##STR1## where the symbols have the meaning described in the application, have retinoid-like or retinoid antagonist-like biological activity.

Claims

1. A compound of the formula ##STR29## wherein X₁ is (C(R₁)₂)_n where R₁ is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;

Z is

--N═

N--,

--N(O)═

N--,

--N═

N(O)--,

--N═

CR₁ --,

--CR₁ ═

N,

--(CR₁ ═

CR₁)_n'"'"',

where n'"'"' is an integer having the value 0-2,

--CO--NR₁ --,

--CS--NR₁ --,

--NR₁ --CO,

--NR₁ --CS,

--COO--,

--OCO--;

--CSO--;

--OCS--;

--CO--CR₁ ═

CRC₁ --;

R₂ is hydrogen, 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, or alkylthio of 1 to 6 carbons;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 0-4;

Y is a phenyl or naphthyl group, optionally substituted with one or two R₂ groups

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;

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, and

R₁₉ is independently hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C₁ - C₁₀ -alkylphenyl, naphthyl, C₁ -C₁₀ -alkylnaphthyl, phenyl-C₁ -C₁₀ alkyl, naphthyl-C₁ -C₁ -alkyl;

heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R₂ groups, further R₁₉ is independently CN, CHO, CH(OR₁₂)₂, CHOR₁₃ O,(CH₂)_p CO₂ H (CH₂)_p CO₂ R₈, (CH₂)_p CH₂ OH, (CH₂)_p CH₂ OR₁₁, (CH₂)_p CH₂ OCOR₁₁, where p is an integer between 0 to 10, or the two R₁₉ groups jointly represent 3 to 8 methylene groups which together with the alkylidene carbon complete a ring, the ring optionally containing 1 to 2 double bonds and the ring being optionally substituted with 1 or 2 R₂ groups with the proviso that at least one of the R₁₉ groups is not hydrogen.

2. A compound in accordance with claim 1 wherein Y is phenyl.

3. A compound in accordance with claim 1 wherein Y is naphthyl.

4. A compound in accordance with claim 1 where n is 1.

5. A compound in accordance with claim 1 where Z is selected from the groups consisting of --(CR₁ ═

CR₁)_n, -- --N═

N--, --CO--CR₁ ═

CR₁ --, --COO--, and --CONH-- where n'"'"' is 0 or 1.

6. A compound in accordance with claim 1 where A is (CH₂)_q.

7. A compound in accordance with claim 1 where B is COOH or a pharmaceutically acceptable salt thereof, COOR₈, or CONR₉ R₁₀.

8. A compound of the formula ##STR30## where R₁ is independently H or alkyl of 1 to 6 carbons;

Z is --N═

N--,

--(CR₁ ═

CR₁)_n '"'"'-- where n'"'"' is an integer having the value 0-2,

--CO--NH--,

--COO--,

--CO--CR₁ ═

CR₁ --;

R₂ is hydrogen, lower alkyl of 1 to 6 carbons;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

m is an integer having the value of 0-3;

o is an integer having the value of 0-4;

Y is phenyl or naphthyl;

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;

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;

R₁₉ is independently hydrogen, alkyl of 1 to 10 carbons, carbocyclic aryl selected from the group consisting of phenyl, C₁ -C₁₀ -alkylphenyl, (CH₂)_p CO₂ R₈, (CH₂)_p CO₂ H where p is an integer between 0 to 10, or the two R₁₉ groups jointly represent 3 to 8 methylene groups which together with the alkylidene carbon complete a ring with the proviso that at least one of the R₁₉ groups is not hydrogen.

9. A compound in accordance with claim 8 where Y is phenyl.

10. A compound in accordance with claim 8 where Y is naphthyl.

11. A compound in accordance with claim 8 where A is (CH₂)_q where q is 0 and where B is COOH or a pharmaceutically acceptable salt thereof, COOR₈, or CONR₉ R₁₀.

12. A compound in accordance with claim 8 where R₁₉ is lower alkyl, or where the two R₁₉ groups jointly represent 3 to 8 methylene groups which together with the alkylidene carbon complete a ring.

13. A compound in accordance with claim 8 where at least one of the R₁₉ groups is phenyl.

14. A compound in accordance with claim 8 where at least one of the R₁₉ groups is COOH or COOR₈.

15. A compound of the formula ##STR31## where Z is --CH═

CH, --N═

N--, CO--CH═

CH, CONH or COO;

Y is phenyl;

R₈ is hydrogen, lower alkyl or (trimethylsilyl)ethyl, and

R₁₉ '"'"' and R₁₉ " independently are H, methyl, ethyl, phenyl, COOH or COOR₈ or the R₁₉ '"'"' and R₁₉ " groups together with the alkyledene carbon form a 6 membered ring, with the proviso that at least one of the R₁₉ groups is not hydrogen.

16. A compound in accordance with claim 15 where the Z group is connnected to the 2-position of the tetrahydronaphthalene ring.

17. A compound in accordance with claim 15 where the Z group is connnected to the 3-position of the tetrahydronaphthalene ring.

18. A compound in accordance with claim 17 where Z is CO--CH═

CH.

19. A compound in accordance with claim 16 where Z is --CH═

CH, C(CH₃)═

CH--CH═

CH--C(CH₃)═

CH--, --N═

N--, CONH, or COO.

20. A compound in accordance with claim 19 where Z is --CH═

CH--.

21. A compound in accordance with claim 20 where R₁₉ '"'"' is CH₃ and R₁₉ " is CH₃.

22. A compound in accordance with claim 20 where R₁₉ '"'"' is --CH₂ CH₃ and R₁₉ " is CH₂ CH₃.

23. A compound in accordance with claim 20 where the R₁₉ '"'"' and R₁₉ " groups together with the alkyledene carbon form a 6 membered ring.

24. A compound in accordance with claim 19 where Z is --N═

N--.

25. A compound in accordance with claim 24 where R₁₉ '"'"' is COOEt.

26. A compound in accordance with claim 24 R₁₉ " is H.

27. A compound in accordance with claim 25 where R₁₉ '"'"' is H.

28. A compound in accordance with claim 19 where Z is --COO--.

29. A compound in accordance with claim 28 where R₁₉ '"'"' is CH₃ and R₁₉ is CH₃.

30. A compound in accordance with claim 19 where Z is --CONH--.

31. A compound in accordance with claim 30 where R₁₉ '"'"' is CH₃ and R₁₉ is CH₃.

32. A compound in accordance with claim 30 where R₁₉ '"'"' is COOEt or COOH.

33. A compound in accordance with claim 30 where R₁₉ is H.

34. A compound in accordance with claim 32 where R₁₉ " is H.

35. A compound in accordance with claim 17 where Z is --CO--CH═

CH--.

36. A compound in accordance with claim 35 where R₁₉ '"'"' is CH₃ and R₁₉ " is CH₃.