Farnesyl transferase inhibitors, preparation thereof and pharmac

Details Farnesyl transferase inhibitors, preparation thereof and pharmac Farnesyl transferase inhibitors, preparation thereof and pharmac

1997-07-15

1998-05-12

Barts, Samuel

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514560, 514562, 560 10, 560427, A61K 3121

Patent

active

057505675

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FR96/00067 filed Jan. 16, 1996.
The present invention relates to new farnesyl transferase inhibitors of general formula: ##STR2## optionally to their salts, to their preparation and to the pharmaceutical compositions which contain them.
The inhibition of farnesyl transferase, and consequently of the farnesylation of the Ras protein, blocks the capacity of the mutated Ras protein to transform normal cells into cancerous cells.
The C-terminal sequence of the Ras gene contains the unit "CAAX" or "Cys-Aaa.sub.1 -Aaa.sub.2 -Xaa", in which Aaa represents an aliphatic amino acid and Xaa represents any amino acid.
It is known that tetrapeptides with a CAAX sequence can inhibit the farnesylation of the Ras protein. For example, peptide inhibitors of farnesyl transferase, Cys-Aaa,-Aaa.sub.2 -Xaa, which are especially represented by the peptides Cys-Val-Leu-Ser, Cys-Val-Ile-Met and Cys-Val-Val-Met which manifest their inhibitory activity at concentrations in the region of 10.sup.-6 M or of 10.sup.-7 M, have been described in PCT Application WO 91/16340 and in Application EP 0,461,869.
It has now been found, and this forms the subject of the present invention, that the peptides of general formula (I) manifest their inhibitory activity (IC.sub.50) at concentrations of the order of 10.sup.-8 or of 10.sup.-9 M.
In the general formula (I), R.sub.1 represents a radical of general formula Y--S--A.sub.1 -- in which Y represents a hydrogen atom or an amino acid residue or a fatty acid residue or an alkyl or alkoxycarbonyl radical, and A.sub.1 represents a straight or branched alkylene radical containing 1 to 4 carbon atoms, optionally substituted at the position a to the >C(X.sub.1) (Y.sub.1) group by an amino, alkylamino, alkanoylamino or alkoxycarbonylamino radical, the straight or branched alkyl or alkanoyl part of which contains 1 to 6 carbon atoms, the carbon atom to which they are bonded, a >C.dbd.O group, containing 1 to 6 carbon atoms, containing 1 to 6 carbon atoms, optionally substituted by a hydroxyl radical, an alkoxy radical containing 1 to 4 carbon atoms, a mercapto radical, an alkylthio radical containing 1 to 4 carbon atoms, an alkylsulphinyl radical containing 1 to 4 carbon atoms or an alkylsulphonyl radical containing 1 to 4 carbon atoms, it being understood that, when R.sub.2 represents an alkyl radical substituted by a hydroxyl radical, R.sub.2 can form a lactone with the carboxyl radical at the .alpha. position, containing 1 to 6 carbon atoms, and atoms, optionally substituted by an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radical containing 1 to 4 carbon atoms, an alkylsulphinyl radical containing 1 to 4 carbon atoms, an alkylsulphonyl radical containing 1 to 4 carbon atoms, a phenyl radical, a phenoxy radical, a phenylthio radical, a phenylsulphinyl radical, a phenylsulphonyl radical, an alkylamino radical containing 1 to 4 carbon atoms or a dialkylamino radical in which each alkyl part contains 1 to 4 carbon atoms, or a phenyl radical, optionally substituted by one or a number of atoms or radicals chosen from halogen atoms and alkyl, alkyloxy, alkylthio or alkanoyl radicals.
More particularly, represents a hydrogen atom or a lysine residue or a fatty acid residue containing up to 20 carbon atoms and A.sub.1 represents an ethylene or propylene radical optionally substituted by an amino radical, the carbon atom to which they are bonded, optionally substituted by a hydroxyl, methoxy, mercapto, methylthio, methylsulphinyl or methylsulphonyl radical, atoms, optionally substituted by an alkoxy radical, or a phenyl radical.
More particularly still, represents a hydrogen atom and A.sub.1 represents an ethylene or propylene radical optionally substituted by an amino radical, the carbon atom to which they are bonded, substituted by a hydroxyl, methoxy, mercapto or methylthio radical, atoms.
The products of general formula (I) in which R.sub.1 represents a 2-mercaptoethyl or 1-amino-2mercaptoethyl radical, X.sub.1 and Y.sub.1 each represent a hydrogen atom

REFERENCES:
patent: 5523456 (1996-06-01), Stokker et al.
patent: 5536750 (1996-07-01), DeSolms et al.

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