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Details for Patent: 4,677,115

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Details for Patent: 4,677,115

Title: Antiglaucoma thieno-thiopyran and thieno-thiepin sulfonamide derivatives, compositions, and method of use thereof
Abstract:Aromatic sulfonamides with a saturated heterocycle fused thereto are carbonic anhydrase inhibitors useful in the treatment of elevated intraocular pressure.
Inventor(s): Baldwin; John J. (Gwynedd Valley, PA), Christy; Marcia E. (Collegeville, PA), Ponticello; Gerald S. (Lansdale, PA)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Filing Date:May 14, 1986
Application Number:06/863,225
Claims:1. A compound of structural formula: ##STR15## wherein A together with the two carbon atoms denoted as a and .beta. is the group: ##STR16## wherein n is 1 or 2;

X is --S--, --SO--, --SO.sub.2 --;

Y is --S--;

R.sup.1, R.sup.2, R.sup.3, R.sup.4 are independently selected from:

(1) hydrogen,

(2) OR.sup.5 wherein R.sup.5 is:

(a) hydrogen,

(b) C.sub.1-5 alkyl, either unsubstituted or substituted with ##STR17## wherein R.sup.6 and R.sup.7 are independently hydrogen or C.sub.1-5 alkyl,

(c) C.sub.1-5 alkanoyl, either unsubstituted or substituted with --OH, --NR.sup.6 R.sup.7 or --COR.sup.8 wherein R.sup.8 is --OH, --NR.sup.6 R.sup.7 or C.sub.1-5 alkoxy,

(d) --CO--R.sup.9, wherein R.sup.9 is --NR.sup.6 R.sup.7

(3) --NR.sup.6 R.sup.7,

(4) --NHR.sup.10 wherein R.sup.10 is:

(a) --SO.sub.2 NR.sup.6 R.sup.7,

(b) --SO.sub.2 R.sup.11, wherein R.sup.11 is C.sub.1-5 alkyl, or

(c) --CONR.sup.6 R.sup.7,

(5) C.sub.1-5 alkyl, either unsubstituted or substituted with

(a) --OR.sup.5,

(b) --CN,

(c) --NR.sup.6 R.sup.7, or

(d) --COR.sup.8,

(6) --SO.sub.2 R.sup.11,

(7) --SO.sub.2 NR.sup.6 R.sup.7, or

(8) --halo;

R.sup.1 and R.sup.3, or R.sup.2 and R.sup.4 taken together represent a double bond;

R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 taken together represent

(1) .dbd.O, or

(2) .dbd.NOR.sup.12 wherein R.sup.12 is hydrogen or C.sub.1-3 alkyl; and one of the --CH.sub.2 -- groups of --(CH.sub.2).sub.n -- can be substituted with --COR.sup.8, --CH.sub.2 R.sup.8 or --CH.sub.2 COR.sup.8.

2. The compound of claim 1, wherein Y is S.

3. The compound of claim 2, wherein X is --S-- or --SO.sub.2 --.

4. The compound of claim 3 wherein n is 1, R.sup.2 is hydrogen, R.sup.3 and R.sup.4 are hydrogen or C.sub.1-5 alkyl, and R.sup.1 is --OH, --CH.sub.2 OH, or --NR.sup.6 R.sup.7.

5. The compound of claim 4 which is

5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide;

5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide;

6,7-dihydro-5H-7-hydroxythieno[3,2-b]thiopyran-2-sulfonamide;

6,7-dihydro-5H-7-hydroxythieno[3,2-b]thiopyran-2-sulfonamide-4,4-dioxide;

5,6-dihydro-4H-4-(N-ethylamino)thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio xide;

5,6-dihydro-4H-4-aminothieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide;

5,6-dihydro-4-hydroxy-5,5-dimethyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide- 7,7-dioxide;

5,6-dihydro-4H-4-hydroxymethylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-diox ide;

5,6-dihydro-4-isobutylamino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio xide; or

5,6-dihydro-4-n-butylamino-4H-thieno[2,3-b]thiopyran-2-sylfonamide-7,7-diox ide.

6. The compound of claim 4 which is 5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide.

7. The compound of claim 4 which is 5,6-dihydro-4-isobutylamino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-di oxide.

8. The compound of claim 4 which is 5,6-dihydro-4H-4-aminothiieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide.

9. The compound of claim 4 which is 5,6-dihydro-4-hydroxy-5,5-dimethyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide -7,7-dioxide.

