Serotonin antagonists

• US 3,987,158 A
• Filed: 01/29/1974
• Issued: 10/19/1976
• Est. Priority Date: 07/07/1964
• Status: Expired due to Term

• Current Assignee: Burroughs Wellcome and Co.
• Original Assignee: Burroughs Wellcome and Co.
• Inventors: Hodson, Harold Francis
• Primary Examiner(s): Rosen, Sam
• Application Number:
  US05/437,738
• Time in Patent Office: 994 Days
• Field of Search: 424/275, 424/326, 424/9, 260/564
• US Class Current: 424/9.2
• CPC Class Codes: C07D 333/16 by oxygen atoms

Abstract

A compound of the formula ##EQU1## or an acid addition salt thereof wherein R¹ and R² are the same or different and each is a phenyl or thien-2-yl group optionally substituted in one or more positions by a substituent selected from the class consisting of halogen, lower alkyl, lower alkoxy, hydroxy, lower alkylthio, phenyl, phenoxy, phenyl-(lower-alkyl) and phenyl-(lower-alkoxy), each of the said phenyl, phenoxy, phenyl-(lower-alkyl) and phenyl-(lower-alkoxy) substituent groups being optionally substituted in one or more positions by a member selected from the class consisting of halogen, lower alkyl, lower alkoxy, hydroxy, and lower alkylthio;

A¹ is a divalent straight or branched alkylene group containing from two to six carbon atoms and one or two divalent atoms which are each an oxygen or sulphur atom, provided that there are at least two carbon atoms between the divalent atom and the --NH-- group and between the two divalent atoms; and

A² is the methylene group --CH₂ --.

Claims

1. A pharmaceutical composition containing a pharmaceutically effective serotonin antagonizing amount of an amidine of the formula:

##EQU2## or a pharmaceutically acceptable acid addition salt thereof wherein R¹ or R² are phenyl or thien-2-yl optionally substituted in one, two, or three positions by substituents halogen, lower alkyl, lower alkoxy, hydroxy, lower alkylthio, phenyl, phenoxy, phenyl - (lower alkyl) or phenyl - (lower alkoxy), each of said substituents phenyl, phenoxy, phenyl - (lower alkyl) and phenyl-(lower alkoxy) being optionally substituted in one or two positions by a member selected from the class consisting of halogen, lower alkyl, lower alkoxy, hydroxy and lower alkylthio;

A¹ is a divalent straight or branched alkylene group containing from two to six carbon atoms and one or two divalent atoms which are each an oxygen or sulphur atom;

provided that there are at least two carbon atoms between the divalent atom and the - NH - group and between the two divalent atoms, and a pharmaceutically acceptable carrier therefore.

2. A composition according to claim 1 in which R¹ is phenyl optionally substituted in one or two positions by phenyl, benzyl, phenoxy -- (lower alkoxy), halogen, lower alkyl or lower alkoxy;

A¹ is an oxalkylene group - O.R³ - where R³ is divalent alkylene group containing 2 to 4 carbons, and R² is phenyl optionally substituted in one or two positions by halogen, lower alkyl or lower alkoxy.

3. A composition according to claim 1 in which R¹ is phenyl optionally substituted in the 3- position by chlorine, bromine, methoxy, ethoxy, methyl and ethyl;

A¹ is an oxyalkylene group -- O.R.³ -- where R³ is butyl-2, 3-ene, isopropylene, ethylene, 2-propyl-1-ene and 1-propyl-2-ene; and

R² is phenyl optionally substituted in the 3- position, the 4- position, the 3, 5- position, the 2, 4- positions and the 3, 4 positions by chlorine, methyl or methoxy.

4. A composition according to claim 1 in which R¹ is thien -2-yl, A¹ is methyleneoxyalkylene group -- Ch₂ OR³ - where R³ is a divalent alkylene group containing 2 to 4 carbons and R² is phenyl optionally substituted in one or two positions by halogen, lower alkyl or lower alkoxy.

