Derivatives of tetrahydropyridines (or 4-hydroxypiperidines)-butylazols of formula (I), wherein R1, R2 and R3, which are similar or different, represent each of them hydrogen, halogen, alkyl C1-C4, trifluoromethyl, hydroxyl, alkoxyl, or two adjacent radicals can form a ring; A is a C atom and the dotted line represents an additional bond, or A is a C atom joined to a hydroxyl group and the dotted line represents absence of additional bond; Z1 is N or CR4; Z2 is N or CR5; Z4 is N or CR7; and R4, R5, R6 and R7, which different, represent hydrogen, halogen, alkyl C3-C4, aryl or substituted aryl, or two adjacent radicals can form part of another ring. These derivatives are useful for the treatment of acute pain, neuropathic pain or nociceptive pain in mammals, including human beings.
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1. A method of treating acute pain, neuropathic pain or nociceptive pain in a mammal which comprises administering to a patient in need thereof an effective amount of a derivative of tetrahydropyridines of formula (II)
##STR00005##
wherein
R1, R2 and R3 are identical or different and are selected from hydrogen, halogen, C1-C4 alkyl group, trifluoroethyl radical, hydroxyl or alkoxyl radical; and two adjacent radicals can form part of a six-member aromatic ring;
A is selected from a carbon atom or a carbon atom bound to a hydroxyl group (C—OH); wherein when A is a carbon atom the dotted line (- - -) represents a bond, and when A is a carbon atom bound to a hydroxyl group (C—OH) the dotted line (- - -) represents no bond;
Z1, is a nitrogen atom or a substituted carbon atom represented by the formula C—R4;
Z2 is a nitrogen atom or a substituted carbon atom represented by the formula C—R5;
Z4 is a nitrogen atom or a substituted carbon atom represented by the formula C—R7;
with the condition that Z1; Z2 and Z4 taken together can represent, at most, two nitrogen atoms; and
R4, R5, R6 and R7, are identical or different and are selected from hydrogen, halogen, C1-C4 alkyl group, aryl or substituted aryl group, and two adjacent radicals can form part of a six-member aromatic ring;
or physiologically acceptable salts thereof.
2. The method as claimed in
3. The method as claimed in
4. The method as claimed in
5. The method as claimed in
6. The method as claimed in
0. 7. The method as claimed in
4-chloro-1-[4-(4hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole;
4,5chloro-1-[4-(4-hydroxy-phenyl-1-piperidinyl)butyl]-2-ethyl-1H-imidazole;
1-[4-(4hydroxy[]phenyl-1-piperdinyl)butyl]-1H-benzimidazole;
1-[(4hydroxy-phenyl-1-piperdinyl)butyl]-1H-1,2,4-triazole;
4-chloro-1-{4-[4chlorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-pyrazole;
4,5-dichloro-1-{4-[4-hydroxy-4-(chlorophenyl)-1-piperidinyl]butyl}-2-methyl-1H-imidazole;
4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]-butyl}-1H-pyrazole;
4,5-dichloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]-butyl}-2H-imidazole;
4,5-dichloro-1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperdinyl]butyl}-2H-methyl-1H-imidazole;
1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)-butyl]-1H-indole 4,5-dichloro-1-{[4-hydroxy-(fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2-methyl-1H-imidazole;
1-[4(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-indole 4,5-dichloro-1-{4-[4hydroxy 4-(4-methylphenyl)1-piperyl]-butyl}-2-methyl-1H-imidazolo;
1-[-4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole;
1-[-4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-imidazole;
2-[-4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-2H-imidazole;
4-chloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-(piperidinyl)-butyl}-1H-pyrazole;
4-chloro-1-{4-[4-hydroxy-4-(4-methoxyphenyl)-1-(piperidinyl)]-butyl}-1H-pyrazole;
1-[4(4hydroxy-4-phenyl-1-piperidinyl)butyl]-2-phenyl-1H-imidazole 1-{4-[4-hydroxy-4-(4-methylphenyl-1-piperidinyl]butyl}-1H-benzimidazole;
4,5-diphenyl-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-imidazole
4-chloro-1-{4-[4-hydroxy-4-(1-naphthyl)-1-piperidinyl]butyl}-1H-pyrazole;
4-chloro-1-{4-[4-hydroxy4-(2-naphthyl-1-piperidinyl]-butyl}-1H-pyrazole;
4-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-pyrazole;
1-{4-[4phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole;
1-{4-[4phenyl-1(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-1,2,4-triazole;
4chloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole;
4,5-dichloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl-}-2-methyl-1H-imidazole;
4chloro-1-{4-[4-(3-trifuoromethylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl-}-1H-pyrazole;
4,5-dichloro-2-methyl-1-{4-[4-(3-trifluoromethylphenyl)-1-(1,2,3,6tetahydropyridinyl)]-butyl}-1H-imidazole;
4-chloro-1-{4-[4-(1-naphthyl)-1-(1,2,3,6-tetrahydropyridinyl]butyl}-1H-pyrazole;
4chloro-1-{4-[4-(2-naphtyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole;
1-{2-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]etil}-1H-benzimidazole;
1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole hydrochloride;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-bencimidazole hydrochloride;
4,5-dichloro-2-methyl-1-{4-[4(3-trifluoromethylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-imidazole-hydrochloride;
