Phosphonic acid derivatives

• US 5,719,303 A
• Filed: 09/06/1995
• Issued: 02/17/1998
• Est. Priority Date: 03/08/1993
• Status: Expired due to Fees

• Current Assignee: Eisai Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai Company Limited (Eisai Medical Research Incorporated)
• Inventors: Kobayashi, Naoki, Yoshida, Ichirou, Eguchi, Yoshihito, Tagami, Katsuya, Ohtsuka, Issei, Fukuda, Yoshio, Hayashi, Kenji, Nakagawa, Makoto, Abe, Shinya, Ikuta, Hironori, Hiyoshi, Hironobu, Kaino, Makoto, Souda, Shigeru
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): VOLLANO, JEAN F
• Application Number:
  US08/530,311
• Time in Patent Office: 895 Days
• Field of Search: 562/13, 558/158
• US Class Current: 558/158
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07F 9/3808 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/3826 Acyclic unsaturated acids
• CPC Class Codes: C07F 9/3839 Polyphosphonic acids
• CPC Class Codes: C07F 9/386 containing hydroxy substituents in the hydrocarbon radicals
• CPC Class Codes: C07F 9/3873 containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4015 Esters of acyclic unsaturated acids
• CPC Class Codes: C07F 9/4025 Esters of poly(thio)phosphonic acids
• CPC Class Codes: C07F 9/404 containing hydroxy substituents in the hydrocarbon radicals
• CPC Class Codes: C07F 9/405 containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
• CPC Class Codes: C07F 9/4056 Esters of arylalkanephosphonic acids C07F9/4025 takes precedence
• CPC Class Codes: C07F 9/4075 Esters with hydroxyalkyl compounds
• CPC Class Codes: C07F 9/572 Five-membered rings
• CPC Class Codes: C07F 9/5728 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/58 Pyridine rings
• CPC Class Codes: C07F 9/59 Hydrogenated pyridine rings
• CPC Class Codes: C07F 9/60 Quinoline or hydrogenated quinoline ring systems
• CPC Class Codes: C07F 9/62 Isoquinoline or hydrogenated isoquinoline ring systems
• CPC Class Codes: C07F 9/65038 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6506 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65068 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/650952 : having the nitrogen atoms in the positions 1 and 4
• CPC Class Codes: C07F 9/650994 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6512 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/653 : Five-membered rings
• CPC Class Codes: C07F 9/65324 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6533 : Six-membered rings
• CPC Class Codes: C07F 9/6539 : Five-membered rings
• CPC Class Codes: C07F 9/6541 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65505 : Phosphonic acids containing oxirane groups; esters thereof
• CPC Class Codes: C07F 9/65515 : the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/65517 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6552 : the oxygen atom being part of a six-membered ring
• CPC Class Codes: C07F 9/65522 : condensed with carbocyclic rings or carbocyclic ring systems
• 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 9/65742 : non-condensed with carbocyclic rings or heterocyclic rings or ring systems
• CPC Class Codes: C07F 9/65746 : the molecule containing more than one cyclic phosphorus atom

Abstract

A phosphonic acid derivative which is useful for medically treating hyperlipemia, represented by the following general formula (I) or a pharmacologically acceptable salt thereof: ##STR1## Representative example of the compound according to the present invention is one represented by the following formula: ##STR2##

Claims

1. A phosphonic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof:

##STR645## wherein R¹ represents a hydrogen atom;

R² and R³ may be the same or different from each other and each represents a hydrogen atom, a lower alkyl group which may have a substituent, an alkali metal or a prodrug ester forming group having the formula ##STR646## wherein R²⁷ represents a hydrogen atom or a lower alkyl group; and

R²⁸ represents an alkyl group which has 1 to 12 carbon atoms and may have a substituent, a cycloalkyl group, an aryl group which may have a substituent, an alkoxy group which has 1 to 12 carbon atoms and may have a substituent, a cycloalkyloxy group, an aryloxy group which may have a substituent, an alkylamino group which has 1 to 12 carbon atoms and may have a substituent, a cycloalkylamino group or an aromatic amino group which may have a substituent;

R^A represents a group represented by the formula;

##STR647## wherein R⁵ represents a hydrogen atom, a lower alkyl group, an alkali metal or a prodrug ester forming group; and

R⁶ represents a lower alkyl group or a group represented by the formula;

--OR⁷ (wherein R⁷ represents a hydrogen atom, a lower alkyl group, an alkali metal or said prodrug ester forming group as defined above); and

R^B represents a group represented by the formula;

S--T-- wherein S represents a group represented by the formula;

##STR648## wherein ring A represents a phenyl ring; and

X represents a single bond, an alkylene chain which may have a substituent, or an alkylene chain having one double bond within the chain which may have a substituent;

