Indole analogs of mevalonolactone and derivatives thereof

• US 5,354,772 A
• Filed: 11/24/1993
• Issued: 10/11/1994
• Est. Priority Date: 11/22/1982
• Status: Expired due to Term

• Current Assignee: Novartis Pharmaceuticals Corporation (Novartis Ag)
• Original Assignee: Sandoz Pharmaceuticals Corp. (Novartis Ag)
• Inventors: Kathawala, Faizulla G.
• Primary Examiner(s): Daus, Donald G.
• Application Number:
  US08/157,595
• Time in Patent Office: 321 Days
• Field of Search: 548/465, 548/467, 548/468, 548/494, 514/414, 514/415, 514/412
• US Class Current: 514/414
• CPC Class Codes: C07D 209/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07F 9/5728 condensed with carbocyclic rings or carbocyclic ring systems

Abstract

Compounds of the formula ##STR1## wherein one of R and R_o is ##STR2## and the other is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom, C_3-6 cycloalkyl or phenyl-(CH₂)_m --,

wherein

R₄ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R_5a is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro, and

m is 1, 2 or 3, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen, R_5a must be hydrogen when R₅ is hydrogen, not more than one of R₄ and R₅ is trifluoromethyl, not more than one of R₄ and R₅ is phenoxy, and not more than one of R₄ and R₅ is benzyloxy,

R₂ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_3-6 cycloalkyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R₃ must be hydrogen when R₂ is hydrogen, not more than one of R₂ and R₃ is trifluoromethyl, not more than one of R₂ and R₃ is phenoxy, and not more than one of R₂ and R₃ is benzyloxy,

X is --(CH₂)_n -- or --CH═CH--, wherein n is 0, 1, 2 or 3, and

Z is ##STR3## wherein R₆ is hydrogen or C_1-3 alkyl, and

R₇ is hydrogen, R_7b or M,

wherein

R_7b is a physiologically acceptable and hydrolyzable ester group, and

M is a pharmaceutically acceptable cation, the use thereof for inhibiting cholesterol biosynthesis and lowering the blood cholesterol level, and therefore, in the treatment of hyperliopoproteinemia and atherosclerosis, pharmaceutical compositions comprising such compounds and processes for and intermediates in the synthesis of such compounds.

Claims

1. A compound of the formula ##STR223## wherein one of R and R_o is and the other is ##STR224## and the other is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom, C_1-3 cycloalkyl or phenyl-(CH₂)_m --,

wherein R₄ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R_5a is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro, or chloro, and

m is 1, 2 or 3, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen, R_5a must be hydrogen when R₅ is hydrogen, not more than one of R₄ and R₅ is trifluoromethyl, not more than one of R₄ and R₅ is phenoxy, and not more than one of R₄ and R₅ is benzyloxy,

R₂ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_3-6 cycloalkyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R₃ must be hydrogen when R₂ is hydrogen, not more than one of R₂ and R₃ is trifluoromethyl, not more than one of R₂ and R₃ is phenoxy, and not more than one of R₂ and R₃ is benzyloxy,

X is --(CH₂)_n -- or --CH═

CH--, wherein n is 0, 1, 2 or 3, and

Z is ##STR225## wherein R₆ is hydrogen or C_1-3 alkyl, and R₇ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, benzyl, or M, wherein M is a cation.

2. A compound according to claim 1 wherein M is a pharmaceutically acceptable cation.

3. A compound according to claim 2 having the formula ##STR226## wherein R₁ is primary or secondary C_1-3 alkyl not containing an asymmetric carbon atom, C_3-6 cycloalkyl or phenyl-(CH₂)_m --, wherein m is 1, 2 or 3,

R₂ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_3-6 cycloalkyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R₃ must be hydrogen when R₂ is hydrogen, not more than one of R₂ and R₃ is trifluoromethyl, not more than one of R₂ and R₃ is phenoxy, and not more than one of R₂ and R₃ is benzyloxy,

R₄ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R_5a is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen, R_5a must be hydrogen when R₅ is hydrogen, not more than one of R₄ and R₅ is trifluoromethyl, not more than one of R₄ and R₅ is phenoxy, and not more than one of R₄ and R₅ is benzyloxy,

R₆ is hydrogen or Cl_1-3 alkyl,

R₇ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, benzyl or M, wherein M is a pharmaceutically acceptable cation, and

X is --(CH₂)_n -- or --CH═

CH--, wherein n is 0, 1, 2 or 3.

4. A compound according to claim 3

wherein

R₁ is primary or secondary C_1-5 alkyl not containing an asymmetric carbon atom,

R₂ is hydrogen or C_1-3 alkyl,

R₃ is hydrogen or Cl_1-3 alkyl, with the proviso that R₃ must be hydrogen when R₂ is hydrogen,

R₄ is hydrogen, C_1-2 alkyl, trifluoromethyl or fluoro,

R₅ is hydrogen or methyl,

R_5a is hydrogen or methyl with the proviso that both R₅ and R_5a must be hydrogen when R₄ is hydrogen and R₅ must be hydrogen when R₅ is hydrogen,

R₆ is hydrogen or methyl,

R₇ is hydrogen, C_1-2 alkyl or M, wherein M is a pharmaceutically acceptable cation, and

X is --CH₂ CH₂ -- or --CH═

CH--.