4-chloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6)-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride;
1-{4-[1-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride;
4,5-dichloro-1-{4-[4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-imidazole hydrochloride;
4-(chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride;
4-(4-chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-benzimidazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole;
2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-imidazole;
2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-benzotriazole hydrochloride;
2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-benzotriazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzotriazole hydrochloride;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzotriazole;
4chloro-1-{4-[4(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl]butyl}-1H-pyrazole hydrochloride;
1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride;
1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride;
2-phenyl-1-{4-[-4-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-imidazole hydrochloride;
1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole;
4-(4-chlorophenyl)-1-[4-(4hydroxy-4-phenyl-1-piperidinyl)butyl]1H-pyrazole;
1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-benzimidazole;
4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]butyl}-1H-pyrazole;
1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-imidazole;
2-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2H-imidazole;
2-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2H-benzotriazole;
1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-benzotriazole;
3-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole;
3-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride;
1-{4-[4-hydroxy-4-(4-fluorophenyl)-1-piperidinyl]butyl}-1H-triazole;
1-{4-[4-hydroxy-4-(4-chlorophenyl)-1-piperidinyl]butyl}-1H-triazole;
4,5-dichloro-1-{4-[4-(4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole citrate;
1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole;
1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride;
1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole;
1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride;
2-phenyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole;
2-phenyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride;
2,5-dimethyl-1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole;
2,5-dimethyl-1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride;
2,5-dimethyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole;
2,5-dimethyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride;
1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole;
1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride;
1-{4-[4-(4-chlorophenyl)-1-1(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-trizole hydrochloride.
0. 8. The method as claimed in
4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole;
4,5-dichloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-2-methyl-1H-imidazole;
1-[4-(4-hydroxy-4-phenyl-1-piperdinyl)butyl]-1H-benzimidazole;
1-[4-(4-hydroxy-4-phenyl-1-piperdinyl)butyl]-1H-1,2,4-triazole;
4-chloro-1-{4-[4-(4-chlorophenyl)-4-hydroxy-1-piperdinyl]butyl}-1H-pyrazole;
4,5-dichloro-1-{4-[4-hydroxy-4-(4-chlorophenyl)-1-piperdinyl]butyl}-2-methyl-1H-imidazole;
4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperdinyl]-butyl}-1H-pyrazole;
4,5-dichloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperdinyl]-butyl}-2-methyl-1H-imidazole;
4,5-dichloro-1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperdinyl]butyl}-2-methyl-1H imidazole;
1-[4-(4-hydroxy-4-phenyl-1-piperdinyl)butyl]-1H-indole;
4,5-dichloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperyl]butyl}-2-methyl-1H imidazole;
1-[4-(4-hydroxy-4-phenyl-1-piperdinyl)butyl]-1H-pyrazole;
1-[4-(4-hydroxy-4-phenyl-1-piperdinyl)butyl]-1H-indazole;
2-[4-(4-hydroxy-4-phenyl-1-piperdinyl)butyl]-2H-indazole;
4-chloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperdinyl]-butyl}-1H-pyrazole;
4-chloro-1-{4-[4-hydroxy-4-(4-methoxyphenyl)-1-piperdinyl]-butyl}-1H-pyrazole;
1-[4-(4-hydroxy-4-phenyl-1-piperdinyl)butyl]-2-phenyl-1H-imidazole;
1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperdinyl]butyl}-1H-benzimidazole;
4,5-diphenyl-1-[4-(4-hydroxy-4-phenyl-1-piperdinyl)butyl]-1H-imidazole;
4-chloro-1-{4-[4-hydroxy-4-(1-naphthyl)-1-piperidinyl]butyl}-1H-pyrazole;
4-chloro-1-{4-[4-hydroxy-4-(2-naphthyl-1-piperidinyl]butyl}-1H-pyrazole;
4-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-pyrazole;
1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole;
1-{4-[4-phenyl-1(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-1,2,4-triazole;
4-chloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole;
4,5-dichloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl-}-2-metyl-1H-imidazole;
4-chloro-1-{4-[4-(3-trifuoromethylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl-}-1H-pyrazole;
4,5-dichloro-2-methyl-1-{4-[4-(3-trifluoromethylphenyl)-1-(1,2,3,6-tetahydropyridinyl)]-butyl}-1H-imidazole;
4-chloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-1H-pyrazole;
4,5-dichloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-2-methyl-1H-imidazole;
