# US 5,703,241 A · Inhibitor of farnesyl-protein transferase

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- Number: US 5,703,241 A
- Document ID: US5703241A
- Status: Granted
- Kind: A
- Application number: 08/729,265
- Filed: 1996-10-10
- Granted: 1997-12-30
- Earliest claimed: 1996-10-10
- Assignees: Merck & Co., Inc.
- Inventors: S. Jane deSolms; Samuel L. Graham
- Web page: https://patentgrep.com/patent/US5703241A

## CPC

- C07K 5/06026: {the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala}
- 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 comprises an analog of the CA.sub.1 A.sub.2 X motif of the protein Ras that is modified by farnesylation in vivo. This CA.sub.1 A.sub.2 X analog inhibits the farnesyl-protein transferase and the farnesylation of certain proteins. Furthermore, this CA.sub.1 A.sub.2 X analog differs from most compounds previously described as inhibitors of farnesyl-protein transferase in that it does not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compound of the instant invention also incorporates a cyclic amine moiety in the A.sup.1 position of the motif. Further contained in this invention are chemotherapeutic compositions containing this farnesyl transferase inhibitor and methods for its production.

## Claims

### Claim 1

A compound which inhibits farnesyl-protein transferase which is:
N-›1-(1H-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine isopropyl ester ##STR5## or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1.

### Claim 3 (depends on 2)

A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of claim 2.

### Claim 4 (depends on 2)

A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 2.