Heteroacetic acid derivatives

• US 5,401,772 A
• Filed: 11/18/1993
• Issued: 03/28/1995
• Est. Priority Date: 07/21/1992
• Status: Expired due to Term

• Current Assignee: Novartis Corporation (Novartis Ag)
• Original Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Inventors: Walker, Gordon N., Yokoyama, deceased, Naokata, Main, Alan J.
• Primary Examiner(s): Dees, Jose G.
• Assistant Examiner(s): BARTS, SAMUEL A
• Application Number:
  US08/154,203
• Time in Patent Office: 495 Days
• Field of Search: 514/534, 514/563, 514/616, 514/619, 514/539
• US Class Current: 514/539
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: C07C 229/18 the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• CPC Class Codes: C07C 233/56 having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
• CPC Class Codes: C07C 323/52 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07J 41/0055 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives

Abstract

Disclosed are compounds of formula ##STR1## wherein R is hydroxy, esterified hydroxy or etherified hydroxy;

R₁ is halogen, trifluoromethyl or lower alkyl;

R₂ is halogen, trifluoromethyl or lower alkyl;

R₃ is halogen, trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl or cycloalkyl-lower alkyl; or

R₃ is the radical ##STR2## wherein R₈ is hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkyl or cycloalkyl-lower alkyl; R₉ is hydroxy or acyloxy; R₁₀ represents hydrogen or lower alkyl; or R₉ and R₁₀ together represent oxo;

R₄ is hydrogen, halogen, trifluoromethyl or lower alkyl;

X is --NR₇, S or O;

W is O or S;

R₅ represents hydrogen, lower alkyl or aryl-lower alkyl;and

R₆ represents hydrogen; or

R₅ and R₆ together represent oxo provided that X represents --NR_7;

R₇ represents hydrogen or lower alkyl;

Z represents carboxyl, carboxyl derivatized as a pharmaceutically acceptable ester or as a pharmaceutically acceptable amide; and pharmaceutically acceptable salts thereof; which are useful as hypocholesteremic agents.

Claims

1. A method of treating hypercholesterolemia in mammals which comprises administering to a mammal in need of such treatment an effective cholesterol-lowering amount of a compound of the formula ##STR17## wherein R is hydroxy, esterified hydroxy or etherified hydroxy;

R₁ is halogen, trifluoromethyl or lower alkyl;

R₂ is halogen, trifluoromethyl or lower alkyl;

R₃ is halogen, trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl or cycloalkyl-lower alkyl;

or

R₃ is the radical ##STR18## wherein R₈ is hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkyl or cycloalkyl-lower alkyl;

R₉ is hydroxy or acyloxy;

R₁₀ represents hydrogen or lower alkyl;

or R₉ and R₁₀ together represent oxo;

R₄ is hydrogen, halogen, trifluoromethyl or lower alkyl;

X is --NR₇ ;

W is O or S;

R₅ and R₆ together represent oxo;

R₇ represents hydrogen or lower alkyl;

Z represents carboxyl, carboxyl derivatized as a pharmaceutically acceptable ester or as a pharmaceutically acceptable amide; and

aryl in any of the above definitions represents carbocyclic aryl;

or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1 which comprises administering a compound of formula I wherein R is located at the 4'"'"'-position, R₁ and R₂ are located at the 3 and 5 positions, and R₃ and R₄ are located at the 3'"'"' and 5'"'"'-positions;

or a pharmaceutically acceptable salt thereof.

3. A method according to claim 1 which comprises administering a compound of formula I wherein X and W represent O.

4. A method according to claim 1 which comprises administering a compound of the formula ##STR19## wherein R is hydroxy, esterified hydroxy or etherified hydroxy;

R₁ and R₂ independently represent halogen, trifluoromethyl or C₁ -C₃ alkyl;

R₃ represents lower alkyl, lower alkanoyl, hydroxy-lower alkyl, carbocyclic arylmethyl, carbocyclic aroyl or carbocyclic aryl-hydroxymethyl;

R₅ and R₆ together represent oxo;

R₇ represents hydrogen or lower alkyl; and

Z represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester or amide;

or a pharmaceutically acceptable salt thereof.