5. A compound according to claim 3

wherein

R₁ is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom,

R₂ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-2 alkoxy, fluoro or chloro, with the proviso that R₃ must be hydrogen when R₂ is hydrogen,

R₄ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro,

R_5a is hydrogen or methyl, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen and R_5a must be hydrogen when R₅ is hydrogen,

R₆ is hydrogen or C_1-2 alkyl,

R₇ is hydrogen, C_1-3 alkyl or M, wherein M is a pharmaceutically acceptable cation, and

X is --(CH₂)_m -- or ##STR227## wherein m is 1, 2 or 3.

6. A compound according to claim 5

wherein

R₁ is C_1-3 alkyl,

R₂ is hydrogen, C_1-3 alkyl, methoxy, fluoro, chloro or 4-, 5- or 6-benzyloxy,

R₃ is hydrogen or C_1-3 alkyl, with the proviso that R₃ must be hydrogen when R₂ is hydrogen,

R₄ is hydrogen, methyl, methoxy, fluoro or chloro,

R₅ is hydrogen, methyl, methoxy, fluoro or chloro,

R_5a is hydrogen or methyl, with the proviso that both R₅ and R_5a must be hydrogen when R₄ is hydrogen and R_5a must be hydrogen when R₅ is hydrogen,

R₆ is hydrogen,

R₇ is hydrogen, C_1-2 alkyl or M, wherein M is a pharmaceutically acceptable cation, and

X is --CH₂ CH₂ -- or ##STR228##

7. A compound according to claim 6 having the formula ##STR229## wherein M.sup.⊕

is a pharmaceutically acceptable cation.

8. A compound to claim 7 in racemic erythro form.

9. The compound according to claim 7 having the formula ##STR230##

10. The compound according to claim 9 having the 3R,5S configuration.

12. A compound according to claim 2 having the formula ##STR232## wherein R₁ is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom, C_3-6 cycloalkyl or phenyl-(CH₂)_m --, wherein m is 1, 2 or 3,

R₂ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_3-6 cycloalkyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R₃ must be hydrogen when R₂ is hydrogen, not more than one of R₂ and R₃ is trifluoromethyl, not more than one of R₂ and R₃ is phenoxy, and not more than one of R₂ and R₃ is benzyloxy,

R₄ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R_5a is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen, R_5a must be hydrogen when R₅ is hydrogen, not more than one of R₄ and R₅ is trifluoromethyl, not more than one of R₄ and R₅ is phenoxy, and not more than one of R₄ and R₅ is benzyloxy,

R₆ is hydrogen or C_1-3 alkyl, and

X is --(CH₂)_n -- or --CH═

CH--, wherein n is 0, 1, 2 or 3.

13. A compound according to claim 12

wherein

R₁ is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom,

R₂ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-2 alkoxy, fluoro or chloro, with the proviso that R₃ must be hydrogen when R₂ is hydrogen,

R₄ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro,

R_5a is hydrogen or methyl, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen and R_5a must be hydrogen when R₅ is hydrogen,

R₆ is hydrogen or C_1-2 alkyl, and

X is ##STR233## wherein m is 1, 2 or 3.

14. A compound according to claim 2 having the formula ##STR234## wherein R₁ is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom, C_3-6 cycloalkyl or phenyl-(CH₂)_m --, wherein m is 1, 2 or 3,

R₂ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_3-6 cycloalkyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R₃ must be hydrogen when R₂ is hydrogen, not more than one of R₂ and R₃ is trifluoromethyl, not more than one of R₂ and R₃ is phenoxy, and not more than one of R₂ and R₃ is benzyloxy,

R₄ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R_5a is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen, R_5a must be hydrogen when R₅ is hydrogen, not more than one of R₄ and R₅ is trifluoromethyl, not more than one of R₄ and R₅ is phenoxy, and not more than one of R₄ and R₅ is benzyloxy,

R₆ is hydrogen or C_1-3 alkyl,

R₇ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, benzyl or M, wherein M is a pharmaceutically acceptable cation, and

X is --(CH₂)_n -- or --CH═

CH--, wherein n is 0, 1, 2 or 3.

15. A compound according to claim 14

wherein

R₁ is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom,

R₂ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-2 alkoxy, fluoro or chloro, with the proviso that R₃ must be hydrogen when R₂ is hydrogen,

R₄ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro,

R_5a is hydrogen or methyl, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen and R_5a must be hydrogen when R₅ is hydrogen,

R₆ is hydrogen or C_1-2 alkyl,

R₇ is hydrogen, C_1-3 alkyl or M, wherein M is a pharmaceutically acceptable cation, and

X is ##STR235## wherein m is 1, 2 or 3.

