Cycloalkyl amine bis-aryl squalene synthase inhibitors

• US 5,451,596 A
• Filed: 12/29/1992
• Issued: 09/19/1995
• Est. Priority Date: 12/29/1992
• Status: Expired due to Fees

• Current Assignee: Rhone-Poulenc Rorer Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Original Assignee: Rhone-Poulenc Rorer Pharmaceuticals Incorporated (Sanofi-Aventis U.S., LLC)
• Inventors: Ullrich, John W., Kiesow, Terence J., Learn, Keith S., Dankulich, William P., Neuenschwander, Kent W., Scotese, Anthony C.
• Primary Examiner(s): DAUS, DONALD G
• Application Number:
  US07/997,818
• Time in Patent Office: 994 Days
• Field of Search: 514/395, 548/217
• US Class Current: 514/375
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 217/52 having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 263/57 Aryl or substituted aryl radicals
• CPC Class Codes: C07D 277/66 with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 307/80 Radicals substituted by oxygen atoms

Abstract

This invention relates to a class of novel polycyclic compounds containing a cycloalkyl ring having substituted thereon a primary amine and which is further linked or bridged to two mono- and/or bicyclic rings and which reduces levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention.

Claims

1. A compound of the formula:

##STR10## where;

Ar I is phenylene;

Ar II is benzoxazolyl;

A is O, S, NR, SO, SO₂, NR--C═

O, O═

C--NR, RC═

CR, C.tbd.C or a bond;

B is (CR₂)_e, O, S, NR, O═

C, SO, SO₂ or a bond;

one of X or Y is R'"'"'";

one of X or Y is H₂ N--(CR₂)_z --;

a and b are independently 0-4 and a+b=0-4;

e is 1-2;

m and n are independently 0-2;

x is 1-6;

y is 0-2;

x+y is 1-6;

z is 0-3;

R'"'"' is hydrogen, C_1-6 -alkyl or hydroxy;

R" is hydrogen, C_1-6 -alkyl or hydroxy;

R'"'"'" is hydrogen, C_1-6 -alkyl, hydroxy or carboxy;

one set of vicinal R" and R'"'"'" groups may form a double bond when x+y=3-6;

R is hydrogen or C_1-6 -alkyl;

R¹ and R² are independently hydrogen, C_1-6 -alkyl, C_1-6 -alkoxy, hydroxy, chloro, fluoro, bromo, trifluoromethyl, amino or mono-or di-C_1-6 -alkylamino; and

its stereoisomers, enantiomers, diastereoisomers and racemic mixtures;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 of the formula:

##STR11##

3. A compound according to claim 1 of the formula:

##STR12##

4. A compound according to claim 2 where:

Ar I is phenylene and

Ar II is benzoxazolyl

where;

R¹ and R² are independently hydrogen, C_1-6 -alkyl, C_1-6 -alkoxy, hydroxy, chloro, fluoro, bromo, trifluoromethyl;

R³ and R⁴ together are O--CH₂ --CH₂, O--CH₂ --CH₂ --CH₂, O--CH₂ --O or O--CH₂ --CH₂ --O;

R'"'"' is hydrogen, C_1-6 -alkyl or hydroxy;

R" is hydrogen, C_1-6 -alkyl or hydroxy; and

R'"'"'" is hydrogen, C_1-6 -alkyl, hydroxy or carboxy.

5. A compound according to claim 3 where:

Ar I is phenylene and

Ar II is benzoxazolyl

where;

R¹ and R² are independently hydrogen, C_1-6 -alkyl, C_1-6 -alkoxy, hydroxy, chloro, fluoro, bromo, trifiuoromethyl;

R³ and R⁴ together are O--CH₂ --CH₂, O--CH₂ --CH₂ --CH₂, O--CH₂ --O or O--CH₂ --CH₂ --O;

R'"'"' is hydrogen, C_1-6 -alkyl or hydroxy;

R" is hydrogen, C_1-6 -alkyl or hydroxy; and

R'"'"'" is hydrogen, C_1-6 -alkyl, hydroxy or carboxy.

