Novel squalene synthetase inhibitors

• US 5,102,907 A
• Filed: 09/13/1990
• Issued: 04/07/1992
• Est. Priority Date: 09/13/1990
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Dufresne, Claude, Huang, Leeyuan, Bergstrom, James D., Onishi, Janet C., Nallin, Mary
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): CHANG, CELIA C
• Application Number:
  US07/582,452
• Time in Patent Office: 572 Days
• Field of Search: 549/363, 514/456
• US Class Current: 514/456
• CPC Class Codes: C07D 493/08 Bridged systems

Abstract

This invention relates to compounds of structural formula (I): ##STR1## which are squalene synthetase inhibitors and thus useful as cholesterol lowering agents.

Claims

1. A compound of structural formula (I) ##STR6## wherein Z₁ Z₂ and Z₃ are each independently selected from a) H;

b) C_1-5 alkyl;

c) C_1-5 alkyl substituted with a member of the group consisting of

i) phenyl,

ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, I, F) or hydroxy;

or a pharmaceutically acceptable salt of a compound of formula (I).

2. A compound of claim 1 wherein the stereochemical configuration of structural formula (I) is selected from the group consisting of:

##STR7##

3. A compound of claim 2 wherein the stereochemical configuration within structural formula (I) is selected from the group consisting of:

##STR8##

4. A compound of claim 3 wherein the stereochemical configuration of structural formula (I) is selected from the group consisting of:

##STR9##

5. A compound of claim 4 in which Z₁, Z₂ and Z₃ are each hydrogen or a pharmaceutically acceptable salt thereof.

6. A compound of claim 4 in which Z₁, Z₂ and Z₃ are each methyl.

7. A compound of claim 1 which is:

##STR10##

9. A pharmaceutical composition comprising a nontoxic anti-cholesterolemically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

10. A composition of claim 9 wherein the therapeutically effective compound is selected from the group consisting of:

##STR11##

11. A method of treating hypercholesterolemia comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of claim 1.

12. A method of claim 11 wherein the therapeutically effective compound is selected from the group consisting of:

##STR12##

8. A compound of molecular formula C₄₀ H₅₀ O₁₄ and molecular weight 754 characterized by the

(a) ¹³ C NMR chemical shifts, as measured in CD₃ OD at 22°

C.;

173.06, 173.04, 172.43, 170.14, 168.46, 143.84, 141.88, 138.78, 130.15 (2×

), 129.36 (2×

), 129.24 (4×

), 127.53, 126.89, 126.61, 107.17, 90.94, 82.15, 81.11, 78.10, 76.57, 75.56, 40.46, 39.62, 37.77, 37.56, 36.87, 36.21, 35.34, 32.43, 30.44, 28.75, 21.25, 21.13, 20.08, 14.32 ppm.

(b) ¹ H NMR chemical shifts, as measured in CD₃ OD at 22°

C.;

7.22 (m, 4H), 7.13 (m, 6H), 6.23 (d, 1.8), 5.36 (m, 2H), 5.24 (s), 4.88 (q, 3.9), 4.03 (d, 1.8), 2.73 (dd, 13.3, 5.6 Hz), 2.54 (t, 7.6, 2H), 2.3 (m, 5H), 2.04 (s, 3H), 2.04 (m, 2H), 1.89 (br t, 7.0, 2H), 1.6 (m, 5H), 1.27 (m, 2H), 0.93 (d, 6.8, 3H), 0.86 (d, 6.8, 3H), ppm.