5. A method of treating hypercholesterolemia in mammals which comprises administering to a mammal in need of such treatment an effective cholesterol-lowering amount of a compound of the formula ##STR20## wherein R is hydroxy, esterified hydroxy or etherified hydroxy;

R₁ represents halogen, trifluoromethyl or C₁ -C₃ alkyl;

R₂ represents halogen, trifluoromethyl or C₁ -C₃ alkyl;

R₃ represents lower alkyl, carbocyclic aroyl, carbocyclic arylmethyl or carbocyclic aryl-hydroxymethyl;

R₇ represents hydrogen or lower alkyl;

Z represents carboxyl or carboxyl derivatized as a pharmaceutically acceptable ester or amide;

or a pharmaceutically acceptable salt thereof.

6. A method according to claim 5 which comprises administering a compound of formula III wherein R represents hydroxy, acyloxy, lower alkoxy or tetrahydropyranyloxy;

or of a pharmaceutically acceptable salt thereof.

7. A method according to claim 5 which comprises administering a compound of formula III wherein R is hydroxy, lower alkanoyloxy, lower alkoxy or tetrahydropyranyloxy;

R₁ and R₂ represent halo or C₁ -C₃ -alkyl;

R₃ is C₁ -C₃ -alkyl or monocyclic carbocyclic arylmethyl;

R₇ is hydrogen or C₁ -C₂ -alkyl;

Z is carboxyl or carboxyl derivatized as a pharmaceutically acceptable ester or amide;

or a pharmaceutically acceptable salt thereof.

8. A method according to claim 5 which comprises administering a compound of formula III wherein Z is carboxyl or carboxyl esterified as a pharmaceutically acceptable ester;

or a pharmaceutically acceptable salt thereof.

9. A method according to claim 5 which comprises administering a compound of formula III wherein R₁ and R₂ represent chloro or methyl;

R₃ is isopropyl, benzyl or benzyl substituted by halogen, lower alkyl, lower alkoxy or trifluoromethyl;

R₇ is hydrogen;

Z is carboxyl or lower alkoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

10. A method according to claim 9 which comprises administering N-[3,5-dimethyl-4-(4'"'"'-hydroxy-3'"'"'-isopropylphenoxy)-phenyl]-oxamic acid or a pharmaceutically acceptable salt thereof.

11. A method according to claim 9 which comprises administering N-[3,5-dichloro-4-(4'"'"'-hydroxy-3'"'"'-isopropylphenoxy)-phenyl]-oxamic acid or a pharmaceutically acceptable salt thereof.

12. A method according to claim 5 which comprises administering a compound of formula III wherein R is hydroxy, lower alkanoyloxy, lower alkoxy or tetrahydropyranyloxy;

R₁ and R₂ represent halo or C₁ -C₃ -alkyl;

R₃ is carbocyclic aroyl or carbocyclic aryl-hydroxymethyl;

R₇ is hydrogen or C₁ -C₂ -alkyl;

Z is carboxyl or carboxyl derivatized as a pharmaceutically acceptable ester or amide;

or a pharmaceutically acceptable salt thereof.

13. A method according to claim 5 which comprises administering a compound of formula III wherein R is hydroxy;

R₁ and R₂ represent chloro or methyl;

R₃ is phenyl-hydroxymethyl or phenyl-hydroxymethyl substituted on phenyl by halogen, lower alkyl, lower alkoxy or trifluoromethyl;

or R₃ is benzoyl or benzoyl substituted by halogen, lower alkyl, lower alkoxy or trifluoromethyl;

R₇ is hydrogen;

Z is carboxyl or lower alkoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

14. A method according to claim 13 which comprises administering ethyl N-[4-[3'"'"'-[(4-fluorophenyl)hydroxymethyl]-4'"'"'-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate or an enantiomer thereof.

15. A method according to claim 13 which comprises administering N-[4-[3'"'"'-[(4-fluorophenyl)hydroxymethyl]-4'"'"'-hydroxyphenoxy]-3,5-dimethylphenyl]oxamic acid, an enantiomer thereof or a pharmaceutically acceptable salt thereof.