Farnesyl transferase inhibitors, their preparation and the pharm

Details Farnesyl transferase inhibitors, their preparation and the pharm Farnesyl transferase inhibitors, their preparation and the pharm

1997-06-18

1999-01-19

Killos, Paul J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

562426, 514534, C07C 3200, A01N 3712

Patent

active

058615296

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new farnesyl transferase inhibitors of general formula: ##STR4## 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.sub.1 -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 hereby incorporated by reference.
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 or an R.sub.4 --S-- radical in which R.sub.4 represents an alkyl radical containing 1 to 4 carbon atoms, optionally substituted by a phenyl radical, or a radical of general formula: ##STR5## in which A.sub.1, X.sub.1, Y.sub.1, R'.sub.1, R.sub.2, R'.sub.2 and R are defined as below, 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 radical, an alkylamino radical containing 1 to 6 straight- or branched-chain carbon atoms, a dialkyl-amino radical in which each alkyl part contains 1 to 6 straight- or branched-chain carbon atoms, an alkanoyl-amino radical containing 1 to 6 straight- or branched-chain carbon atoms or an alkoxycarbonylamino radical in which the alkyl part contains 1 to 6 straight- or branched-chain carbon atoms, X.sub.1 and Y.sub.1 each represent a hydrogen atom or form, together with the carbon atom to which they are bonded, a >C.dbd.O group, R'.sub.1 represents a hydrogen atom or a methyl radical, R.sub.2 represents a straight or branched alkyl, alkenyl or alkynyl radical 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, R'.sub.2 represents a hydrogen atom or a methyl radical, and R represents a hydrogen atom or an alkyl radical containing 1 to 6 carbon 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, it being understood that the radical ##STR6## is in the 5- or 6-position of the naphthyl ring.
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REFERENCES:
S. Graham et al., "Pseudopeptide Inhibitors of Ras Farnesvl-Protein Transferase", J. Med. Chem., 37(6):725-732 (1994).

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