Inhibitors of farnesyl-protein transferase
AssigneeMerck & Co., Inc.
InventorsSheo B. Singh, George M. Garrity, Olga Genillourd, Russell B. Lingham, Isabel Martin, Mary N. Omstead, Keith C. Silverman, Deborah L. Zink
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Abstract
The present invention is directed to compounds which inhibit farnesyl-protein transferase (FPTase) 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.
Claims20
A compound which inhibits farnesyl-protein transferase of the formula I:
- ##STR11## wherein:
- R.sup.1, R.sup.3, R.sup.4 and R.sup.5 are independently selected from:
- a) hydrogen;
- b) C.sub.1-5 alkyl;
- and
- c) C.sub.1-5 alkyl substituted wth a member of the group consisting of:
- i) phenyl,
- ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy;
- and
- R.sup.2 is selected from hydrogen, C.sub.1-4 alkyl, benzoyl or acetyl;
- wherein the dashed line represents the presence of a second bond, which results in a double bond, or the absence of a second bond;
- and
- wherein at least two R.sup.1, R.sup.3, R.sup.4 or R.sup.5 are hydrogen;
- or a pharmaceutically acceptable salt thereof.
A compound which inhibits farnesyl-protein transferase of the formula II:
- ##STR12## wherein:
- R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently selected from:
- a) hydrogen;
- b) C.sub.1-5 alkyl;
- and
- c) C.sub.1-5 alkyl substituted wth a member of the group consisting of:
- i) phenyl,
- ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy;
- and
- R.sup.2 is selected from hydrogen, C.sub.1-4 alkyl, benzoyl or acetyl;
- wherein the dashed line represents the presence of a second bond, which results in a double bond, or the absence of a second bond;
- and
- wherein at least two R.sup.1, R.sup.3, R.sup.4 or R.sup.5 are hydrogen;
- or a pharmaceutically acceptable salt thereof.
A prodrug of a compound which inhibits farnesyl-protein transferase of the formula I:
- ##STR13## wherein:
- R.sup.1, R.sup.3, R.sup.4 and R.sup.5 are independently selected from:
- a) hydrogen;
- b) C.sub.1-5 alkyl;
- and
- c) C.sub.1-5 alkyl substituted wth a member of the group consisting of:
- i) phenyl,
- ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy;
- R.sup.2 is selected from hydrogen, C.sub.1-4 alkyl, benzoyl or acetyl;
- provided either one or none of R.sup.1, R.sup.3, R.sup.4 or R.sup.5 is hydrogen;
- and
- wherein the dashed line represents the presence of a second bond, which results in a double bond, or the absence of a second bond.
A prodrug of a compound which inhibits farnesyl-protein transferase of the formula II:
- ##STR14## wherein:
- R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently selected from:
- a) hydrogen;
- b) C.sub.1-5 alkyl;
- and
- c) C.sub.1-5 alkyl substituted wth a member of the group consisting of:
- i) phenyl,
- ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy;
- R.sup.2 is selected from hydrogen, C.sub.1-4 alkyl, benzoyl or acetyl;
- provided either one or none of R.sup.1, R.sup.3, R.sup.4, R.sup.5 or R.sup.6 is hydrogen;
- and
- wherein the dashed line represents the presence of a second bond, which results in a double bond, or the absence of a second bond.
Dependencies are inferred from the claim text.