Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 4 to 5 amino acid residues in defined sequence
Patent
1997-08-01
1999-01-05
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
4 to 5 amino acid residues in defined sequence
530329, 530331, 514 18, 548535, 562557, A61K 3807
Patent
active
058564390
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
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 more particularly 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 10.sup.-7 M, have been described in PCT Application WO 91/16340 and in Application EP 0,461,869.
SUMMARY OF THE INVENTION
The present invention relates to the new farnesyl transferase inhibitors of formula: ##STR3## to their preparation and to the pharmaceutical compositions which contain them.
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 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 6 carbon atoms, optionally substituted by a phenyl radical, or a radical of general formula ##STR4## in which A.sub.1, X.sub.1, Y.sub.1, R.sub.2, R'.sub.2, X.sub.2, Y.sub.2, X, R.sub.3, R'.sub.3 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 .alpha. to the >C(X.sub.1) (Y.sub.1) group by an amino radical, an alkylamino radical containing 1 to 4 carbon atoms, an alkanoylamino radical containing 1 to 4 carbon atoms or an alkoxycarbonylamino radical in which the alkyl part contains 1 to 4 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.2 represents a straight or branched alkyl radical containing 1 to 4 carbon atoms, optionally substituted by a cyclohexyl radical,
R'.sub.2 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms,
X.sub.2 and Y.sub.2 each represent a hydrogen atom or form, together with the carbon atom to which they are bonded, a >C.dbd.O group,
R.sub.3 represents a straight or branched containing alkyl radical containing 1 to 4 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.3 represents an alkyl radical substituted by a hydroxyl radical, R.sub.3 can form a lactone with the carboxyl radical at the .alpha. position,
R'.sub.3 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms,
X represents an oxygen or sulphur atom, and
R represents a hydrogen atom or an alkyl radical, 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 a
Lukton David
Martin Michael B.
Parker III Raymond S.
Rhone-Poulenc Rorer S.A.
Tsang Cecilia J.
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