4,5-dichloro-1-{4-[4-[phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-2-methyl-1H-imidazole;
4,5-dichloro-1-{4-[4-[phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-2-methyl-1H-imidazole hydrochloride;
4,5-dichloro-1-{4-[4-[phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-2-methyl-1H-imidazole dihydrochloride;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-indole;
1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-indole;
4,5-dichloro-2-methyl-1-{4-[4-(4-methylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole;
1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-pyrazole;
1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-indazole;
2-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-indazole;
4-chloro-1-{4-[4-(4-methylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-pyrazole;
4-chloro-1-{4-[4-(4-methoxyphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-pyrazole;
4-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]propyl}-1H-pyrazole;
4,5-dichloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]propyl}-2-methyl-1H-imidazole;
2-phenyl-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole;
1-{4-[4-(4-methylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-benzimidazole;
4,5-diphenyl-1-{4-[4-[phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-imidazole;
4-chloro-1-{4-[4-(1-naphthyl)-1-(1,2,3,6-tetrahydropyridinyl]butyl}-1H-pyrazole;
4-chloro-1-{4-[4-(2-naphthyl)-1-(1,2,3,6-tetrahydropyridinyl]butyl}-1H-pyrazole;
1-{2-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]ethyl}-1H-benzimidazole;
1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole hydrochloride;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole hydrochloride;
4,5-dichloro-2-methyl-1-{4-[4-(3-trifluoromethylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-imidazole-hydrochloride;
4-chloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6)-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride;
1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazole hydrochloride;
4,5-dichloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride;
4-(4-chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-pyrazole hydrochloride;
4-(4-chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-pyrazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-triazole hydrochloride;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-benzimidazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazole;
2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-indazole;
2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-benzotriazole hydrochloride;
2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-benzotriazole;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzotriazole hydrochloride;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzotriazole;
4-chloro-1-{4-[4(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl]butyl}-1H-pyrazole hydrochloride;
1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride;
1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride;
2-phenyl-1-{4-[-4-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-1H-imidazole hydrochloride;
1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride;
1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole;
4-(4-chlorophenyl)-1-[4-(4-hydroxy-4-phenyl-1-piperdinyl)butyl]1H-pyrazole;
1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-benzimidazole;
4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]butyl}-1H-pyrazole;
1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-indazole;
2-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2H-indazole;
2-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2H-benzotriazole;
1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-benzotriazole;
3-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazole;
3-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazole hydrochloride;
1-{4-[4-hydroxy-4-(4-fluorophenyl)-1-piperidinyl]butyl}-1H-triazole;
1-{4-[4-hydroxy-4-(4-chlorophenyl)-1-piperidinyl]butyl}-1H-triazole;
4,5-dichloro-1-{4-[4-(4-hydrophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2 methyl-1H-imidazole hydrochloride;
4,5-dichloro-1-{4-[4-(4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride;
1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole citrate;
1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole;
1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride;
1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole;
1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride;
2-phenyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole; 2-phenyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride;
2,5-dimethyl-1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole;
2,5-dimethyl-1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride;
2,5-dimethyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole;
2,5-dimethyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride;
1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole;
1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride; and
1-{4-[4-(4-chlorophenyl)-1-1(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole citrate,
in the preparation of a medicament for the treatment of acute pain, neuropathic pain or nociceptive pain in mammals, including man.