6. A compound according to claim 4 of the formula ##STR13## where:

A is O, S, NR, CH═

CH or a bond;

B is (CR₂)_e, O═

C, O, S, NR or a bond;

a and b are independently 0-3 and a+b═

0-3;

e is 1-2;

m and n are independently 0-2;

x is 1-6;

y is 0-2;

x+y is 1-6;

z is 0-3;

R'"'"' is hydrogen, C_1-6 -alkyl or hydroxy;

R'"'"'" is hydrogen, C_1-6 -alkyl, hydroxy or carboxy;

R" is hydrogen, C_1-6 -alkyl or hydroxy;

one set of vicinal R" and R'"'"'" groups may form a double bond when x+y=3-6;

R is hydrogen or C_1-6 -alkyl; and

R¹ and R² are independently hydrogen, C_1-6 -alkyl, C_1-6 -alkoxy, hydroxy, chloro, fluoro, bromo or trifluoromethyl.

7. A compound according to claim 5 of the formula ##STR14## where:

A is CH═

CH, O, S, NR or a bond;

B is (CR₂)_e, O═

C, O, S, NR or a bond;

a and b are independently 0-3 and a+b═

0-3;

e is 1-2;

m and n are independently 0-2;

x is 1-6;

y is 0-2;

x+y is 1-6;

z is 0-3;

R'"'"' is hydrogen, C_1-6 -alkyl or hydroxy;

R" is hydrogen, C_1-6 -alkyl or hydroxy;

R'"'"'" is hydrogen, C_1-6 -alkyl, hydroxy or carboxy;

one set of vicinal R" and R'"'"'" groups may form a double bond when x+y=3-6;

R is hydrogen or C_1-6 -alkyl; and

R¹ and R² are independently hydrogen, C_1-6 -alkyl, C_1-6 -alkoxy, hydroxy, chloro, fluoro, bromo or trifluoromethyl.

8. A compound according to claim 6 where:

A is O or a bond;

B is a bond;

a is 0-1;

b is 0-1;

m and n are independently 0-1;

x is 1-6;

y is 0-2;

x+y is 1-6;

z is 0-1;

R, R'"'"', R", R'"'"'" and R¹ are hydrogen or hydroxy; and

R² is hydrogen, C_1-6 -alkyl, C_1-6 -alkoxy or chloro, fluoro or bromo.

9. A compound according to claim 7 where:

A is O or a bond;

B is a bond;

a is 0-1;

b is 0-1;

m and n are independently 0-1;

x is 1-6;

y is 0-2;

x+y is 1-6;

z is 0-1;

R, R'"'"', R", R'"'"'" and R¹ are hydrogen or hydroxy; and

R² is hydrogen, C_1-6 -alkyl, C_1-6 -alkoxy or chloro, fluoro or bromo.

10. A compound according to claim 6 which is trans-2-[4-(benzoxazol-2-yl)benzyloxy]cyclohexylamine or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 6 which is cis-2-[(4-benzoxazol-2-yl)benzyloxy]cyclohexylamine or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 6 which is trans-2-amino-[4-(benzoxazol -2-yl)benzyloxy]cyclopentane or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 6 which is trans-2-(4-[benzoxazol-2-yl]benzyloxy)cycloheptylamine or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 7 which is 2α

-hydroxy-3β

[(4-benzoxazol-2-yl)benzyloxy]cyclohexyl-1β

-amine or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 7 which is 2β

-hydroxy-3β

[(4-benzoxazol-2-yl)benzyloxy]cyclohexyl-1α

-amine or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 7 which is 1-amino-[4-(benzoxazol-2-yl)benzyloxymethyl]cyclopentane or a pharmaceutically acceptable salt thereof.

17. A method of lowering or maintaining reduced cholesterol levels in a patient requiring such treatment which comprises administering to such patient a squalene synthase inhibitor effective amount of a compound of the formula according to claim 1.

18. A method for inhibiting cholesterol biosynthesis which comprises administering to a patient in need of such inhibition a squalene synthase inhibiting effective amount of a compound according to claim 1.

19. A method according to claim 18 where the patient is in need of a hypocholesterolemic or hypolipidemic agent.

20. A method according to claim 19 for treating atherosclerosis.

21. A pharmaceutical composition comprising a squalene synthetase inhibitor effective amount of a compound according to claim 1 in admixture with a pharmaceutical carrier.

22. A pharmaceutical composition according to claim 21 which further includes an HMG CoA reductase inhibitor.