Phosphorus-containing squalene synthetase inhibitors and method for their preparation

Abstract

Abstract Compounds which are inhibitors of cholesterol biosynthesis (by inhibiting de novo squalene biosynthesis), and thus are useful as hypocholesterolemic agents and anti atherosclerotic agents are provided which have the structure wherein m is 1, 2 or 3; n is 0, 1, 2 or 3; Y 1 and Y 2 are H or halogen; R 2 , R 3 and R 4 may be the same or different and are independently H, metal ion, C 1 to C s alkyl or C 3 to C 12 alkenyl; X is O, S, NH or NCH 2 R 15 wherein R 15 is H or C 1 to C 5 alkyl; and R 1 is R 5 -Q 1 -Q 2 -Q 3 - wherein Q 1 , Q 2 and Q 3 are the same or different and are independently or a single bond, with the proviso that if Q 1 is a bond, then Q 2 and Q 3 are bonds and if Q 2 is a bond, then Q 3 is a bond, and wherein R 6 is H, alkyl, halo, or haloalkyl, R 7 is H, halo, alkyl or alkylthio; R 8 is H, halogen, trimethylsilyl or lower alkyl; R 9 is H or lower alkyl-; R 16 -C≡C-CH 2 - (wherein R 16 is H or lower alkyl) or CH 3 (CH 2 )p where p is an integer from 2 to 7; R 10 , and R" are the same or different and are independently H, lower alkyl, halogen, haloalkyl or lower alkenyl or R 10 and R 11 can be taken together to form (CH 2 ) s where s is an integer from 2 to 7; and R 13 an R 14 are the same or different and are independently lower alkyl, with the proviso that if all of Q 1 , Q 2 and Q 3 are bonds, then both R 10 and R" cannot be H and R 5 cannot be alkyl(CH 2 ) P - with p≦4; including all stereoisomers thereof. New intermediates, new methods of preparation and a method for using such compounds to inhibit cholesterol biosynthesis are also provided.

Inventors

• 👤 Scott Adams Biller
• 👤 Michael Joseph Sofia

Bibliographic Details