Pyrazoline derivatives, their preparation and application as medicaments

Abstract

The present invention relates to new pyazoline derivatives of formula and to physiologically acceptable salts thereof, to the method for their preparation and to their application as medicaments.

1. A derivative of pyrazoline of formula (I) 
                 
 
       wherein
 R 1  represents hydrogen, a methyl, fluoromethyl, difluormethyl, trifluoromethyl, carboxylic acid, lower carboxylate of 1 to 4 carbon atoms, carboxamide or cyano group;  
 R 2  represents a hydrogen or methyl group;  
 R 3 , R 4 , R 7  and R 8 , are the same or different, represent hydrogen, chlorine, fluorine, methyl, trifluoromethyl or methoxy group;  
 R 5  represents hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylsulphonyl, aminosulphonyl or acetoaminosulphonyl group;  
 R 6  represents hydrogen, chlorine, fluroine, methyl, or trifluromethyl, methoxy, trifluoromethoxy, methylsulphonyl, aminosulphonyl or acetylaminosulphonyl group, with the provisio that one of R 5  or R 6  represents hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy, or trifluoromethoxy and the other of R 5  or R 6  represents a methylsulfonyl, aminosulphonyl, or a acetylaminosulphonyl group;  
 with the provision that when R 1  represents a methyl group then  
 R 2  represents a hydrogen atom or a methyl group;  
 R 3  and R 8 , are the same or different, and represent hydrogen, chlorine, fluorine, methyl or trifluoromethyl group;  
 R 4  represents hydrogen, fluorine, methyl, trifluoromethyl or methoxy group;  
 R 5  represents fluorine, triflouromethyl, trifluoromethoxy, and R 6  methylsulfonyl or amino sulphonyl group;  
 R 6  represents hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylsulphonyl or aminosulphonyl group, with the proviso that one of R 5  or R 6  represents hydrogen, chlorine, fluorine, methyl, trifluoromethyl, and the other of R 5  or R 6  represent methylsulphonyl or aminosulphonyl; and  
 R 7  represents hydrogen, chlorine, fluorine, methyl, trifluoromethyl or methoxy group; or a physiologically acceptable salt thereof.  
 
     
     
       2. A compound according to  claim 1 , selected from the group: consisting of
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-3-trifluoromethyl 1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-methyl-5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-1-(4-methylphenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-phenyl-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-5-phenyl- 1-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-fluorophenyl)-3-trifluoromethyl -1H-pyrazole;  
 4,5-dihydro-5-(4-fluorophenyl)-1-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-1-(4-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-5-(3,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 5-(2,4-dichlorophenyl)-4,5-dihydro-1-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-5-(2,4-dichlorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-(2-methylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-(3-methylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-(2-fluorophenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-5-(2-fluorophenyl)-1-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-(3-fluorophenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-(3-fluorophenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-5-(3-fluorophenyl)-1-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-(4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-5-(3-chloro-4-fluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-3-trifluoromethyl-5-(4-trifluoromethoxyphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-5-(2,3-difluorophenyl)-4,5-dihydro-3-trifluoromethoxyphenyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-(2,4-dimethylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 5-(3,4-difluorophenyl)-4,5-dihydro-1-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-5-(4-fluorophenyl)-3-methyl-1H-pyrazole;  
 4,5-dihydro-5-(4-fluorophenyl)-3-methyl-1-(4-methylsulphonylphenyl)-1H-pyrazole;  
 1-(4-aminosulfonylphenyl)-4,5-dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazole;  
 4,5-dihydro-3-methyl-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl)-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-3-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-1H-pyrazole-3-carboxylic acid;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-1H-pyrazole-3-carboxylic acid;  
 4,5-dihydro-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl)-1H-pyrazole-3-carboxylic acid;  
 Methyl 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-1H-pyrazole-3-carboxylate;  
 Methyl 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-1H-pyrazole-3-carboxylate;  
 Methyl 4,5-dihydro-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl)-1H-pyrazole-3-carboxylate;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-1H-pyrazole-3-carboxamide;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-1H-pyrazole-3-carboxamide;  
 4,5-dihydro-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl)-1H-pyrazole-3-carboxamide;  
 3-cyano-4,5-dihydro-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl)-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(3,4-dimethylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(3-methyl-4-methoxyphenyl-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(3-fluoro-4-methoxyphenyl)-3-trifluorome-til-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(2-fluoro-4-methoxyphenyl)-3-trifluorome-til-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(2,4-dimenthoxyphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-fluoro-2-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-3-difluoromethyl-4,5-dihydro-5-(2,4-dimethylphenyl)-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(2,3,4-trifluorophenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-5-(2-chloro-4-fluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(2-fluoro-4-trifluoromethylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-5-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(2-methyl-3-fluorophenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(2-methyl-4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-3-difluoromethyl-4,5-dihydro-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-fluoro-2-trifluoromethylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(2,4-difluorophenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-5-(2-chlorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-5-(4-chloro-2-fluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-fluoro-2-methylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(2-fluoro-4-methylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-acetylaminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 1-(4-chlorophenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-1-phenyl-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-1-(2-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(4-chloro-2-methylphenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-1-(3-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-1-(3-methylphenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-1-(2,4-dimethylphenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(2-chlorophenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 4,5-dihydro-1-(2-methylphenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 1-(2,4-dichlorophenyl)-4,5-dihydro-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
 (+)-1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole;  
 (−)-1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-2H-pyrazole;  
 (+)-4,5-dihydro-1-(4-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole; and  
 (−)-4,5-dihydro-1-(4-fluorophenyl)-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole;  
   4 , 5 - dihydro -   5   -(   4   - methyl - sulphonylphenyl )-   3   - trifluoromethyl )-   1   -(   2   - trifluoromethylphenyl )-   1 H - pyrazole;    
 
       or a physiologically acceptable salts thereof. 
     
