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Details for Patent: 5,354,752

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Details for Patent: 5,354,752

Title: Disubstituted acetylenes bearing a diazinyl group having retinoid like activity
Abstract:Retinoid-like activity is exhibited by compounds of the formula ##STR1## where X is S, O, or NR' where R' is hydrogen or lower alkyl; R is hydrogen or lower alkyl; A is pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-4; and B is H, --COOH or a pharmaceutically acceptable salt, ester or amide thereof, --CH.sub.2 OH or an ether or ester derivative, or --CHO or an acetal derivative, or --COR.sub.1 or a ketal derivative where R.sub.1 is --(CH.sub.2).sub.m CH.sub.3 where m is 0-4, or a pharmaceutically acceptable salt thereof.
Inventor(s): Chandraratna; Roshantha A. S. (El Toro, CA)
Assignee: Allergan, Inc. (Irvine, CA)
Filing Date:Oct 28, 1993
Application Number:08/145,438
Claims:1. A compound of the formula ##STR11## where X is S or O; R is hydrogen or lower alkyl; A is pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-4; and B is H, --COOH or a pharmaceutically acceptable salt thereof, or an ester thereof with a saturated aliphatic alcohol of ten or fewer carbon atoms, or with a cyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbon atoms, or with phenol or with a lower alkylphenol, or an amide or a mono or di-substituted amide thereof, the subtituents on the amide being selected from a group consisting of saturated aliphatic radicals of ten or fewer carbon atoms, cyclic or saturated aliphatic cyclic radicals of 5 to 10 carbon atoms, and phenyl or lower alkylphenyl radicals, or B is CH.sub.2 OH or an ester derivative thereof derived from a saturated aliphatic acid of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic acid of 5 to 10 carbon atoms, or from benzoic acid, or an ether derivative thereof derived from a saturated aliphatic radical of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic radical of 5 to 10 carbon atoms, or from phenyl or lower alkylphenyl radical, or B is --CHO or a lower alkyl acetal derivative thereof, or an acetal derivative thereof formed with a lower alkyl diol, or B is --COR.sub.1 or a lower alkyl ketal derivative thereof, or a ketal derivative thereof formed with a lower alkyl diol, where R.sub.1 is --(CH.sub.2).sub.m CH.sub.3 where m is 0-4, or a pharmaceutically acceptable salt of the compound defined in said formula.

2. A compound of claim 1 where X is S.

3. A compound of claim 1 where X is O.

4. A compound of claim 3 where A is pyridazinyl.

5. A compound of claim 2 where A is pyrimidinyl.

6. A compound of claim 2 where A is pyrazinyl.

7. A compound of claim 3 where A is pyrazinyl.

8. A compound of claim 2 where A is pyrimidinyl and B is --CH.sub.2 OH or a lower alkyl ether or lower alkyl acid ester thereof.

9. A compound of claim 2 where A is pyrimidinyl and B is --CHO or an acetal derivative thereof.

10. A compound of claim 2 where A is pyridazinyl.

11. A compound of claim 3 where A is pyrimidinyl.

12. A compound of claim 5 which is ethyl 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-acetate, 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-acetic acid, ethyl 5-(4,4-dimethylthiochroman-6-yl) ethynyl-pyrimidin-2-yl-pentanoate, 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoic acid, or a pharmaceutically acceptable salt thereof.

13. A compound of claim 5 which is ethyl 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-acetate, 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-acetic acid, ethyl 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoate, 5-(4 ,4,7-trimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoic acid, or a pharmaceutically acceptable salt thereof.

14. A compound of claim 4 which is ethyl 5-(4,4-dimethylchroman-6-yl)ethynyl-pyridazin-3-yl-acetate, 5-(4,4-dimethylchroman-6-yl)ethynyl-pyridazin-3-yl-acetic acid, ethyl 5-(4,4-dimethylchroman-6-yl)ethynyl-pyridazin-3-yl-pentanoate, 5-(4,4-dimethylchroman-6-yl)ethynyl-pyridazin-3-yl-pentanoic acid, ethyl 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyridazin-3-yl-acetate, 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyridazin-3-yl-acetic acid, ethyl 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyridazin-3-yl-pentanoate, 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyridazin-3-yl-pentanoic acid or a pharmaceutically acceptable salt thereof.

15. A compound of claim 6 which is ethyl 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-acetate, 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-acetic acid, ethyl 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-pentanoate, 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-pentanoic acid, or a pharmaceutically acceptable salt thereof.

16. A compound of claim 6 which is ethyl 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-acetate, 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-acetic acid, ethyl 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-pentanoate, 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-pentanoic acid, or a pharmaceutically acceptable salt thereof.

