Nitrogen containing heterocyclic compounds, their production and use

• US 5,304,565 A
• Filed: 03/07/1991
• Issued: 04/19/1994
• Est. Priority Date: 03/07/1990
• Status: Expired due to Fees

• Current Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Nishikawa, Kohei, Morimoto, Akira
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Grumbling, Matthew V.
• Application Number:
  US07/666,037
• Time in Patent Office: 1,139 Days
• Field of Search: 544/283, 544/287, 544/153, 544/276, 514/259, 514/261, 514/312, 514/340, 514/345, 514/350, 514/351, 546/153, 546/276, 546/298, 546/300, 546/301, 546/302
• US Class Current: 514/340
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 239/36 as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 239/91 with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings

Abstract

Nitrogen-containing heterocyclic compounds of the formula (I): ##STR1## wherein Y is N or CH; R¹, which may be optionally bound through a hetero atom, is a hydrocarbon residue which may be substituted; R² and R³ which may be same or different, are each independently hydrogen, cyano, nitro, optionally substituted lower alkyl, or --COD wherein D is alkoxy, hydroxy, halogen, or optionally substituted amino: or R² and R³ are taken together to form a benzene ring which may be substituted; the dotted line is a chemical bond; Z is bound to a hetero nitrogen atom and is a group having the formula: ##STR2## wherein R⁴ is hydrogen, halogen or nitro, and R⁵ is a residue capable of forming an anion or a residue convertible into an anion; A is a direct bond or a spacer having atomic length of two or less between the phenylene group and the phenyl group; and n is an integer of 1 or 2; and the pharmaceutically acceptable salts thereof, have potent angiotensin II antagonist activity and antihypertensive activity, thus being useful as therapeutic agents for treating circulatory system diseases such as hypertensive diseases, heart diseases, strokes, etc.

Claims

1. A compound of the formula:

##STR50## wherein Y is CH;

R¹, optionally bound through a hetero atom, is (i) a hydrocarbon residue which may be substituted or (ii) a heteroaryl group;

R² and R³ which are the same or different, are each independently hydrogen, cyano, nitro, optionally substituted lower alkyl, or --COD wherein D is alkoxy, hydroxy, halogen, or optionally substituted amino;

the dotted line is a chemical bond;

Z is bound to a hetero nitrogen atom and is a group having the formula;

##STR51## wherein R⁴ is hydrogen, halogen or nitro, and R⁵ is a residue capable of forming an anion or a residue convertible into an anion;

A is a direct bond or a spacer having atomic length of two or less between the phenylene group and the phenyl group; and

n is an integer of 1 or 2;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein R² is --COD wherein D is alkoxy, hydroxy, halogen or an optionally substituted amino;

and R³ is hydrogen or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 wherein R¹ is C_1-8 alkyl;

R² is --COD wherein D is halogen, C_1-4 alkoxy, hydroxy or optionally substituted amino; and

R³ is hydrogen or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition for antagonizing angiotensin II which comprises a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier, excipient or diluent.

5. A compound according to claim 1, wherein R¹ is an acyclic or cyclic hydrocarbon residue which is optionally substituted with hydroxyl, lower (C_1-4) alkoxy, lower (C_1-4) alkyl, halogen, nitro, optionally substituted amino, acyloxy, or aryl which may be optionally substituted with halogen, nitro, lower (C_1-4) alkoxy, or lower (C_1-4) alkyl on the benzene ring.

6. A compound according to claim 5, wherein the acyclic hydrocarbon residue is a lower alkyl of 1 to 8 carbon atoms, lower alkenyl of 2 to 8 carbon atoms, or lower alkynyl of 2 to 8 carbon atoms.

7. A compound according to claim 5, wherein the cyclic hydrocarbon residue is an alicyclic hydrocarbon residue of 3 to 8 carbon atoms or an aromatic hydrocarbon residue of 6 to 12 carbon atoms.

8. A compound according to claim 5, wherein the optionally substituted amino group is amino, N-lower (C_1-4) alkyl amino, N,N-dilower (C_1-4) alkyl amino, N-arylamino, N-aralkylamino, or alicyclic amino.

9. A compound according to claim 5, wherein the acyloxy group is lower (C_1-4) alkanoyloxy, or aroyloxy.

10. A compound according to claim 1, wherein R² is lower (C_1-4) alkoxycarbonyl, carbamoyl, N-lower (C_1-4) alkylcarbamoyl, N,N-dilower (C_1-4) alkylcarbamoyl, N-arylcarbamoyl, N-aralkylcarbamoyl, N-heteroarylcarbamoyl, N-heteroaralkylcarbamoyl, or alicyclic carbamoyl, wherein said alkyl, aryl and heteroaryl groups are optionally substituted with alkyl, hydroxyl, optionally substituted amino, halogen, nitro, or lower (C_1-4) alkoxy.

11. A compound according to claim 1, wherein R² is straight or branched lower alkyl of 1 to about 8 carbon atoms optionally substituted with hydroxyl, lower (C_1-4) alkoxy, optionally esterified carboxyl, lower (C_1-4) alkyl, halogen, nitro, optionally substituted amino, acyloxy or aryl optionally substituted with halogen, nitro, lower (C_1-4) alkoxy, or lower (C_1-4) alkyl on the benzene ring.

12. A compound according to claim 1, wherein R² is straight or branched lower alkyl of 1 to 8 carbon atoms optionally substituted with hydroxyl, lower (C_1-4) alkoxy, lower (C_1-4) alkoxycarbonyl, lower (C_1-4) alkyl, halogen, nitro, amino, N-lower (C_1-4) alkyl amino, N,N-dilower (C_1-4) alkyl amino, N-arylamino, N-aralkylamino, alicyclic amino, lower (C_1-4) alkanoyloxy, aroyloxy or aryl optionally substituted with halogen, nitro, lower (C_1-4) alkoxy, or lower (C_1-4) alkyl on the benzene ring.

13. A method for antagonizing angiotensin II in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

14. A compound of claim 2 which is ethyl 6-n-butyl-1-[[2'"'"'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]-4-oxo-1,4-dihydronicotinate.

15. A compound according to claim 1, wherein R⁴ is hydrogen.

16. A compound according to claim 1, wherein R⁵ is carboxyl, lower (C_1-4) alkoxycarbonyl, cyano, tetrazolyl, trifluoromethanesulfonic amide, phosphoric acid, or sulfonic acid.

17. A compound according to claim 1, wherein R⁵ is carboxyl or tetrazolyl.

18. A compound according to claim 1, wherein R⁵ is tetrazolyl.

19. A compound according to claim 1, wherein R⁵ is in the ortho position.

20. A compound according to claim 1, wherein A is a direct bond, lower (C_1-4) alkylene, ##STR52##

21. A compound of claim 1 wherein R¹ is optionally bound through a hetero atom which is nitrogen, oxygen or sulfur.

22. A compound of claim 1 wherein R¹ is optionally bound through a hetero atom which is nitrogen, oxygen or sulfur and said spacer is a divalent chain in which the number of atoms between the phenylene groups is up to 2.

23. A compound of claim 1 wherein R¹ is optionally bound through a hetero atom which is nitrogen, oxygen or sulfur and said spacer is a member selected from the group consisting of C₁ -₄ alkylene, --C(═

O)--, --O--, --S--, --N(H)--, --C(═

O)N(H)--, --OC(H²)--, --OS(H²)-- and --C(H)═

C(H)--.