4-[(8-substituted)-6-chromanoyl]-and 4-[8-substituted)-chroman-6-YL-ethynyl]-benzoic and phenylacetic acids, their esters and salts having cytochrome P450RAI inhibitory activity
View Patent ↗Compounds of the formula where the variables are defined in the specification have cytochrome P450RAI-1 and P450RAI-2 inhibitory activity, and are suitable for treatment of mammals with conditions which are treatable with retinoids, or which are controlled by or responsive to the organism's native retinoic acid. Formulations containing the compounds of the invention can also be co-administered with retinoids and/or Vitamin A to enhance or prolong the effects of medications containing retinoids, Vitamin A, or of the organism's native retinoic acid.
1. A compound of the formula
wherein Z is C≡C;
R 1 is alkyl having 1 to 6 carbons;
R 2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons or alkylthio of 1 to 6 carbons;
R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons or alkylthio of 1 to 6 carbons;
m is an integer having the values of 0 to 6;
n is an integer having the values of 0 to 2;
o is an integer having the values 0 to 4;
p is an integer having the values 0, 1, or 2;
Y is CH≡C—, CH≡C—CH 2 —; CH 2 ═CH—or —C≡N;
R is is H, alkyl of 1 to 6 carbons, —CH 2 OR 4 , —CH 2 —O—COR 4 , or a cation of a pharmaceutically acceptable base, and
R 4 is alkyl having 1 to 6 carbons.
2. A compound in accordance with claim 1 where Y is CN.
3. A compound in accordance with claim 2 where p is one (1).
4. A compound in accordance with claim 1 wherein R 1 is methyl and m is 4.
5. A compound in accordance with claim 4 wherein the methyl groups are attached to the 2,2 and 4,4 positions of the chroman ring.
6. A compound in accordance with claim 1 wherein the R 2 group is alkyl or halogen and n is 1 or 2.
7. A compound in accordance with claim 1 wherein n is zero.
8. A compound in accordance with claim 1 wherein the phenyl group is 1,4 (para) substituted with the chroman-6-yl-ethynyl and (CH 2 ) p COOR groups.
9. A compound in accordance with claim 8 wherein o is zero, or o is one (1) and R 3 is halogen or alkyl.
10. A compound in accordance with claim 9 wherein o is one (1) and R 3 is fluoro and the fluoro group is located in 1,2 (ortho) position relative to the (CH 2 ) p COOR group.
11. A compound in accordance with claim 1 wherein o is zero, or o is one (1) and R 3 is halogen or alkyl.
12. A compound in accordance with claim 1 wherein Y is CH≡C—.
13. A compound in accordance with claim 12 wherein p is one (1).
14. A compound in accordance with claim 1 wherein Y is CH≡C—CH 2 —.
15. A compound in accordance with claim 14 wherein p is one (1).
16. A compound of the formula
wherein Y is CH≡C—or CH≡C—CH 2 —;
R 3 is H or F;
R is H, alkyl of 1 to 6 carbons, —CH 2 OR 4 , —CH 2 —O—COR 4 , or a cation of a pharmaceutically acceptable base, and
R 4 is alkyl having 1 to 6 carbons.
17. A compound in accordance with claim 16 where Y is CH≡C—.
18. A compound in accordance with claim 17 wherein R 3 is H.
19. A compound in accordance with claim 18 wherein R is H, or a cation of a pharmaceutically acceptable base.
20. A compound in accordance with claim 18 wherein R is methyl.
21. A compound in accordance with claim 17 wherein R 3 is F.
22. A compound in accordance with claim 21 wherein R is H, or a cation of a pharmaceutically acceptable base.
23. A compound in accordance with claim 16 wherein R is methyl.
24. A compound in accordance with claim 16 where Y is CH≡C—CH 2 —.
25. A compound in accordance with claim 24 where R 3 is H.
26. A compound in accordance with claim 25 wherein R is H, or a cation of a pharmaceutically acceptable base.
27. A compound in accordance with claim 25 wherein R is methyl.
28. A compound of the formula
wherein R 3 is H or F;
R is H, alkyl of 1 to 6 carbons, —CH 2 OR 4 , —CH 2 —O—COR 4 , or a cation of a pharmaceutically acceptable base, and
R 4 is alkyl having 1 to 6 carbons.
29. A compound in accordance with claim 28 wherein R 3 is F.
30. A compound in accordance with claim 29 wherein R is H, or a cation of a pharmaceutically acceptable base.
31. A compound in accordance with claim 30 wherein R is CH 2 OCOCH3.
32. A pharmaceutical composition for administration to a mammal, comprising a pharmaceutically acceptable excipient and an effective dose of one or more compounds in accordance with the formula below, to inhibit the enzyme cytochrome P450RAI in said mammal in need of such inhibition
wherein Z is COO or C≡C;
R 1 is alkyl having 1 to 6 carbons;
R 2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons or alkylthio of 1 to 6 carbons;
R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons or alkylthio of 1 to 6 carbons;
m is an integer having the values of 0 to 6;
n is an integer having the values of 0 to 2;
o is an integer having the values 0 to 4;
p is an integer having the values 0, 1, or 2;
Y is CH≡C—, CH≡C—CH 2 —; CH 2 ═CH—or —C≡N;
R is H, alkyl of 1 to 6 carbons, —CH 2 OR 4 , —CH 2 ,—O—COR 4 , or a cation of a pharmaceutically acceptable base, and
R 1 is alkyl having 1 to 6 carbons.
33. A pharmaceutical composition in accordance with claim 32 wherein in the formula of the compound Z is COO.
34. A pharmaceutical composition in accordance with claim 33 wherein the compound has the formula
35. A pharmaceutical composition in accordance with claim 33 wherein the compound has the formula
36. A pharmaceutical composition in accordance with claim 32 wherein the compound has the formula
37. A pharmaceutical composition in accordance with claim 32 wherein the compound has the formula
38. A pharmaceutical composition in accordance with claim 32 wherein the compound has the formula