Aminoguanidines as melanocortin receptor ligands
There are described compounds of general formula (I) and isomeric forms thereof wherein n is 0, 1, 2 or 3, saturated or unsaturated; most preferably at least one of R 1 to R 5 represents halogen; at least one of R 1 , R 2 , R 3 , R 4 and R 5 is selected from —S—R or —COOR, or two or more Of R 1 -R 5 comprise a linking group such as —S—(CH2) m S—, where m is 1, 2 or 3 and R is selected from alkyl having 1 to 5 carbon atoms, cycloalkyl having 3-6 carbon atoms, hydroxy, and aryl having 6 to 10 carbon atoms, such groups being optionally substituted, and when R 1 is selected from —S—R, then at least one of R 2 , R 3 and R 5 is most preferably selected from halogen; and R 1 , R 2 , R 3 , R 4 and R 5 are otherwise the same or different and are selected from hydrogen, halogen, alkyl having 1 to 5 carbon atoms, electron donor groups such as alkoxy having 1-5 carbon atoms or hydroxy, electron acceptor groups selected from cyano, nitro, trifluoroalkyl or amide; alkylamino, benzoyloxy, nitroxy, phenyl or sulpho; and pharmacologically acceptable salts thereof. Compounds described have activity on the melanocortin receptors and have application in the treatment of a wide range of inflammatory, arthritic or central nerve regeneration conditions.
1. A compound of general formula (I)
and isomeric forms thereof
wherein n is 0, 1, 2 or 3, with saturated or unsaturated bonds;
at least one of R 1 to R 5 represents halogen;
at least one of R 1 , R 2 , R 3 , R 4 and R 5 is —S—R, or two of R 1 -R 5 form a linking group —S—(CH 2 ) m —S—, where m is 1, 2 or 3; and
R is selected from alkyl having 1 to 5 carbon atoms, cycloalkyl having 3-6 carbon atoms, hydroxy, and aryl having 6 to 10 carbon atoms, such groups being optionally substituted;
and wherein when R 1 is —S—R, then at least one of R 2 , R 3 or R 5 is selected from halogen;
and R 1 , R 2 , R 3 , R 4 and R 5 are otherwise the same or different and are selected from hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1-5 carbon atoms or hydroxy, cyano, nitro, trifluoroalkyl or amide; alkylamino, benzoyloxy, nitroxy, phenyl and sulpho;
and pharmacologically acceptable salts thereof.
2. A compound as claimed in claim 1 wherein n is 0 or 1.
3. A compound as claimed in claim 1 wherein the linking group is a methylenedithio group.
4. A compound as claimed in claim 3 wherein the linking group is a 2,3-, 3,4- or 4,5-methylenedithio group.
5. A compound as claimed in claim 1 wherein the halogen is fluoro or chloro.
6. A compound having one of the following formulae:
1:1 N-(2-Methylthio-3-chlorobenzylideneamino)guanidine
1:2 N-(2-Chloro-4-Methoxy-3-methylthiobenzylideneamino)guanidine
1:4 N-(2-Chloro-3-Methoxy-4-methylthiobenzylideneamino)guanidine
1:5 N-(2-Chloro-3,4-dimethylthiobenzylideneamino)guanidine
1:6 N-(5-Chloro-2,3-dihydro-benzo[1,4]dithiin-6-ylmethyleneamino)-guanidine
1:7 N-(2-Methylthio-3-chlorophenylpropylideneamino)guanidine
1:8 N-(2-Chloro-4-Methoxy-3-methylthiophenylpropylideneamino)guanidine
1:10 N-(2-Chloro-3-Methoxy-4-methylthiophenylpropyliideneamino)guanidine
1:11 N-(2-Chloro-3,4-dimethylthiophenylpropylideneamino)guanidine
1:12 N-[3-(5-Chloro-2,3-dihydro-benzo[1,4]dithiin-6-yl)-allylideneamino]-guanidine
or a pharmacologically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound as claimed in claim 1 , together with one or more pharmaceutically acceptable adjuvants, carriers or excipients.
8. A method of treating inflammation, an arthritic condition or for inducing central nerve regeneration which comprises administering to a subject in need thereof an effective amount of a compound (IA)
wherein n is 0, 1, 2 or 3, with saturated or unsaturated bonds;
at least one of R 1 , R 2 , R 3 , R 4 and R 5 is —S—R, or two of R 1 -R 5 form a linking group —S—(CH 2 ) m —S— where m is 1, 2 or 3;
R is selected from alkyl having 1 to 5 carbon atoms, alkoxy having 1-5 carbon atoms; cycloalkyl having 3-6 carbon atoms; and aryl having 6 to 10 carbon atoms, such groups being optionally substituted
and R 1 , R 2 , R 3 , R 4 and R 5 are otherwise the same or different and are selected from hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms or hydroxy, cyano, nitro, trifluoroalkyl or amide; alkylamino, benzoyloxy, nitroxy, phenyl and sulpho;
and pharmacologically acceptable salts thereof.
9. The method of claim 8 , wherein the arthritic condition is arthritis.
10. A method of treating pain which comprises administering to a subject in need thereof an effective amount of a compound (IA)
wherein n is 0, 1, 2 or 3, with saturated or unsaturated bonds;
at least one of R 1 , R 2 , R 3 , R 4 and R 5 is —S—R, or two of R 1 -R 5 form a linking group —S—(CH 2 ) m —S— where m is 1, 2 or 3;
R is selected from alkyl having 1 to 5 carbon atoms, alkoxy having 1-5 carbon atoms;
cycloalkyl having 3-6 carbon atoms; and aryl having 6 to 10 carbon atoms, such groups being optionally substituted
and R 1 , R 2 , R 3 , R 4 and R 5 are otherwise the same or different and are selected from hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms or hydroxy, cyano, nitro, trifluoroalkyl or amide; alkylamino, benzoyloxy, nitroxy, phenyl and sulpho;
and pharmacologically acceptable salts thereof.