# US 5,708,033 A · Amide derivatives and their therapeutic use

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- Number: US 5,708,033 A
- Document ID: US5708033A
- Status: Granted
- Kind: A
- Application number: 08/732,476
- Filed: 1996-11-08
- Granted: 1998-01-13
- Earliest claimed: 1994-05-10
- Assignees: Glaxo Wellcome Inc.
- Inventors: James Leroy Kelley; David Lee Musso
- Web page: https://patentgrep.com/patent/US5708033A

## CPC

- C07C 233/11: with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07C 17/14: in the side-chain of aromatic compounds
- C07C 45/46: Friedel-Crafts reactions
- C07C 57/58: containing six-membered aromatic rings
- C07C 57/60: having unsaturation outside the rings
- C07C 57/62: containing six-membered aromatic rings and other rings
- C07C 57/76: containing halogen outside the carbonyl halide groups
- C07C 59/56: containing halogen
- C07C 69/65: of unsaturated acids
- C07C 69/732: of unsaturated hydroxy carboxylic acids
- C07C 2602/08: the other ring being five-membered, e.g. indane
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound of formula (I), wherein R.sup.1 and R.sup.2 are independently selected from chloro, fluoro, bromo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 haloalkyl provided that both R.sup.1 and R.sup.2 are not fluoro; R.sup.3 and R.sup.4 are independently selected from hydrogen and C.sub.1-6 alkyl, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof, their use in medicine, particularly the phrophylaxis or treatment of conditions associated with inflammation, arthritis, or pain, pharmaceutical compositions comprising them, and processes for their preparation are disclosed. ##STR1##

## Claims

### Claim 1

A compound of the formula (I): ##STR13## wherein R.sup.1 and R.sup.2 are independently selected from chloro, fluoro, bromo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 haloalkyl provided that both R.sup.1 and R.sup.2 are not fluoro;
R.sup.3 and R.sup.4 are independently selected from hydrogen and (C.sub.1-6 alkyl; or a pharmaceutically acceptable salt, solvate, or ester thereof.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 wherein at least one of R.sup.1 and R.sup.2 is chloro.

### Claim 3

A compound of formula (1A) ##STR14## wherein R.sup.1a is chloro, R.sup.2a is chloro, fluoro, bromo or methyl, and R.sup.3 and R.sup.4 are independently selected from hydrogen, methyl and ethyl; or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 4 (depends on 1)

A compound as claimed in claim 1 which is;
(E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-methylacetamide;
(E)-2-(4-chloro-6-fluoro-1-indanylidene)acetamide;
(E)-2-(4,6-dichloro-1-indanylidene)acetamide;
(E)-2-(6-fluoro-4-methyl-1-indanylidene)acetamide;
(E)-2-(6-fluoro-4-methyl-1-indanylidene)-N-methylacetamide;
(E)-2-(6-chloro-4-fluoro-1-indanylidene)acetamide;
(E)-2-(4-bromo-6-fluoro-1-indanylidene)acetamide; or
(E)-2-(4-chloro-6-methyl-1-indanylidene)acetamide.
or a pharmaceutically acceptable salt, solvate or ester thereof.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising at least one compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, together with one or more pharmaceutically acceptable carders therefor.

### Claim 6 (depends on 1)

A method for the treatment of conditions associated with inflammation, arthritis or pain in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt, solvate ester thereof.

### Claim 7 (depends on 1)

A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises either:
(a) reacting a compound of the formula (II): ##STR15## with an amine NHR.sup.3 R.sup.4 wherein R.sup.1 -R.sup.4 are as hereinbefore defined in claim 1 and X is a leaving group;
(b) by reaction of a compound of formula (III): ##STR16## with a suitable coupling reagent followed by reaction with an amine HNR.sup.3 R.sup.4 wherein R.sup.1 -R.sup.4 are as defined in claim 1;
(c) by reacting the compound R.sup.3 R.sup.4 NC(O)CH.sub.2 PO(OR.sup.6)2, wherein R.sup.3 and R.sup.4 are as defined in claim 1 and R.sup.6 is C.sub.1-6 alkyl with a base, followed by reaction with a compound of formula (V): ##STR17## wherein R.sup.1 and R.sup.2 are as defined in claim 1. (d) by reacting the compound R.sup.3 R.sup.4 NC(O)CH.sub.2 P.sup.(+) (Ph).sub.3 Cl.sup.(-), wherein R.sup.3 and R.sup.4 are as defined in claim 1 and Ph phenyl with a suitable base, followed by reaction with a compound of formula (V);
each of the above being optionally followed by
(e) converting the compound of formula (I) so prepared into a salt, or ester thereof.

### Claim 8 (depends on 7)

An intermediate of formula (II) or (III) as defined in claim 7 or of formula (IV) ##STR18## wherein R.sup.1 and R.sup.2 are as defined in claim 7.

### Claim 9

An intermediate selected from
2-(4-chloro-6-fluoro-1-hydroxy-1-indanyl)acetic acid
(E)-2-(4-Chloro-6-fluoro-1-indanylidene)acetic acid
(E)-2-(4-Chloro-6-fluoro-1-indanylidene)acetyl chloride
2-(4,6-Dichloro-1-hydroxy-1-indanyl)acetic acid
(E)-(4,6-Dichloro-1-indanylidene)acetic acid
(E)-2-(4,6-Dichloro-1-indanylidene)acetyl chloride
2-(6-Fluoro-1-hydroxy-4-methyl-1-indanyl)acetic acid
(E)-2-(6-Fluoro-4-methyl-1-indanylidene)acetic acid
(E)-2-(6-Fluoro-4-methyl-1-indanylidene)acetyl chloride
2-(6-Chloro-4-fluoro-1-hydroxy-1-indanyl)acetic acid
(E)-2-(6-Chloro-4-fluoro-1-indanylidene)acetic acid
(E)-2-(6-Chloro-4-fluoro-1-indanylidene)acetyl chloride
2-(4-Bromo-6-fluoro-1-hydroxy-1-indanylidene)acetic acid
(E)-2-(4-Bromo-6-fluoro-1-indanylidene)acetic acid
(E)-2-(4-Bromo-6-fluoro-1-indanyl)acetyl chloride
2-(4-Chloro-6-methyl-1-hydroxy-1-indanyl)acetic acid
(E)-2-(4-Chloro-6-methyl-1-indanylidene)acetic acid and
(E)-2-(4-Chloro-6-methyl-1-indanylidene)acetyl chloride.