10. 5,6-dihyd ro-4H-4-hydroxymethylthieno-[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide.

11. (S,R)- and (R,R)-5,6-Dihydro-4-[2-methoxy-2-phenylacetoxy]thieno[2,3-b]thiopyran-2-su lfonamide-7,7-dioxide.

12. An ophthalmic composition for the treatment of elevated intracular pressure comprising an ophthalmologically acceptable carrier and an effective intracular pressure lowering amount of a compound defined in claim 1.

13. The composition of claim 12 wherein Y is S.

14. The composition of claim 12 wherein Y is --S--, and X is --S-- or --SO.sub.2 --.

15. The composition of claim 12 wherein Y is --S--, X is --S-- or --SO.sub.2 --, n is 1, R.sup.2 is hydrogen, R.sup.3 and R.sup.4 are hydrogen or C.sub.1-5 alkyl, and R.sup.1 is --OH, --CH.sub.2 OH, or NR.sup.6 R.sup.7.

16. The commposition of claim 12 wherein the compound is:

5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide;

5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide;

6,7-dihydro-5H-7-hydroxythieno[3,2-b]thiopyran-2-sulfonamide;

6,7-dihydro-5H-7-hydroxythieno[3,2-b]thiopyran-2-sulfonamide-4,4-dioxide;

5,6-dihydro-4H-4-(N-ethylamino)thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio xide;

5,6-dihydro-4H-4-aminothieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide;

5,6-dihydro-4-hydroxy-5,5-dimethyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide- 7,7-dioxide;

5,6-dihydro-4H-4-hydroxymethylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-diox ide;

5,6-dihydro-4-isobutylamino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio xide; or

5,6-dihydro-4-n-butylamino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-diox ide.

17. The composition of claim 12 wherein the compound is 5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide.

18. The composition of claim 12 wherein the compound is 5,6-dihydro-4-isobutylamino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-di oxide.

19. The composition of claim 12 wherein the compound is 5,6-dihydro-4H-4-aminothieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide.

20. The composition of claim 12 wherein the compound is 5,6-dihydro-4-hydroxy-5,5-dimethyl-4H-thieno[2,3-b]-thiopyran-2-sulfonamid e-7,7-dioxide.

21. The composition of claim 12 wherein the compound is 5,6-dihydro-4H-4-hydroxymethylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio xide.

22. A method of treating elevated intraocular pressure, including glaucoma, which comprises the topical optical administration of an effective intraocular pressure lowering amount of a compound as defined in claim 1.

23. The method of claim 22, wherein Y is --S--.

24. The method of claim 22, wherein Y is --S--, and X is --S-- or --SO.sub.2 --.

25. The method of claim 22, wherein Y is --S--, X is --S-- or --SO.sub.2 --, n is 1, R.sup.2 is hydrogen, R.sup.3 and R.sup.4 are hydrogen or C.sub.1-4 alkyl, and R.sup.1 is --OH, --CH.sub.2 OH or NR.sup.6 R.sup.7.

26. The method of claim 22 wherein the compound is:

5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide;

5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide;

6,7-dihydro-5H-7-hydroxythieno[3,2-b]thiopyran-2-sulfonamide;

6,7-dihydro-5H-7-hydroxythieno[3,2-b]thiopyran-2-sulfonamide-4,4-dioxide;

5,6-dihydro-4H-4-(N-ethylamino)thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio xide;

5,6-dihydro-4H-4-aminothieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide;

5,6-dihydro-4-hydroxy-5,5-dimethyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide- 7,7-dioxide;

5,6-dihydro-4H-4-hydroxymethylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-diox ide;

5,6-dihydro-4-isobutylamino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio xide; or

5,6-dihydro-4-n-butylamino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-diox ide.

27. The method of claim 22 wherein the compound is 5,6-dihydro-4H-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide.

28. The method of claim 22 wherein the compound is 5,6-dihydro-4-isobutylamino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-di oxide.

29. The method of claim 22 wherein the compound is 5,6-dihydro-4H-4-aminothieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide.

30. The method of claim 22 wherein the compound is 5,6-dihydro-4-hydroxy-5,5-dimethyl-4H-thieno[2,3-b]-thiopyran-2-sulfonamid e-7,7-dioxide.

31. The method of claim 22 wherein the compound is 5,6-dihydro-4H-4-hydroxymethylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-dio xide.
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