IP Library › Granted Patent US 6,949,661
Granted Patent B2
US 6,949,661 · App. 10/672,849 · Granted Sep 27, 2005

3-substituted-3-(substitutedsulfonyl or sulfanyl) pyrrolidine-2,5-diones useful for inhibition of farnesyl-protein transferase

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Quick Facts
Patent No.
US 6,949,661
App. No.
10/672,849
Granted
Sep 27, 2005
Kind
B2
Abstract

The invention relates to compounds of Formula (I), to processes for their preparation and pharmaceutical compositions thereof, that inhibit the Ras farnesyl-protein transferase enzyme (FPTase), and may be used as an alternative to, or in conjunction with, traditional cancer therapy for the treatment of ras oncogene-dependent tumors, such as cancers of the pancreas, colon, bladder, and thyroid.

Claims (20)

1. A process for the preparation of a compound of Formula (I).

wherein:

R 1 is a moiety

R 2 is a moiety

n is an integer of 1 and 3-9;

m is an integer of 0 or 2;

R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, halogen, nitro, trifluoromethoxy, phenoxy optionally mono or di substituted, and benzyloxy optionally mono or di substituted;

R 5 , and R 6 , are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, halogen, nitro, phenyl optionally mono or di-substituted, phenoxy optionally mono or di-substituted, trifluoromethyl, trifluoromethoxy, and methanesulphonyl wherein mono or di-substitutents of phenyl, phenoxy, or benzyloxy are independently selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, halogen, nitro, trifluoromethyl, trifluoromethoxy, methanesulphonyl, and phenyl;

or a pharmaceutically acceptable salt thereof,

which comprises

reacting a compound of the formula

with an alkyne of the formula

wherein LG is a leaving group

in the presence of a base to give a compound of Formula (I)

or a pharmaceutically acceptable salt thereof.

2. The process according to claim 1 wherein the base is selected from alkali metal hydrides, alkali metal alkyls and alkali metal amide bases.

3. The process according to claim 2 where the alkali metal hydride is sodium hydride.

4. The process according to claim 2 wherein the alkali metal alkyl is butyl lithium.

5. The process according to claim 2 wherein the alkali metal amide base is selected from lithium diisopropylamide and lithium bis(trimethylsilyl)amide.

6. The process according to claim 1 wherein the leaving group is p-toluenesulfonyloxy, iodo or bromo.