6-(cyanoguanidinophenyl)pyridazinones as cardiac stimulants

• US 4,654,342 A
• Filed: 01/14/1985
• Issued: 03/31/1987
• Est. Priority Date: 01/13/1984
• Status: Expired due to Fees

• Current Assignee: Smith Kline & French Laboratories Limited (GSK plc)
• Original Assignee: Smith Kline & French Laboratories Limited (GSK plc)
• Inventors: Slater, Robert A.
• Primary Examiner(s): Berch, Mark L.
• Application Number:
  US06/690,911
• Time in Patent Office: 806 Days
• Field of Search: 544/239, 514/247
• US Class Current: 514/247
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: C07C 279/28 having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
• CPC Class Codes: C07D 237/04 having less than three double bonds between ring members or between ring members and non-ring members

Abstract

This invention relates to cyanoguanidine derivatives that have utility in the treatment of congestive heart failure. A specific compound of this invention is 6-[4-(N³ -methyl-N² -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone.

Claims

1. A compound of the formula (I):

##STR10## or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen or methyl and R² is hydrogen or C_1-4 alkyl.

2. A compound according to claim 1 wherein R¹ is methyl.

3. A compound according to claim 1 wherein R² is C_1-4 alkyl.

4. A compound according to claim 2 wherein R² is C_1-4 alkyl.

5. A compound according to claim 4 wherein R² is methyl or ethyl.

6. A compound according to claim 1 which is:

6-[4-(N³ -methyl-N² -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N³ -ethyl-N² -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N³ -isopropyl-N² -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N³ -butyl-N² -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N² -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, or

6-[4-(N³ -methyl-N² -cyanoguanidino)phenyl]-4,5-dihydro-3(2H)-pyridazinone.

7. A compound according to claim 1 which is 6-[4-(N³ -methyl-N² -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone.

8. A compound according to claim 7 which is (-)-6-[4-(N³ -methyl-N² -cyanoguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone.

9. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition which comprises a compound according to claim 7 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition which comprises a compound according to claim 8 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition according to claim 9 in unit dose form adapted for oral administration.

13. A pharmaceutical composition according to claim 10 in unit dose form adapted for oral administration.

14. A pharmaceutical composition according to claim 11 in unit dose form adapted for oral administration.

15. A method of treating congestive heart failure in a mammal comprising administering an effective amount of a composition of claim 9.

16. A method of treating congestive heart failure in a mammal comprising administering an effective amount of a compoistion of claim 10.

17. A method of treating congestive heart failure in a mammal comprising administering an effective amount of a composition of claim 11.

18. A method of stimulating cardiac activity in a mammal comprising administering an effective amount of a composition of claim 9.

19. A method of stimulating cardiac activity in a mammal comprising administering an effective amount of a composition of claim 10.

20. A method stimulating cardiac activity in a mammal comprising administering an effective amount of a composition of claim 11.

21. A method of effecting bronchodilatation in a mammal comprising administering an effective amount of a composition of claim 9.

22. A method of effecting bronchodilatation in a mammal comprising administering an effective amount of a composition of claim 10.

23. A method of effecting bronchodilatation in a mammal comprising administering an effective amount of a composition of claim 11.

24. A compound of the formula (V):

##STR11## wherein R¹ is hydrogen or methyl and L² is selected from the group consisting of benzylthio, C_1-6 alkylthio, C_1-6 alkoxy, phenoxy and benzyloxy.

25. A compound according to claim 24 wherein R¹ is methyl and L² is phenoxy, C_1-6 alkoxy or C_1-4 alkylthio.

26. A compound according to claim 25 wherein L² is methylthio.

27. A compound according to claim 25 wherein L² is ethoxy.