New CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions

Abstract

The present invention relates to the CGRP-antagonists of general formula I wherein R 1 , R 2 , R 3 , R 4 and X are defined as in claim 1 , the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, mixtures and salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, as well as those compounds of general formula I in which one or more hydrogen atoms are replaced by deuterium, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof.

1 . A compound of the formula 
     
       
         
         
             
             
         
       
       wherein 
       X denotes CH 2 , NH, C 1-3 -alkyl-N, O or S, 
       R 1  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein
 R 1.1  denotes H, halogen, HO, F 3 C or C 1-6 -alkyl-O, 
 
       R 2  denotes a group of the formulae II 
     
     
       
         
         
             
             
         
       
       wherein
 R 2.1  denotes H, halogen, C 1-3 -alkyl-O, C 1-3 -alkyl or F 3 C, 
 R 2.2  denotes H, H 2 N, HO, H 3 C—O, H—C(O)—O or C 1-3 -alkyl-C(O)-O, 
 R 2.3  denotes H, halogen, C 1-3 -alkyl or F 3 C, or 
 
       R 2  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       wherein
 R 2.4  denotes H or H 3 C, 
 
       R 3  denotes a group of the formulae III 
     
     
       
         
         
             
             
         
       
       wherein
 R 3.1  denotes H, C 1-3 -alkyl or R 3.1.1 —(O)C, 
 R 3.1.1  denotes HO or C 1-6 -alkyl-O, 
 R 3.2  denotes H or C 1-3 -alkyl and 
 R 3.3  denotes a free pair of electrons or the oxygen atom, 
 
       R 4  denotes a 4- to 7-membered oxycycloalkyl group optionally substituted by R 4.1  and
 R 4.1  denotes NC, HO, C 1-3 -alkyl or C 1-3 -alkyl-O, 
 
       or a tautomer or salt thereof. 
     
   
   
       2 . A compound of the formula I according to  claim 1 , wherein
 X denotes CH 2 , NH or O,   R 1  denotes a moiety selected from the group consisting of   
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein
 R 1.1  denotes H, Cl, Br, HO, F 3 C or H 3 C—O, 
 
       R 2  denotes a group of the formulae II 
     
     
       
         
         
             
             
         
       
       wherein
 R 2.1  denotes H, Cl, Br, H 3 C—O, H 3 C, F 3 C or H 3 C—H 2 C, 
 R 2.2  denotes H 2 N, HO, H 3 C—O, H—C(O)—O or H 3 C—C(O)—O, 
 R 2.3  denotes H, Cl, Br, H 3 C or F 3 C, or 
 
       R 2  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       wherein
 R 2.4  denotes H or H 3 C, 
 
       R 3  denotes a group of the formulae III 
     
     
       
         
         
             
             
         
       
       wherein
 R 3.1  denotes H or H 3 C, 
 R 3.2  denotes H or H 3 C and 
 R 3.3  denotes a free pair of electrons or the oxygen atom, 
 
       R 4  denotes a 4- to 7-membered oxycycloalkyl group optionally substituted by R 4.1  and
 R 4.1  denotes HO or C 1-3 -alkyl, 
 
       or a tautomer or salt thereof. 
     
   
   
       3 . A compound of the formula I according to  claim 1 , wherein
 X denotes CH 2 , NH or O,   R 1  denotes a moiety selected from the group consisting of   
     
       
         
         
             
             
         
       
       wherein
 R 1.1  denotes H or H 3 C—O, 
 
       R 2  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein
 R 2.1  denotes H 3 C or F 3 C, 
 R 2.2  denotes H 2 N or HO, 
 R 2.4  denotes H or H 3 C, 
 
       R 3  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       and 
       R 4  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       or a tautomer or salt thereof. 
     
   
   
       4 . A compound of the formula I according to  claim 1 , wherein
 R 1  denotes a moiety selected from the group consisting of   
     
       
         
         
             
             
         
       
       R 2  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       R 3  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       R 4  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       or a tautomer or salt thereof. 
     
   
   
       5 . A compound of the formula I according to  claim 1 , wherein
 R 1  denotes a moiety selected from the group consisting of   
     
       
         
         
             
             
         
       
       R 2  denotes a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       R 3 —R 4  together represent a moiety selected from the group consisting of 
     
     
       
         
         
             
             
         
       
       or a tautomer or salt thereof. 
     