16. A compound according to claim 2 having the formula ##STR236## wherein R₁ is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom, C_3-6 cycloalkyl or phenyl-(CH₂)_m --, wherein m is 1, 2 or 3,

R₂ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_3-6 cycloalkyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R₃ must be hydrogen when R₂ is hydrogen, not more than one of R₂ and R₃ is trifluoromethyl, not more than one of R₂ and R₃ is phenoxy, and not more than one of R₂ and R₃ is benzyloxy,

R₄ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R_5a is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen, R_5a must be hydrogen when R₅ is hydrogen, not more than one of R₄ and R₅ is trifluoromethyl, not more than one of R₄ and R₅ is phenoxy, and not more than one of R₄ and R₅ is benzyloxy,

R₆ is hydrogen or C_1-3 alkyl, and

X is --(CH₂)_n -- or --CH═

CH--, wherein n is 0, 1, 2 or 3.

17. A compound according to claim 16

wherein

R₁ is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom,

R₂ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-2 alkoxy, fluoro or chloro, with the proviso that R₃ must be hydrogen when R₂ is hydrogen,

R₄ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro,

R_5a is hydrogen or methyl, with the provisos that both R₅ and R_5a a must be hydrogen when R₄ is hydrogen and R_5a must be hydrogen when R₅ is hydrogen,

R₆ is hydrogen or C_1-2 alkyl, and

X is ##STR237## wherein m is 1, 2 or 3.

18. A pharmaceutical composition comprising an effective amount of a compound according to claim 2 and a pharmaceutically acceptable carrier, said effective amount being an amount sufficient to inhibit cholesterol biosynthesis in a mammal.

19. A pharmaceutical composition according to claim 18 wherein the compound is a compound of the formula ##STR238## wherein M.sup.⊕

is a pharmaceutically acceptable cation.

20. A pharmaceutical composition according to claim 19 wherein the compound is a compound of the formula ##STR239## wherein M.sup.⊕

is a pharmaceutically acceptable cation, in racemic erythro form.

21. A pharmaceutical composition according to claim 20 wherein the compound is the compound of the formula ##STR240## in racemic erythro form.

22. A method of inhibiting cholesterol biosynthesis comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 2, said effective amount being an amount effective for inhibiting cholesterol biosynthesis.

23. A method of inhibiting cholesterol biosynthesis according to claim 22 wherein the compound is a compound of the formula ##STR241## wherein M.sup.⊕

is a pharmaceutically acceptable cation.

24. A method of inhibiting cholesterol biosynthesis according to claim 23 wherein the compound is a compound of the formula ##STR242## wherein M.sup.⊕

is a pharmaceutically acceptable cation, in racemic erythro form.

25. A method of inhibiting cholesterol biosynthesis according to claim 24 wherein the compound is the compound of the formula ##STR243## in racemic erythro form.

26. A method of treating atherosclerosis comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 2, said effective amount being an amount effective for the treatment of atherosclerosis.

27. A method of treating atherosclerosis according to claim 26 wherein the compound is a compound of the formula ##STR244## wherein R₁ is primary or secondary C_1-6 alkyl not containing an asymmetric carbon atom, C_3-6 cycloalkyl or phenyl-(CH₂)_m --, wherein m is 1, 2 or 3,

R₂ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_3-6 cycloalkyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₃ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R₃ must be hydrogen when R₂ is hydrogen, not more than one of R₂ and R₃ is trifluoromethyl, not more than one of R₂ and R₃ is phenoxy, and not more than one of R₂ and R₃ is benzyloxy,

R₄ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, C_1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R₅ is hydrogen, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R_5a is hydrogen, C_1-2 alkyl, C_1-2 alkoxy, fluoro or chloro, with the provisos that both R₅ and R_5a must be hydrogen when R₄ is hydrogen, R_5a must be hydrogen when R₅ is hydrogen, not more than one of R₄ and R₅ is trifluoromethyl, not more than one of R₄ and R₅ is phenoxy, and not more than one of R₄ and R₅ is benzyloxy,

R₆ is hydrogen or C_1-3 alkyl,

R₇ is hydrogen, C_1-3 alkyl, n-butyl, i-butyl, t-butyl, benzyl or M, wherein M is a pharmaceutically acceptable cation, and

X is --(CH₂)_n -- or --CH═

CH-- wherein n is 0, 1, 2 or 3.

28. A method of treating atherosclerosis according to claim 27 wherein the compound is a compound of the formula ##STR245## wherein M.sup.⊕

is a pharmaceutically acceptable cation.

29. A method of treating atherosclerosis according to claim 28 wherein the compound is a compound of the formula ##STR246## wherein M.sup.⊕

is a pharmaceutically acceptable cation, in racemic erythro form.

30. A method of treating atherosclerosis according to claim 29 wherein the compound is the compound of the formula ##STR247## in racemic erythro form.

11. The compound of the formula ##STR231## in racemic erythro form.