Phosphonic diester derivatives

• US 5,985,858 A
• Filed: 06/26/1998
• Issued: 11/16/1999
• Est. Priority Date: 12/27/1995
• Status: Expired due to Fees

• Current Assignee: Otsuka Pharmaceutical Factory Incorporated (Otsuka Holdings Company Limited)
• Original Assignee: Otsuka Pharmaceutical Factory Incorporated (Otsuka Holdings Company Limited)
• Inventors: Miki, Shinya, Sato, Keigo, Sakai, Yasuhiro, Inoue, Yasuhide, Miyata, Kazuyoshi, Tsuda, Yoshihiko, Shoji, Yasuo
• Primary Examiner(s): AMBROSE, MICHAEL GEORGE
• Application Number:
  US09/091,946
• Time in Patent Office: 508 Days
• Field of Search: 514/85, 514/92, 514/95, 544/337, 548/119, 549/6
• US Class Current: 514/95
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: C07F 9/650952 having the nitrogen atoms in the positions 1 and 4
• CPC Class Codes: C07F 9/6539 Five-membered rings
• CPC Class Codes: C07F 9/655345 the sulfur atom being part of a five-membered ring
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

A phosphonic diester derivative represented by the following formula (1): ##STR1## wherein R¹ represents a cycloalkyl group; a phenyl group which may have 1 to 3 substituents selected from the group consisting of a lower alkoxy group, a lower alkyl group, a halogen atom, a halogen-substituted lower alkyl group, a lower alkanoyl group, a nitro group, a benzoyl group, a cyano group, an N-lower alkylcarbamoyl group, an N-phenyl-lower alkylcarbamoyl group, an N-(halogen-substituted phenyl)carbamoyl group and an N,N-di-lower alkylcarbamoyl group; a 1,3,4-thiadiazol-2-yl group having a halogen-substituted lower alkyl group as a substituent; a thiazolyl group; a pyridyl group which may be substituted by a halogen atom; a benzothiazol-2-yl group having 1 to 2 lower alkoxy groups on the phenyl ring; or a 4,5-dihydrothieno[3,2-e]benzothiazol-2-yl group; R² represents a hydrogen atom or a phenyl lower alkyl group; R³ and R⁴ each represents a lower alkyl group; and A represents a heterocyclic ring selected from the group consisting of a pyrazine ring, a thiophene ring and a phenyl-substituted thiazole ring; the derivative being of value as an agent for treating and preventing hyperlipidemia, diabetes and cataract, or as an antitumor agent.

Claims

1. A phosphonic diester derivative represented by the following formula (1):

##STR60## wherein R¹ represents a cycloalkyl group;

a phenyl group which may have 1 to 3 substituents selected from the group consisting of a lower alkoxy group, a lower alkyl group, a halogen atom, a halogen-substituted lower alkyl group, a lower alkanoyl group, a nitro group, a benzoyl group, a cyano group, an N-lower alkylcarbamoyl group, an N-phenyl-lower alkylcarbamoyl group, an N-(halogen-substituted phenyl)carbamoyl group and an N,N-di-lower alkylcarbamoyl group;

a 1,3,4-thiadiazol-2-yl group having a halogen-substituted lower alkyl group as a substituent;

a thiazolyl group;

a pyridyl group which may be substituted by a halogen atom;

a benzothiazol-2-yl group having 1 to 2 lower alkoxy groups on the phenyl ring;

or a 4,5-dihydrothieno[3,2-e]benzothiazol-2-yl group;

R² represents a hydrogen atom or a phenyl lower alkyl group;

R³ and R⁴ each represents a lower alkyl group; and

A represents a heterocyclic ring selected from the group consisting of a pyrazine ring, a thiophene ring and a phenyl-substituted thiazole ring.

2. The phosphonic diester derivative according to claim 1 wherein R² is a hydrogen atom.

3. The phosphonic diester derivative according to claim 2 wherein A is a thiophene ring.

4. The phosphonic diester derivative according to claim 3 wherein R¹ is a 1,3,4-thiadiazol-2-yl group having a halogen-substituted lower alkyl group as a substituent, a thiazolyl group, a benzothiazol-2-yl group having one lower alkoxy group on the phenyl ring, a 4,5-dihydrothieno[3,2-e]benzothiazol-2-yl group or a phenyl group which has a halogen atom as a substituent and which may further have a substituent selected from the group consisting of a lower alkanoyl group, a cyano group and an N,N-di-lower alkylcarbamoyl group.

5. The phosphonic diester derivative according to claim 4 which is diethyl 5-[N-(2-acetyl-4-chlorophenyl)carbamoyl]-2-thienylmethylphosphonate.

6. A pharamaceutical composition for treating and preventing hyperlipidemia comprising an effective amount of the phosphonic diester derivative according to claim 1 and a pharmaceutically acceptable carrier.

7. A pharmactical composition for treating and preventing hyperlipidemia comprising an effective amount of the phosphonic diester derivative according to claim 4 and a pharmaceutically acceptable carrier.

8. A pharamaceutical composition for treating and preventing hyperlipidemia comprising an effective amount of the phosphonic diester derivative according to claim 5 and a pharmaceutically acceptable carrier.

9. A method of treatment or prevention of hyperlipidemia, comprising administering a therapeutically effective amount of the phosphonic diester derivative according to claim 1 to a subject in need thereof.