# US 5,710,324 A · Inhibitors of nitric oxide biosynthesis

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- Number: US 5,710,324 A
- Document ID: US5710324A
- Status: Granted
- Kind: A
- Application number: 08/317,458
- Filed: 1994-10-04
- Granted: 1998-01-20
- Earliest claimed: 1990-02-26
- Assignees: Merrell Pharmaceuticals Inc.
- Inventors: Jeffrey P. Whitten; Ian A. McDonald; Laurie E. Lambert; Niall S. Doherty
- Web page: https://patentgrep.com/patent/US5710324A

## CPC

- C07K 5/06086: {with the first amino acid being basic}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention is directed to a new class of compound which are useful as inhibitors of the biosynthesis of nitric oxide.

## Claims

### Claim 1

A compound of the formula: ##STR9## in which X is represented by cyano, cyclopropyl, 2-propyne, 2, 3-butadiene or NHR.sub.2, in which R.sub.2 is represented by H, or C.sub.1-6 alkyl;
R is represented by an amino acid or OM in which M is represented by H, C.sub.1-6 alkyl, benzyl, phenyl, or pivoyl methyl ether;
Z is represented by O or NR.sub.1, in which R.sub.1 is represented by H, --CF.sub.3, --CH.sub.2 CF.sub.3, or C.sub.1-6 alkyl; and
W is represented by a substituent selected from the group consisting of CH.sub.2 --NH--, --(CH.sub.2).sub.2 --NH--, --NH--NH--, --CH.sub.2 --NH--NH, --CH.sub.2 --O--NH and --O--NH;
and the pharmaceutical acceptable salts thereof; with the following proviso's;
1) that when W is --NH--NH or --(CH.sub.2).sub.2 --NH-- then Z must be represented by O, and
2) that when X is --NHR.sub.2 and Z is --NHR.sub.1 then R.sub.1 and R.sub.2 must t be represented by the same C.sub.1-6 alkyl substituent, and
3) that when Z is represented by O and X is represented by NR.sub.1 then W must be --CH.sub.2 --NH-- or --(CH.sub.2).sub.2 --NH--, and
4) that when W is represented by CH.sub.2 --NH, Z is represented by NH, and X is NHR.sub.2, then R.sub.2 is not represented by H.

### Claim 2 (depends on 1)

A compound according to claim 1 in which X is cyclopropyl.

### Claim 3 (depends on 2)

A Compound according to claim 2 in which R is represented by --OM in which M is represented by H, C.sub.1-6 alkyl, benzyl, phenyl, pivoyl methyl ester.

### Claim 4 (depends on 3)

A Compound according to claim 3 in which R is represented by --OM where M is represented by H.

### Claim 5 (depends on 2)

A Compound according to claim 2 in which R is represented by an amino acid.

### Claim 6 (depends on 2)

A Compound according to claim 2 in which Z is represented by NR.sub.1.

### Claim 7 (depends on 2)

A Compound according to claim 2 in which Z is represented by O.

### Claim 8 (depends on 1)

A compound according to claim 1 in which W is represented by --CH.sub.2 --NH--.

### Claim 9 (depends on 1)

A compound according to claim 1 in which Z is NR1 where R1 is H.

### Claim 10 (depends on 1)

A Compound according to claim 1 in which X is represented by 2-propyne, or 2,3 butadiene.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 in admixture with a pharmaceutically acceptable carrier.

### Claim 12

A compound of the formula: ##STR10## in which X is cyclopropyl and
R is OM, with M represented by H, and
Z is represented by NR1, with R1 represented by H, and
W is CH2--NH.

### Claim 13 (depends on 12)

A pharmaceutical composition consisting of a compound according to claim 12 in admixture with a pharmaceutically acceptable carrier.