# US 5,334,591 A · Tricyclic thienothiopyran carbonic anhydrase inhibitors

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- Number: US 5,334,591 A
- Document ID: US5334591A
- Status: Granted
- Kind: A
- Application number: 08/026,363
- Filed: 1993-03-04
- Granted: 1994-08-02
- Earliest claimed: 1991-10-15
- Assignees: Merck & Co., Inc.
- Inventors: John J. Baldwin; Kenneth L. Shepard; Gerald S. Ponticello; Theresa M. Williams
- Web page: https://patentgrep.com/patent/US5334591A

## CPC

- C07D 495/18: Bridged systems
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Conformationally constrained tricyclic thienothiopyran compounds are topically effective carbonic anhydrase inhibitors useful in the treatment of ocular hypertension and glaucoma associated therewith.

## Claims

### Claim 1

A compound of structural formula ##STR52## having a cis configuration, the enantiomers and mixtures thereof, or an ophthalmologically acceptable salt thereof wherein:
R is: ##STR53## R.sub.1 is: 1) H;
2) C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.1-6 alkyl substituted with F, OH, C.sub.1-5 alkyl-S(O).sub.m -- or C.sub.1-5 alkyl-O--;
3) phenyl or benzyl wherein the phenyl groups optionally are substituted by C.sub.1-3 alkyl, halogen, CF.sub.3, OH, or C.sub.1-3 alkoxy;
R.sub.2, R.sub.3, R.sub.5, R.sub.6, and R.sub.7 are independently H or C.sub.1-4 alkyl or R.sub.2 and R.sub.3 together are .dbd.O; and
R4 is
1) H or C.sub.1-6 alkyl;
2) C.sub.1-6 alkyl substituted with
a) hydroxy,
b) C.sub.1-3 alkyl-O--,
c) hydroxy-C.sub.1-3 alkyl-O--,
d) C.sub.1-3 alkyl-O--C.sub.1-3 alkyl-O--,
e) hydroxy-C.sub.1-3 alkyl-O--C.sub.1-3 alkyl-O--,
f) (C.sub.1-3 alkyl).sub.2 -N--,
g) hydroxy-C.sub.1-3 alkyl-NH--,
h) C.sub.1-3 alkyl-O--C.sub.1-3 alkyl-NH--,
i) hydroxy-C.sub.1-3 alkyl-O--C.sub.1-3 alkyl-NH--,
j) C.sub.1-3 alkyl-S(O).sub.m --,
k) hydroxy-C.sub.1-3 alkyl-S(O).sub.m --,
l) C.sub.1-3 alkyl-O--C.sub.1-3 alkyl-S(O).sub.m --,
m) hydroxy-C.sub.1-3 alkyl-O--C.sub.1-3 alkyl-S(O).sub.m --,
n) C.sub.1-3 alkyl-S(O).sub.m -C.sub.1-3 alkyl-O--,
o) hydroxy-C.sub.1-3 alkyl-S(O).sub.m --C.sub.1-3 alkyl-O--,
p) C.sub.1-3 alkyl-S(O).sub.m --C.sub.1-3 alkyl-S(O).sub.m --
q) hydroxy-C.sub.1-3 alkyl-S(O).sub.m --C.sub.1-3 alkyl-S(O).sub.m --,
3) C.sub.2-3 alkenyl or C.sub.2-6 alkenyloxy; m and n are 0, 1, or 2.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R.sub.2, R.sub.3, R.sub.5, R.sub.6 and R.sub.7 are independently H or C.sub.1-6 alkyl; and R.sub.4 is H, C.sub.1-6 alkyl or C.sub.1-6 alkyl substituted with hydroxy, C.sub.1-3 alkoxy, hydroxy-C.sub.1-3 alkoxy, C.sub.1-3 alkoxy-C.sub.1-3 alkoxy, C.sub.1-3 alkylamino or C.sub.1-3 alkoxy, C.sub.1-3 alkylamino.

### Claim 3 (depends on 2)

The compound of claim 2 wherein m is 2.

### Claim 4 (depends on 3)

The compound of claim 3 wherein R.sub.2, R.sub.3, R.sub.5, R.sub.6 and R.sub.7 are hydrogen.

### Claim 5 (depends on 1)

A compound of claim 1 wherein n is 0 and m is 0, 1 or 2.

### Claim 6 (depends on 1)

A compound of claim 1 wherein n is 0 and m is 2.

### Claim 7 (depends on 1)

A compound of claim 1 having the name
4-ethyl-2-[2-(2-methoxyethoxy)ethyl-2,3,4,5-tetrahydro-2,5-methanothieno[3, 2-f ]-1,4-thiazepine-7-sulfonamide-1,1-dioxide hydrochloride,
5-(4-methoxybenzyl)-2-methyl-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g] -1,5-thiazocine-8-sulfonamide-1,1-dioxide,
5-(4-methoxybenzyl)-2-methoxypropyl-3,4,5,6-tetrahydro-2H-2,6-methanothieno [3,2-g]-1,5-thiazocine-8-sulfonamide-1,1-dioxide,
2-methyl-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g]-1,5-thiazocine-8-su lfonamide-1,1-dioxide hydrochloride,
5-isobutyl-4-oxo-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g]-1,5-thiazoc ine-8-sulfonamide,
5-isobutyl-4-oxo-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g]-1,5-thiazoc ine-8-sulfonamide-1,1-dioxide,
5-isobutyl-3,4,5,6-tetrahydro-2H-2,6-methanothieno-[3,2-g]-1,5-thiazocine-8 -sulfonamide-1,1-dioxide-hydrochloride,
5-propyl-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g]-1,5-thiazocine-8-su lfonamide-1,1-dioxide hydrochloride,
2,5-methanothieno[3,2-f]-1,4-thiazepine-7-sulfonamide-4-propyl-2,3,4,5-tetr ahydro-1,1-dioxide.cndot.HCl,
cis(S,S)2,5-methanothieno[3,2-f]-1,4-thiazepine-7-sulfonamide-4-ethyl-2,3,4 ,5-tetrahydro-1,1-dioxide.cndot.HCl 2methoxypropyl-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g[-1,5-thiazoci ne.

### Claim 8 (depends on 1)

A composition for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim 1.

### Claim 9 (depends on 1)

A method of treating elevated intraocular pressure comprising the administration to a member of a mammalian species in need of such treatment of an effective intraocular pressure lowering amount of claim 1.

### Claim 10 (depends on 1)

The compound of claim 1 wherein R is H.