5. A composition according to claim 1, wherein said amidine is N-(2-3- methoxy phenoxypropyl) --3-methylphenylacetamidine and pharmaceutically acceptable salt thereof.

6. A composition according to claim 1 wherein said amidine is N-(2-m-benzylphenoxypropyl) -3, 4-dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

7. A composition according to claim 1 wherein said amidine is N - (2-m-phenoxyphenoxypropyl) -3, 4- dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

8. A composition according to claim 1 wherein said amidine is N-[2-m-(methylthio)phenoxypropyl] - 3, 4- dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

9. A composition according to claim 1 wherein said amidine is N-[2-(5-chloro-2-thenyloxy)propyl]-3, 4- dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

10. A composition according to claim 1 wherein said amidine is N-(2-m-methylthiophenoxypropyl)-m-methylphenylacetamidine and pharmaceutically acceptable salt thereof.

11. A composition according to claim 1 wherein said amidine is N-(2-2¹ -thenyloxypropyl)-3, 4- dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

12. A composition according to claim 1 wherein said amidine is N-(2-m-fluorophenoxypropyl)-m-methylphenylacetamidine and pharmaceutically acceptable salt thereof.

13. A composition according to claim 1 wherein said amidine is N-(2-fluorophenoxypropyl)-3, 4-dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition according to claim 1 comprising in combination an amidine of the formula ##STR24## or a pharmaceutically acceptable acid addition salt thereof wherein R³ is divalent alkylene having 2 to 4 carbons, R² is hydrogen, lower alkyl, lower alkoxy, halogen or benzyloxy and R¹ is ##STR25## wherein R⁴ is lower alkyl, lower alkoxy, halogen, hydrogen, benzyloxy, phenoxy, lower alkylthio, benzyl or phenyl and a pharmaceutically acceptable carrier therefor.

15. A pharmaceutical composition according to claim 1 comprising a compound of the formula ##STR26## or a pharmaceutically acceptable acid addition salt thereof wherein R¹ is 2-2¹ thenyloxypropyl or 2-(5-chloro-2-thenyloxy) propyl and wherein R² is hydrogen, halogen or lower alkyl and a pharmaceutically acceptable carrier therefor.

16. A pharmaceutical composition according to claim 1 comprising a compound selected from the class consisting of N-(2-3¹ -methylbenzyloxypropyl9-4-chlorophenylacetamidine, N-(2-3¹ -benzyloxybenzyloxypropyl)-4-chlorophenylacetamidine, N-(2-m-chlorobenzyloxypropyl)-3,4-dimethylphenylacethamidine and pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier therefor.

17. A pharmaceutical composition according to claim 1 comprising N-(2-phenylthiopropyl)-m-methylphenylacetamidine or a pharmaceutically acceptable salt thereof and a pharmaceutically carrier therefor.

18. A method of antagonizing 5-hydroxytryptamine or its formation in the body of an animal which comprises administering to an animal an effective serotonin antagonizing amount of ##EQU3## or a pharmaceutically acceptable acid addition salt thereof wherein R¹ and R² are phenyl or thien-2-yl optionally substituted in one, two, or three positions by substituents halogen, lower alkyl, lower alkoxy, hydroxy, lower alkylthio, phenyl, phenoxy, phenyl - (lower alkyl) or phenyl - (lower alkoxy, each of said substituents phenyl, phenoxy, phenyl-(lower alkyl) and phenyl-(lower alkoxy) being optionally substituted in one or two positions by a member selected from the class consisting of halogen, lower alkyl, lower alkoxy, hydroxy and lower alkylthio;

A¹ is a divalent straight or branched alkylene group containing from two to six carbon atoms and one or two divalent atoms which are each an oxygen or sulphur atom, provided that there are at least two carbon atoms between the divalent atom and the -- NH -- group and between the two divalent atoms, and a pharmaceutically acceptable carrier therefor.

19. A method according to claim 18 in which R¹ is phenyl optionally substituted in one or two positions by phenyl, benzyl, phenoxy - (lower alkoxy), halogen, lower alkyl or lower alkoxy;

A¹ is an oxalkylene group -- O.R³ -- wherein R³ is divalent alkylene group containing 2 to 4 carbons, and R² is phenyl optionally substituted in one or two positions by halogen, lower alkyl or lower alkoxy.