     
       3. A procedure for preparing a derivative of pyrazoline of formula (I), according to  claim 1 , by reacting a compound of formula (II) 
                 
 
       wherein R 1  represents hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl and carboxylic acid groups, and R 2 , R 3 , R 4  and R 5  have the same meaning as claimed in  claim 1 , with a phenylhydrazine of formula (III) in base or salt form 
                 
 
       wherein R 6 , R 7  and R 8  have the same meaning as claimed in  claim 1 . 
     
     
       4. A procedure for the preparation of a derivative of pyrazoline of general formula (I), according to  claim 1 , wherein R 1 , represents an alkyl carboxylate with less than 1 to 4 carbon atoms and R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  have the same meaning as that claimed in  claim 1 , which comprises reacting a compound of formula (I) in which R 1  represents a carboxylic acid group (COOH) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  have the same meaning as that claimed in  claim 1 , with a suitable reagent to form the acid chloride, and then carrying out an esterification reaction with an aliphatic alcohol of 1 to 4 carbon atoms in the presence of an organic base, or by direct reaction of carboxylic acid with the corresponding saturated anhydrous alcohol with gaseous hydrogen chloride. 
     
     
       5. A procedure for the preparation of a derivative of pyrazoline of formula (I), according to  claim 1 , wherein R 1  represents a carboxylic acid group and R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  have the same meaning as claimed in  claim 1 , which comprises reacting a compound of formula (I) wherein R1 represents a carboxylic acid group (COOH) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  have the same meaning as claimed in  claim 1 , with a suitable reagent for forming the corresponding acid chloride, and then reacting with ammonia. 
     
     
       6. A procedure for the preparation of a derivative of pyrazoline of general formula (I), according to  claim 1 , wherein R 1  represents a cyano group and R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  have the same meaning as claimed in  claim 1 , which comprises reacting a compound of formula (I) wherein R 1  represents a carboxamide group and R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  have the same meaning as that indicated in  claim 1 , with either thionyl dimethylformamide-chloride or methanosulphonyl chloride. 
     
     
       7. A procedure for the preparation of a derivative of pyrazoline of formula (I), according to  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7  and R 8  have the same meaning as that claimed in  claim 1  and R 6  represents an acetylaminosulphonyl group, or R 1 , R 2 , R 3 , R 4 , R 6 , R 7  and R 8  have the same meaning as that claimed in  claim 1  and R 5  represents an acetylaminosulphonyl group, which comprises reacting a compound of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7  and R 8  have the meaning claimed in  claim 1  and R 6  represents a aminosulphonyl group, or R 1 , R 2 , R 3 , R 4 , R 6 , R 7  and R 8  have the meaning claimed in  claim 1  and R 5  represents a aminosulphonyl group, with, either acetyl chloride or acetic anhydride. 
     
     
       8. Procedure for the preparation of a derivative of pyrazoline of formula (I), according to  claim 1 , enantiomerically pure, which comprises effecting the resolution of a racemic mixture of the compound of formula (I) by chromatography with chiral stationary phase or formation of a salt with an enantiomerically pure acid. 
     
     
       9. A procedure for the preparation of a physiologically acceptable salt of a derivative of pyrazoline of formula (I), according to  claim 1 , which comprises reacting a compound of formula (I) with an inorganic acid or with an organic acid in the presence of a suitable solvent. 
     
     
       10. A pharmaceutical composition, containing at least, a derivative of pyrazoline of formula (I), or a physiologically acceptable salt thereof, according to  claim 1 , and pharmaceutically acceptable excipients. 
     
     
       11. A method of treatment of inflammation or of the treatment of other disorders associated with inflammation comprising administering a derivative of pyrazoline of formula (I), or a pharmaceutically acceptable salt thereof, according to  claim 1 , to a patient in need thereof. 
     
     
       12. The method of treatment according to  claim 11 , wherein the disorder associated with inflammation is arthritis. 
     
     
       13. The method of treatment according to  claim 11 , wherein the disorder associated with inflammation is pain. 
     
     
       14. The method of treatment according to  claim 11 , wherein the disorder associated with inflammation is fever. 
     
     
       15. The procedure according to  claim 4  wherein the suitable reagent to for the acid chloride is thionyl chloride or oxalyl chloride. 
     
     
       16. The procedure according to  claim 4  wherein the organic base is triethylamine or pyridine. 
     
     
       17. The procedure according to  claim 5  wherein the suitable reagent to form the corresponding acid chloride is thionyl chloride or oxalyl chloride. 
     
     
       18. A method for treating a migraine comprising administering a derivative of pyrazoline of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof to a patient in need thereof. 
     
     
       19. A method for treating menstrual disorders comprising administering a derivative of pyrazoline of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof to a patient in need thereof. 
     
     
       20. A method for treating asthma or bronchitis comprising administering a derivative of pyrazoline of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof to a patient in need thereof. 
     
     
       21. A method for treating skin disorders selected from psoriasis, eczema, burns and dermatitis comprising administering a derivative of pyrazoline of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof to a patient in need thereof. 
     
     
       22. A method for treating tendinitis or bursitis comprising administering a derivative of pyrazoline of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof to a patient in need thereof. 
     
     
       23. A method for treating gastrointestinal afflications selected from inflamed intestine, Crohn's disease, gastritis, irritated colon syndrome and ulcerous colitis comprising administering to  claim 1  or a pharmaceutically acceptable salt to a patient in need thereof.