# US 5,352,705 A · Inhibitors of farnesyl protein transferase

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 5,352,705 A
- Document ID: US5352705A
- Status: Granted
- Kind: A
- Application number: 07/905,927
- Filed: 1992-06-26
- Granted: 1994-10-04
- Earliest claimed: 1992-06-26
- Assignees: Merck & Co., Inc.
- Inventors: Albert A. Deana, deceased; S. Jane deSolms; Samuel L. Graham; Robert L. Smith
- Web page: https://patentgrep.com/patent/US5352705A

## CPC

- C07C 323/25: the carbon skeleton being acyclic and saturated
- A61P 3/06: Antihyperlipidemics
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 5/0606: {the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr}
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

## Claims

### Claim 1

A compound of the formula: ##STR8## wherein: ##STR9## ##STR10## R.sup.1 is an alkyl group, hydrogen, an acyl group, an alkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms which alternatively may be substituted with an aryl group;
R.sup.2 is the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, or aromatic groups, selected from the group consisting of allyl, cyclohexyl, phenyl, or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substitutents may be substituted with an aromatic ring;
R.sup.3 is an aromatic ring or in the alternative, an alkyl group or an aryl substituted alkane, wherein the aromatic ring is unsubstituted or in the alternative, substituted with one or more groups selected from the group consisting of alkyl, halo, alkoxy, trifluoromethyl or sulfamoyl groups, and which may be polycyclic;
or the pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

The compound of claim 1 which is:
N-[2<R)-Amino-3-mercaptopropyl]-L-isoleucine phenethylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-benzylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-3methylbutylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-3-phenylpropylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucyl-L-phenylalaninol,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-N'-methylbenzylamide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4-methoxybenzyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dichlorobenzyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4-trifluoromethylbenzyl)amide
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dichlorophenethyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(1-indanyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dimethylbenzyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,3-dichlorobenzyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4-sulfamoylbenzyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucineanilide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dimethylphenyl)amide,
N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,3-dimethylphenyl)amide,
L-Cysteinyl-L-isoleucine-phenethylamide,
N-(2(R)-Amino-3-mercaptopropyl)-L-alaninebenzylamide,
N-Benzyl-[2(S)-(2(R)-Amino-3-mercaptopropyl)amino]butyramide,
N-(2(R)-Amino-3-mercaptopropyl)-L-norleucinebenzylamide, or
N-(2(R)-Amino-3-mercaptopropyl)-L-norvalinebenzylamide.

### Claim 3 (depends on 1)

The compound of claim 1 which is: N-[2 (R)-Amino-3-mercaptopropyl]-L-isoleucine-3-chlorophenethylamide ##STR11##

### Claim 4 (depends on 1)

The compound of claim 1 which is: N-[2 (R)-Amino-3-mercaptopropyl]-L-isoleucine-2,3-dichlorobenzylamide ##STR12##

### Claim 5 (depends on 1)

The compound of claim 1 which N-[2 (R)-Amino-3-mercaptopropyl]-L-isoleucine-anilide ##STR13##

### Claim 6 (depends on 1)

The compound of claim 1 which is: N-[2 (R)-Amino-3-mercaptopropyl]-L-isoleucine-2,3-dimethylphenylamide ##STR14##

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 2)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of compound of claim 2.

### Claim 9 (depends on 3)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of compound of claim 3.

### Claim 10 (depends on 4)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of compound of claim 4.

### Claim 11 (depends on 5)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of compound of claim 5.

### Claim 12 (depends on 6)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of compound of claim 6.