Aminoalkyl furan derivatives

• US 4,128,658 A
• Filed: 07/25/1977
• Issued: 12/05/1978
• Est. Priority Date: 08/04/1976
• Status: Expired due to Term

• Current Assignee: Allen & Hanburys Limited (GSK plc)
• Original Assignee: Allen & Hanburys Limited (GSK plc)
• Inventors: Bradshaw, John, Clitherow, John W., Price, Barry J.
• Primary Examiner(s): Raymond, Richard
• Application Number:
  US05/818,762
• Time in Patent Office: 498 Days
• Field of Search: 260/347.2, 260/347.3, 260/347.7, 424/285
• US Class Current: 514/471
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 275/03 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/38 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/64 Sulfur atoms

Abstract

Compounds of the general formula I: ##STR1## and physiologically acceptable salts thereof and N-oxides and hydrates, in which R₁ and R₂ which may be the same or different represent hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl or lower alkyl interrupted by an oxygen atom or a group ##STR2## in which R₄ represents hydrogen or lower alkyl or R₁ and R₂ may, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain other heteroatoms selected from O and ##STR3## R₃ is hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl; X is --CH₂ --, O or S;

Y represents ═ S, ═ O, ═ NR₅ or ═ CHR₆ ;

Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms;

R₅ is H, nitro, cyano, lower alkyl, aryl, alkylsulphonyl, or arylsulphonyl;

R₆ represents nitro, arylsulphonyl or alkylsulphonyl;

M is an integer from 2 to 4; and

N is 1 or 2; or when X ═ S, or --CH₂ --, n is zero, 1 or 2.

These compounds have H₂ -antagonist activity. Intermediates in the production thereof are also provided.

Claims

1. A compound of the general formula I:

##STR39## or a physiologically acceptable salt, N-oxide or hydrate thereof in which R₁ and R₂ which may be the same or different represent hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo or lower alkyl interrupted by an oxygen atom or a group ##STR40## in which R₄ represents hydrogen or lower alkyl;

R₃ is hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl;

X is --CH₂ --, O or S;

Y represents ═

S, ═

O, ═

NR₅ or ═

CHR₆ ;

Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms;

R₅ is H, nitro, cyano, lower alkyl, phenyl, phenyl substituted by alkyl, alkoxy or halo, alkylsulphonyl, or arylsulphonyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo;

R₆ represents nitro, arylsulphonyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo or alkylsulphonyl;

m is an integer from 2 to 4; and

n is 1 or 2;

or when X ═

S, or --CH₂ --, n is zero, 1 or 2.

2. A compound as claimed in claim 1 in which R₁ and R₂ independently represent hydrogen, alkyl, phenylalkyl, or dialkylamino alkyl, Alk represents a straight alkylene chain of 1 to 4 carbon atoms, Y is ═

S, ═

O, ═

CHNO₂ or ═

NR₅ where R₅ is hydrogen, nitro, cyano, lower alkyl, alkylsulphonyl or benzenesulphonyl, and X, m, n, and R₃ have the meanings given in claim 1.

3. A compound as claimed in claim 1 in which the lower alkyl groups have 1 to 8 carbon atoms.

4. A compound as claimed in claim 1 in which the alkenyl groups have 3 to 6 carbon atoms.

5. A compound as claimed in claim 1 in which n + m is 3 or 4.

6. A compound as claimed in claim 1 in which Alk represents a methylene group.

7. A compound as claimed in claim 1 in which R₁ is H or C_1-4 alkyl and R₂ is C_1-4 alkyl.

8. A compound as claimed in claim 1 in which R₁ and R₂ are independently methyl or ethyl.

9. A compound as claimed in claim 1 in which X is a sulphur atom.

10. A compound as claimed in claim 1 in which X represents a group --CH₂ --.

11. A compound as claimed in claim 1 in which R₁ and R₂ independently represent hydrogen, alkyl of 1 to 3 carbon atoms or phenethyl;

Alk represents an alkylene chain of 1 to 3 carbon atoms;

Y is ═

S, ═

CHNO₂, or ═

NR₅, where R₅ is nitro, cyano, methylsulphonyl or benzenesulphonyl;

R₃ represents hydrogen, alkyl of 1 to 3 carbon atoms, propenyl or alkoxyalkyl of 3 carbon atoms;

n + m is 3 or 4, and X is as defined in claim 1.

