# US 5,350,579 A · A87689 compounds employed as a phospholipase A.sub.2 (PLA.sub.2) inhibitor to treat inflammatory diseases

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- Number: US 5,350,579 A
- Document ID: US5350579A
- Status: Granted
- Kind: A
- Application number: 08/103,845
- Filed: 1993-08-09
- Granted: 1994-09-27
- Earliest claimed: 1991-08-01
- Assignees: Eli Lilly and Company
- Inventors: Dennis R. Berry; Anne H. Dantzig; Manuel Debono; Robert Hamill; R. Michael Molloy; Raymond C. Yao
- Web page: https://patentgrep.com/patent/US5350579A

## CPC

- C12P 1/06: by using actinomycetales
- C12N 1/205: Bacterial isolates
- C12R 2001/01: Bacteria or Actinomycetales {; using bacteria or Actinomycetales}
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12R: INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS

## Abstract

Fermentation product A87689 is produced by a strain of Amycolatopsis mediterranei selected from NRRL 18815 and NRRL 18851, or an A87689-producing mutant thereof. A87689, its C.sub.1-6 -alkyl ether and C.sub.1-6 -alkanoyl ester derivatives and pharmaceutically acceptable salts thereof are phospholipase A.sub.2 inhibitors that are useful as antiinflammatory agents. Fermentation products known as BU-3889V, its components and pharmaceutically acceptable salts thereof, are phospholipase A.sub.2 inhibitors that are also useful as antiinflammatory agents.

## Claims

### Claim 1

A method of inhibiting PLA.sub.2 activity in animals which comprises administering a PLA.sub.2 -inhibiting amount of a compound selected from A87689, which in its calcium salt form has the following characteristics:
Molecular weight=1222.418
Empirical formula=C.sub.66 H.sub.70 O.sub.20 Ca
FAB-MS (M+1): Found: 1223.4175,
Calculated: 1223.4254; and
IR: as shown in FIG. 1 of the drawings, a C.sub.1 -C.sub.6 alkyl ether or a C.sub.1 -C.sub.6 alkanoyl ester of A87689, or a pharmaceutically acceptable salt thereof, to said animal.

### Claim 2

A method of treating arthritic disease in animals which comprises administering to said animal a compound selected from A87689, which in its calcium salt form has the following characteristics:
Molecular weight=1222.418
Empirical formula=C.sub.66 H.sub.70 O.sub.20 Ca
FAB-MS (M+1): Found: 1223.4175,
Calculated: 1223.4254; and
IR: as shown in FIG. 1 of the drawings, a C.sub.1 -C.sub.6 alkyl ether or a C.sub.1 -C.sub.6 alkanoyl ester of A87689, or a pharmaceutically acceptable salt thereof.

### Claim 3

A method of treating asthma in animals which comprises administering to said animal an amount of a compound selected from A87689, which in its calcium salt form has the following characteristics:
Molecular weight=1222.418
Empirical formula=C.sub.66 H.sub.70 O.sub.20 Ca
FAB-MS (M+1): Found: 1223.4175,
Calculated: 1223.4254; and
IR: as shown in FIG. 1 of the drawings, a C.sub.1 -C.sub.6 alkyl ether or a C.sub.1 -C.sub.6 alkanoyl ester of A87689, or a pharmaceutically acceptable salt thereof, sufficient to reduce the inflammation of an asthmatic animal's respiratory system.

### Claim 4

A method of inhibiting PLA.sub.2 activity in animals which comprises administering a PLA.sub.2 -inhibiting amount of at least one compound selected from the group consisting of BU-3889V A.sub.1, BU-3889V A.sub.2, BU-3889V A.sub.3, BU-3889V D.sub.1, BU-3889V D.sub.2, BU-3889V D.sub.3, or a pharmaceutically acceptable salt thereof, to said animal.

### Claim 5

A method of reducing inflammation in animals which comprises administering to said animal an inflammation-inhibiting amount of at least one compound selected from the group consisting of BU-3889V A.sub.1, BU-3889V A.sub.2, BU-3889V A.sub.3, BU-3889V D.sub.1, BU-3889V D.sub.2, BU-3889V D.sub.3, or a pharmaceutically acceptable salt thereof.

### Claim 6

A method of treating arthritic disease in animals which comprises administering to said animal an effective amount of at least one compound selected from the group consisting of BU-3889V A.sub.1, BU-3889V A.sub.2, BU-3889V A.sub.3, BU-3889V D.sub.1, BU-3889V D.sub.2, BU-3889V D.sub.3, or a pharmaceutically acceptable salt thereof.

### Claim 7

A method of treating asthma in animals which comprises administering to said animal an amount of at least one compound selected from the group consisting of BU-3889V A.sub.1, BU-3889V A.sub.2, BU-3889V A.sub.3, BU-3889V D.sub.1, BU-3889V D.sub.2, BU-3889V D.sub.3, or a pharmaceutically acceptable salt thereof, sufficient to reduce the inflammation of an asthmatic animal's respiratory system.

### Claim 8

A method of reducing inflammation in an animal which comprises administering to said animal an inflammation inhibiting amount of a compound selected from the group consisting of
(a) A87689, which in its calcium salt form has the following characteristics:
Molecular weight=1222.418
Empirical formula=C.sub.66 H.sub.70 O.sub.20 Ca
FAB-MS (M+1): Found: 1223.4175,
Calculated: 1223.4254; and
IR: as shown in FIG. 1 of the drawings;
(b) A C.sub.1-6 -alkyl ether of C.sub.1-6 -alkanoyl ester derivative of A87689; or
(c) a salt of A87689 or of said ether or ester derivative.

### Claim 9 (depends on 8)

A method according to claim 8 wherein said compound is C.sub.1-6 alkyl ether of A87689, or a pharmaceutically acceptable salt thereof.