17. A compound of claim 10 which is ethyl 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-acetate, 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-acetic acid, ethyl 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-pentanoate, 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-pentanoic acid, ethyl 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-acetate, 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-acetic acid, ethyl 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-pentanoate, 5-(4 ,4,7-trimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-pentanoic acid or a pharmaceutically acceptable salt thereof.

18. A compound of claim 11 which is ethyl 5-(4,4-dimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-acetate, 5-(4,4-dimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-acetic acid, ethyl 5-(4,4-dimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoate, 5-(4,4-dimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoic acid, ethyl 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-acetate, 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-acetic acid, ethyl 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoate, 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoic acid, or a pharmaceutically acceptable salt thereof.

19. A compound of claim 7 which is ethyl 5-(4,4-dimethylchroman-6-yl)ethynyl-pyrazin-3-yl-acetate, 5-(4,4-dimethylchroman-6-yl)ethynyl-pyrazin-3-yl-acetic acid, ethyl 5-(4,4-dimethylchroman-6-yl)ethynyl-pyrazin-3-yl-pentanoate, 5-(4,4-dimethylchroman-6-yl)ethynyl-pyrazin-3-yl-pentanoic acid, ethyl 5-(4,4,7-trimethylchroman-6-yl) ethynyl-pyrazin-3-yl-acetate, 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrazin-3-yl-acetic acid, ethyl 5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrazin-3-yl-pentanoate, 5-(4,4,7 -trimethylchroman-6-yl) ethynyl-pyrazin-3-yl-pentanoic acid, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula ##STR12## where X is S or O; R is hydrogen or lower alkyl; A is pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-4; and B is H, --COOH or a pharmaceutically acceptable salt thereof, or an ester thereof with a saturated aliphatic alcohol of ten or fewer carbon atoms, or with a cyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbon atoms, or with phenol or with a lower alkylphenol, or an amide or a mono or di-substituted amide thereof, the subtituents on the amide being selected from a group consisting of saturated aliphatic radicals of ten or fewer carbon atoms, cyclic or saturated aliphatic cyclic radicals of 5 to 10 carbon atoms, and phenyl or lower alkylphenyl radicals, or B is CH.sub.2 OH or an ester derivative thereof derived from a saturated aliphatic acid of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic acid of 5 to 10 carbon atoms, or from benzoic acid, or an ether derivative thereof derived from a saturated aliphatic radical of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic radical of 5 to 10 carbon atoms, or from phenyl or lower alkylphenyl radical, or B is --CHO or a lower alkyl acetal derivative thereof, or an acetal derivative thereof formed with a lower alkyl diol, or B is --COR.sub.1 or a lower alkyl ketal derivative thereof, or a ketal derivative thereof formed with a lower alkyl diol, where R.sub.1 is --(CH.sub.2).sub.m CH.sub.3 where m is 0-4, or a pharmaceutically acceptable salt of the compound defined in said formula.

21. A composition according to claim 20 useful for treating psoriasis in a mammal.

22. A method of treating psoriasis in a mammal which method comprises administering alone or in conjunction with a pharmaceutically acceptable excipient, a therapeutically effective amount of a compound of the formula ##STR13## where X is S or O; R is hydrogen or lower alkyl; A is pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-5; and B is H, --COOH or a pharmaceutically acceptable salt thereof, or an ester thereof with a saturated aliphatic alcohol of ten or fewer carbon atoms, or with a cyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbon atoms, or with phenol or with a lower alkylphenol or an amide or a mono or di-substituted amide thereof, the subtituents on the amide being selected from a group consisting of saturated aliphatic radicals of ten or fewer carbon atoms, cyclic or saturated aliphatic cyclic radicals of 5 to 10 carbon atoms, and phenyl or lower alkylphenyl radicals, or B is CH.sub.2 OH or an ester derivative thereof derived from a saturated aliphatic acid of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic acid of 5 to 10 carbon atoms, or from benzoic acid, or an ether derivative thereof derived from a saturated aliphatic radical of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic radical of 4 to 10 carbon atoms, or from phenyl or lower alkylphenyl radical, or B is --CHO or a lower alkyl acetal derivative thereof, or an acetal derivative thereof formed with a lower alkyl diol, or B is --COR.sub.1 or a lower alkyl ketal derivative thereof, or a ketal derivative thereof formed with a lower alkyl diol, where R.sub.1 is --(CH.sub.2).sub.m CH.sub.3 where m is 0-4, or a pharmaceutically acceptable salt of the compound defined in said formula.
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