HMG-CoA reductase inhibitors and method

• US 7,420,059 B2
• Filed: 11/15/2004
• Issued: 09/02/2008
• Est. Priority Date: 11/20/2003
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Shi, Yan, Robl, Jeffrey, O'Connor, Stephen P.
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US10/989,138
• Publication Number:
  US 20050171140A1
• Time in Patent Office: 1,387 Days
• Field of Search: 546/23, 546/113
• US Class Current: 546/23
• CPC Class Codes: C07D 211/76 attached in position 2 or 6
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Compounds are provided having the following structure

and pharmaceutically acceptable salts thereof,

wherein R₁, R₂, R₃, R₄, U, V, W, Y, and n are as defined above,

• • which compounds are HMG CoA reductase inhibitors and thus are active in inhibiting cholesterol biosynthesis, modulating blood serum lipids, for example, lowering LDL cholesterol and/or increasing HDL cholesterol, and treating hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia and atherosclerosis as well as Alzheimer'"'"'s disease and osteoporosis and may be employed as hormone replacement therapy.

A method for treating the above diseases employing the above compounds is also provided.

Claims

1. A compound having the structure

5. The compound as defined in claim 1 wherein R₁ is aryl;

and R₂ is selected from alkyl or cycloalkyl;

R₄ is H;

n is 0.

16. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

2. A compound having the structure

3. The compound as defined in claim 2 wherein U, V, W and Y are as defined below.

4. The compound as defined in claim 2 where the A group is in the form of a free acid, a physiologically acceptable and hydrolyzable ester or δ

lactone thereof, or an alkali metal salt, alkaline earth metal salt or an amino acid salt.

6. The compound as defined in claim 4 wherein R₁ is phenyl which contains 1 or 2 substituents,

R₂ is alkyl or cycloalkyl;

R₄ is H; and

7. The compound as defined in claim 6 wherein R₁ is 4-fluorophenyl, 4-fluoro-3-methylphenyl, or 3,5-dimethylphenyl;

and

R₂ is isopropyl, t-butyl or cyclopropyl.

8. The compound as defined in claim 2 wherein A has the structure

9. The compound as defined in claim 2 in the form of its calcium salt, sodium salt or arginine salt.

10. The compound as defined in claim 2 where

R₁ is aryl;

R₂ is alkyl or cycloalkyl;

11. The compound as defined in claim 2 wherein

12. The compound as defined in claim 2 wherein

R₁ is 4-fluorophenyl,

R₂ is isopropyl,

R₃ is selected from SO₂CH₃, SO₂CH₂CH₃, SO₂(1-methylimidazol-4-yl), SO₂CH(CH₃)₂, SO₂Ph, C(O)CH₃, or CH₃,

R₄ is H,

U is selected from C═

O, a bond or —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

V is selected from a bond or —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

W is —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

Y is selected from C═

O or —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by a ‘

alkyl substituent’

,

n is 0 and

A is

13. The compound as defined in claim 2 wherein

R₁ is 4-fluorophenyl;

R₂ is isopropyl;

R₃ is selected from SO₂CH₃, SO₂CHCH₃, SO₂(1-methylimidazol-4-yl), SO₂CH(CH₃), SO₂Ph, C(O)CH₃ or CH₃;

R₄ is H; and

U, V, W mid Y are —

CH₂CH₂—

, —

CH₂CH₂ CH₂—

, —

CH₂CH₂CH₂CH₂—

, or

14. The compound defined in claim 2 having the structure

17. A method for treating hypercholesterolemia, dyslipidemia, hyperlipidemia, hyperlipoproteinemia, LDL Pattern B, LDL Pattern A, or hypertriglyceridemia for inhibiting cholesterol biosynthesis or lowering blood serum cholesterol levels and/or modulating blood serum cholesterol levels, lowering LDL cholesterol and/or increasing HDL cholesterol, or treating dyslipidemia, mixed dyslipidemia, LDL Pattern B, LDL Pattern A, hyperlipidemia, hypercholesterolemia, hypo oc-lipoproteinemia, hyperlipoproteinemia or hypertriglyceridemia, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 2.

15. A compound having the structure