12. A compound as claimed in claim 1 in which R₁ and R₂ independently represent H, alkyl of 1 to 3 carbon atoms, phenethyl;

Alk represents an alkylene group of 1 to 3 carbon atoms;

Y is ═

S, ═

CHNO₂, or ═

NR₅, where R₅ is nitro, cyano, methylsulphonyl or benzenesulphonyl;

X is S or --CH₂ --;

R₃ is hydrogen, methyl or methoxyethyl;

n is 1 and m is 2 or 3.

13. A compound as claimed in claim 1 in which R₁ is hydrogen, methyl or ethyl;

R₂ is methyl or ethyl;

Alk represents a methylene group;

Y is ═

NCN, ═

NNO₂, or ═

CHNO₂ ;

R₃ is hydrogen or methyl;

X is S or --CH₂ --; and

n is 1 and m is 2.

14. A compound as claimed in claim 1 which is N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'"'"'-methylthiourea.

15. A compound as claimed in claim 1 which is N-cyano-N'"'"'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine.

16. A compound as claimed in claim 1 which is N-[2-[[[5-(dimethylamino)methyl-2furanyl]methyl]thio]ethyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.

17. A compound as claimed in claim 1 which is N-cyano-N'"'"'-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine.

18. A compound as claimed in claim 1 which is N-[2-[[[5-(diethylamino)methyl-2furanyl]methyl]thio]ethyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.

19. A compound as claimed in claim 1 which is N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'"'"'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine.

20. A compound as claimed in claim 1 which is N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'"'"'-(2-methoxyethyl)thiourea.

21. A compound as claimed in claim 1 which is N-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.

22. A compound as claimed in claim 1 which is N-[3-[[5-(dimethylamino)methyl-2-furanyl]thio]propyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.

23. A compound as claimed in claim 1 which is N-[-2-[[[5-(ethylmethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.

24. A compound as claimed in claim 1 which is N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'"'"'-nitroguanidine.

25. A compound as claimed in claim 1 which is N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'"'"'-methanesulphonyl-N"-methylguanidine.

26. A compound as claimed in claim 1 which is N-[4-[5-(dimethylamino)methyl-2-furanyl]butyl]-N'"'"'-methylthiourea.

27. A compound as claimed in claim 1 which is N-benzene-sulphonyl-N'"'"'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine.

28. A compound as claimed in claim 1 which is N-[5-[5-(dimethylamino)methyl-2-furanyl]pentyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.

29. A compound as claimed in claim 1 which is N-cyano-N'"'"'-[5-[5-(dimethylamino)methyl2-furanyl]pentyl]-N'"'"'-methylguanidine

30. A compound as claimed in claim 1 which is N-[4-[5-(dimethylamino)methyl-2-furanyl]butyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.

31. A compound as claimed in claim 1 which is N-cyano-N'"'"'-[4-[5-(dimethylamino)methyl-2-furanyl]butyl]-N"-methylguanidine.

32. A compound as claimed in claim 1 which is N-[2-[[[5-[3 [dimethylamino]propyl]-2-furanyl]methyl]thio]ethyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.

33. A compound as claimed in claim 1 which is N-[2-[[[5-[[2-(dimethylamino)ethyl]amino]methyl-2-furanyl]methyl]thio]ethyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.

34. A compound as claimed in claim 1 which is a physiologically acceptable acid addition salt.

35. A compound as claimed in claim 34 which is a hydrochloride.

36. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in claim 1 in association with a pharmaceutically acceptable carrier or diluent.

37. A composition as claimed in claim 36 in a form suitable for oral, topical or parenteral administration or administration by suppository.

38. A composition as claimed in claim 37 in oral form as tablets.

39. A composition as claimed in claim 38 in the form of slow release tablets.

40. A composition as claimed in claim 39 containing 20 to 200 mg of active ingredient per tablet.

41. A composition as claimed in claim 37 in topical form as a spray, ointment or cream.

42. A method of treating a condition mediated through histamine H₂ -receptors which comprises administering to a patient an effective amount of a compound as claimed in claim 1 to relieve said condition.

43. A method as claimed in claim 42 in which the condition is peptic ulceration.

44. A method as claimed in claim 42 in which the condition is an allergic skin condition.

45. The hydrochloride of N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'"'"'-methyl-2-nitro-1,1-ethenediamine.