Nederlandse Organisatie Voor Toegepast-natuurwetenschappelijk Onderzoek

Adrianus Petrus Valentijn

Gijsbert Arie Van Der Marel

Jacobus Hubertus Van Boom

Louis Hartog Cohen

The invention provides a method for inhibiting protein isoprenylation by administration of a polyisoprenyl pyrophosphate analogue. The polyisoprenyl pyrophosphate analogue may have formula 1, ##STR1## wherein: Pren represents a C.sub.10 -C.sub.30 terpenoid group or a derivative thereof; A.sup.1, A.sup.2, A.sup.3 and A.sup.4 independently represent a direct bond or a C.sub.1 -C.sub.4 alkylene or alkenylene group, optionally having substituents selected from methyl, hydroxy, methoxy, mercapto, methylthio, amino, methylamino, dimethylamino, halogen and a group having formula --X.sup.5 --A.sup.5 --P(.dbd.Z.sup.2)Y.sup.2 Y.sup.3 ; A.sup.5 represents a direct bond or a C.sub.1 -C.sub.4 alkylene or alkenylene group; X.sup.1, X.sup.2, X.sup.3, X.sup.4 and X.sup.5 independently represent a direct bond, oxygen, sulphur, imino or methylimino; Y.sup.1, Y.sup.2 and Y.sup.3 independently represent hydroxy, alkoxy, mercapto, alkylthio, amino, mono- or di-alkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or arylalkyl, whereby one of Y.sup.1, Y.sup.2 and Y.sup.3 may also represent a C.sub.7 -C.sub.30 alkyl or alkenyl group or a group having formula --X.sup.5 --A.sup.5 --P(.dbd.Z.sup.2)Y.sup.2 Y.sup.3 and two of Y.sup.1, Y.sup.2 and Y.sup.3 may together represent an oxygen or sulfur atom or an imino or methylene group; Z.sup.1 and Z.sup.2 independently represent oxygen or sulphur; and n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. The invention further provides a pharmaceutical composition containing such a polyisoprenyl pyrophosphate analogue, which composition is suitable for the treatment of carcinomas such as by the inhibition of the isoprenylation of a member of the ras protein family.

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Leiden, Netherlands

Adrianus Petrus Valentijn