   
   
       6 . A compound selected from the group consisting of: 
     
       
         
               
               
             
                   
               
                 No. 
                 Structure 
               
                   
               
                 (1) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (2) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
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                 (12) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
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                 (15) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (16) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
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                 (19) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (20) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (21) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (22) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (23) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
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                 (27) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (28) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (29) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (30) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (31) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (32) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (33) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (34) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (35) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (36) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (37) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (38) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (39) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (40) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (41) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (42) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (43) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (44) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (45) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (46) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (47) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (48) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (49) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (50) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
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                 (57) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (58) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (59) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (60) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (61) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (62) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (63) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (64) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (65) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (66) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
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                 (68) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (69) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (70) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (71) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (72) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (73) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (74) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (75) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (76) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (77) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (78) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (79) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (80) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (81) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (82) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (83) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (84) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (85) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (84a) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (85a) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (86) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (87) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (88) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (89) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (90) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (91) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (92) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (93) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (94) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (95) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (96) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (97) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (98) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (99) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (100) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (101) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (102) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (103) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (104) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (105) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (106) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (107) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (108) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (109) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (110) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (111) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (112) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (113) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (114) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (115) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (116) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (117) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (118) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (119) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (120) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (121) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (122) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (123) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (124) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (125) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (126) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (127) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (128) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (129) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (130) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (131) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (132) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (133) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (134) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (135) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (136) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (137) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (138) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (139) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (140) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (141) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (142) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (143) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (144) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (145) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (146) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (147) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (148) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (149) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (150) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (151) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (152) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (153) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (154) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (155) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (156) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (157) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (158) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (159) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (160) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (161) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (162) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (163) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (164) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (165) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (166) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (167) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (168) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (169) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (170) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (171) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (172) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (173) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (174) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (175) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (176) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (177) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (178) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (179) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (180) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (181) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (182) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (183) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (184) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (185) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (186) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (187) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (188) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (189) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (190) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (191) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (192) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (193) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (194) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (195) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (196) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (197) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (198) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (199) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (200) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (201) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (202) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (203) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (204) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (205) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (206) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (207) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (208) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (209) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (210) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (211) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (212) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (213) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 (214) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
           
              
              
              
             
             
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
       or a tautomer or salt thereof. 
     
   
   
       7 . A physiologically acceptable salt of a compound according to  claim 1 ,  2 ,  3 ,  4 ,  5  or  6 . 
   
   
       8 . A pharmaceutical composition containing a compound according to  claim 1 ,  2 ,  3 ,  4 ,  5  or  6  or a physiologically acceptable salt thereof together with one or more inert carriers and/or diluents. 
   
   
       9 . A method for the treatment of migraine, cluster headache and tension headache, which comprises the administration to a person suffering from the same a therapeutic amount of a compound according to  claim 1 ,  2 ,  3 ,  4 ,  5  or  6  or a physiologically acceptable salt thereof together. 
   
   
       10 . A method for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), which comprises the administration to a person suffering from the same a therapeutic amount of a compound according to  claim 1 ,  2 ,  3 ,  4 ,  5  or  6  or a physiologically acceptable salt thereof together. 
   
   
       11 . A method for the treatment of cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, lichen, prurigo, pruriginous toxidermies and severe itching, inflammatory diseases, e.g. inflammatory diseases of the joints such as osteoarthritis, rheumatoid arthritis or neurogenic arthritis, generalised soft tissue rheumatism (fibromyalgia), neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma and COPD, diseases accompanied by excessive vasodilatation and resultant reduced blood supply to the tissues, e.g. in particular shock and sepsis, chronic pain, such as e.g. diabetic neuropathies, neuropathies induced by chemotherapy, HIV-induced neuropathies, post-herpetic neuropathies, neuropathies induced by tissue trauma, trigeminal neuralgias, temporomandibular dysfunctions, CRPS, back pain and visceral diseases such as for example IBS (irritable bowel syndrome) or inflammatory bowel syndrome, for relieving pain in general or for the preventive or acute therapeutic treatment of the symptoms of hot flushes caused by vasodilatation and increased blood flow in menopausal oestrogen-deficient women and hormone-treated patients with prostate carcinoma and castrated men, which comprises the administration to a person suffering from the same a therapeutic amount of a compound according to  claim 1 ,  2 ,  3 ,  4 ,  5  or  6  or a physiologically acceptable salt thereof together.