20. A method according to claim 18 in which R¹ is phenyl optionally substituted in the 3- position by chlorine, bromine, methoxy, ethoxy, methyl and ethyl,

A¹ is an oxyalkylene group -- O.R³ -- wherein R³ is butyl-2, 3-ene, isopropylene, ethylene, 2-propyl-1-ene and 1-propyl-2-ene;

and R² is phenyl optionally substituted in the 3- position, the 4- position, the 3, 5- position, the 2, 4- positions and the 3, 4 positions by chlorine, methyl or methoxy.

21. A method according to claim 18 in which R¹ is thien -2-yl, A¹ is methyleneoxyalkylene group -- CH₂ OR³ - wherein R³ is a divalent alkylene group containing 2 to 4 carbons and R² is phenyl optionally substituted in one or two positions by halogen, lower alkyl or lower alkoxy.

22. A method according to claim 18 in which said amidine is N-(2-3- methoxy phenoxypropyl) -3- methylphenylacetamidine and pharmaceutically acceptable salt thereof.

23. A method according to claim 18 wherein said amidine is N-(2-m-benzylphenoxypropyl)-3, 4- dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

24. A method according to claim 18 wherein said amidine is N-(2-m-phenoxyphenoxypropyl)-3, 4- dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

25. A method according to claim 18 wherein said amidine is N-[2-m-(methylthio) phenoxypropyl] - 3, 4- dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

26. A method according to claim 18 wherein said amidine is N-[2-(5-chloro-2-thenyloxy)propyl]-3, 4- dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

27. A method according to claim 18 wherein said amidine is N-(2-m-methylthiophenoxypropyl)-m-methylphenylacetamidine and pharmaceutically acceptable salts thereof.

28. A method according to claim 18 wherein said amidine is N-(2-2¹ -thenyloxypropyl)-3,4-dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

29. A method according to claim 18 wherein said amidine is N-(2-m-fluorophenoxypropyl)-m-methylphenylacetamidine and pharmaceutically acceptable salt thereof.

30. A method according to claim 18 wherein said amidine is N-(2-m-fluorophenoxypropyl)-3, 4-dimethylphenylacetamidine and pharmaceutically acceptable salt thereof.

31. A method according to claim 18 comprising in combination an amidine of the formula ##STR27## or a pharmaceutically acceptable salt acid addition salt thereof wherein R³ is divalent alkylene having 2 to 4 carbons, R² is hydrogen, lower alkyl, lower alkoxy, halogen or benzyloxy and R¹ is ##STR28## wherein R⁴ is lower alkyl, lower alkoxy, halogen, hydrogen, benzyloxy, phenoxy, lower alkylthio, benzyl, or phenyl and a pharmaceutically acceptable carrier therefor.

32. A method according to claim 18 comprising a compound of the formula ##STR29## or a pharmaceutically acceptable acid addition salt thereof wherein R¹ is 2-2¹ -thenyloxypropyl or 2-(5-chloro-2-thenyloxy) propyl and wherein R² is hydrogen, halogen or lower alkyl and a pharmaceutically acceptable carrier therefor.

33. A method according to claim 18 comprising a compound selected from the class consisting of N-(2-3¹ -methylbenzyloxypropyl)-4-chlorophenylacetamidine, N-(2-3¹ -benzyloxybenzyloxypropyl)-4-chlorophenylacetamidine, N-(2-m-chlorobenzyloxypropyl)-3,4-dimethylphenylacetamidine and pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier therefor.

34. A method according to claim 18 comprising N-(2-phenylthiopropyl)-m-methylphenylacetamidine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.

35. A method according to claim 18 in which the animal is a rat and is administered 5-hydroxytryptamine and then is administered an effective 5-hydroxytryptamine antagonizing amount of the composition to study the effect of 5-hydroxytryptamine in a rat.