R⁸, R⁹, R¹⁰, R¹¹ and R¹² may be the same or different from one another and each represents

(1) a hydrogen atom,

(2) an alkyl group which may have a substituent,

(3) an alkenyl group which may have a substituent,

(4) a lower alkoxy group which may have a substituent,

(5) a carbamoyl group which may have a substituent,

(6) a carbamoyloxy group which may have a substituent,

(7) a hydroxyl group,

(8) an acyl group,

(9) a halogen atom,

(10) a group represented by the following formula;

##STR649## wherein R¹³ and R¹⁴ may be the same or different from each other and each represents a lower alkyl group which may have a substituent;

p is 0 or 1; and

q is an integer of 0 to

     4) or (11) a group represented by the formula;

##STR650## wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ may be the same or different from one another and each represents a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group which may have a substituent;

ring B represents a phenyl ring; and

Y represents an alkylene chain which may have a substituent, an alkylene chain having at least one double bond in the chain which may have a substituent, an alkylene chain having at least one triple bond within the chain which may have a substituent, a group represented by the formula;

##STR651## a group represented by the formula;

--O--, or a single bond, or alternatively two adjacent groups of R⁸, R⁹, R¹⁰, R¹¹ and R¹² may together form a ring; and

T represents

(1) a group represented by the formula;

##STR652## (wherein R²³ represents a cycloalkyl group, a cycloalkylalkyl group, a lower alkyl group which have a substituent or a lower alkenyl group which may have a substituent;

W represents a group represented by the formula;

--O--, or a single bond; and

s and t are independent of each other and are each an integer of 0 to

     4).

2. A pharmaceutical composition which comprises a therapeutically effective amount of the phosphonic acid derivative or the pharmacologically acceptable salt thereof as set forth in claim 1 and a pharmaceutically acceptable filler.

3. A method for medically treating a disease against which a squalene synthetase inhibiting action is efficacious which comprises administering a therapeutically effective amount of the phosphonic acid derivative or the pharmacologically acceptable salt thereof as set forth in claim 1 to a patient suffering from said disease against which a squalene synthetase inhibiting action is efficacious.

4. A method for medically treating hyperlipemia which comprises administering a therapeutically effective amount of the phosphonic acid derivative or the pharmacologically acceptable salt thereof as set forth in claim 1 to a patient suffering from hyperlipemia.

5. A method for medically treating hypertension which comprises administering a therapeutically effective amount of the phosphonic acid derivative or the pharmacologically acceptable salt thereof as set forth in claim 1 to a patient suffering from hypertension.

8. A phosphonic acid derivative according to claim 1 from the group consisting of ##STR659##

9. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR660##

10. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR661##

11. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR662##

12. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR663##

13. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR664##

14. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR665##

15. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR666##

16. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR667##

17. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR668##

18. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR669##

19. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR670##

20. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR671##

21. A phosphonic acid derivative according to claim 1 selected from the group consisting of ##STR672##

6. A phosphonic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof:

##STR653## wherein R¹ represents a hydrogen atom;

R² and R³ may be the same or different from each other and each represents a hydrogen atom, a lower alkyl group which may have a substituent, an alkali metal or a prodrug ester forming group having the formula ##STR654## wherein R²⁷ represents a hydrogen atom or a lower alkyl group; and

R²⁸ represents an alkyl group which has 1 to 12 carbon atoms and may have a substituent, a cycloalkyl group, an aryl group which may have a substituent, an alkoxy group which has 1 to 12 carbon atoms and may have a substituent, a cycloalkyloxy group, an aryloxy group which may have a substituent, an alkylamino group which has 1 to 12 carbon atoms and may have a substituent, a cycloalkylamino group or an aromatic amino group which may have a substituent;

R^A represents a group represented by the formula;

##STR655## wherein R⁵ represents a hydrogen atom, a lower alkyl group, an alkali metal or a prodrug ester forming group; and

R⁶ represents a lower alkyl group or a group represented by the formula;

--OR⁷ wherein R⁷ represents a hydrogen atom, a lower alkyl group, an alkali metal or a prodrug ester forming group as defined above; and

R^B represents a group represented by the formula;

S--T-- wherein S represents a group represented by the formula;

##STR656## wherein ring A represents a phenyl ring;

X is an alkylene chain having one double bond in the chain;

R⁸, R⁹, R¹⁰, R¹¹ and R¹² each represents a hydrogen atom; and

T represents a group represented by the formula;

##STR657## (wherein R²³ represents a hydrogen atom, a cycloalkyl group, a cycloalkylalkyl group, a lower alkyl group which have a substituent or a lower alkenyl group which may have a substituent;

W represents a single bond; and

s and t are independent of each other and are each an integer of 0 and 4.

7. A compound having the formula ##STR658##