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The present invention relates to the use of derivatives of tetrahydropyridines (or 4-hydroxypyperidines)butylazoles of general formula (I), as well as their physiologically acceptable salts, in the preparation of medicaments useful in human and/or veterinary therapy for the treatment of acute pain, neuropathic pain and nociceptive pain, either alone or in combination with other analgesics, producing in this case a synergy.
In our patent application WO 96/04287 compounds of general formula (I) are disclosed
##STR00001##
that have an affinity for the cry and 5HT1A receptors, and which are claimed as medicaments useful for the treatment of anxiety, psychosis, epilepsy, convulsion, amnesia, cerebro-vascular diseases and senile dementia.
We have now discovered that the compounds of general formula (I), as well as their pharmaceutically acceptable salts, are especially useful for the preparation of medicaments, useful in human and/or veterinary therapy for the prophylaxis, alleviation or curing of acute pain, neuropathic pain and nociceptive pain, either alone or in combination with other analgesics, giving rise in this case to a synergy.
The present invention relates to the use of derivatives of tetrahydropyridines (or 4-hydroxypyperidine)butylazoles of general formula:
##STR00002##
where
The term “a halogen atom” represents a fluorine, chlorine or bromine atom.
The term “aryl or substituted aryl” represents a phenyl radical or a phenyl radical substituted by halogen.
The term “alkoxy” represents a methoxyl or ethoxyl radical.
The term “G1-G4 alkyl” represents a straight chain or branched radical that is based on a saturated hydrocarbon of 1 to 4 atoms of carbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl y terebutyl for example.
Physiologically acceptable salts of the compounds of general formula (I) refer both to salts formed with inorganic acids and organic acids, in particular, to salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, lactic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinamic acid, salicylic acid and alkyl, cycloalkyl or arylsulphonic acids.
The use of derivatives of general formula (I) for the treatment of pain refers to the use of analgesics in clinical practice. The term acute pain includes, but is not limited to, headache, arthritis, muscular tension or dysmenorrhea. The term neuropathic pain includes, but is not limited to, chronic back pains, pain associated with arthritis, herpes, pain associated with cancer, pain of a phantom limb, pain during childbirth or neuropathic pain resistant to opoids. The term nociceptive pain includes, but is not limited to, post-operation pain, dental pain, pain arising from surgery, pain caused by serious burns, post-natal pain or pain related with the genitourinary tract.
The derivatives of general formula (I) can be prepared according to the procedures disclosed in out patent application WO 96/04287.
In human therapy, the dosage administered of the compounds of the present invention varies as a function of the seriousness of the affliction to be treated. Normally the dosage will lie between 1 and 100 mg/day. The compounds of the invention can be administered as the only active ingredient or in conjunction with another analgesic in 2 proportion of one part of compound of general formula (I) with around one to ten parts of the other analgesic, with the aim of provoking a synergy. Other analgesics include, but are not limited to, non-steroid anti-inflammatory compounds such as aspirin or indomethacine, other analgesics such as paracetamol, narcotic analgesics or related compounds such as morphine, meperidine or pentazocine. The compounds of the invention, with a suitable pharmaceutical formulation, are administered by different routes, such as orally, transdermically, parenterally, subcutaneously, intranasally, intramuscularly or intravenously. Pharmaceutical compositions that contain compounds of general formula (I) are disclosed in out patent application WO 96/04287.
Illustrative examples of compounds included in the scope of the present invention include compounds that are characterised by the data indicated in tables 1 and 2.
TABLE 1
##STR00003##
Ex.
R1
R2
R3
R4
R5
Z1
Z2
R6
Z4
m.p.
IR cm−1
1H-RMN (300 MHz), δ (solvent)
1
H
H
H
H
H
N
CH
Cl
CH
102-103° C.
3364 (b.a., OH),
1.56(quin, J=7.1Hz, 2H), 1.65(b.a., 1H); 1.76
2950, 2810, 1375,
(d, J=12.4Hz, 2H); 1.90(quin, J=7.6Hz, 2H); 2.20(m,
1130, 991, 969,
2H); 2.40-2.55(a.c., 4H); 2.83(d, J=9.5Hz, 2H); 4.11
760, 696, 605
(t, JH=8Hz, 2H); 7.21-7.42(a.c., 5H); 7.52(d,J=8.5Hz,
KBr
2H) (CDCl3)
2
H
H
H
H
H
C—CH3
N
Cl
CCl
86-89° C.
3196 (b.a., OH),
1.59(m, J=5.3 J′=6.6, 2H); 1.70-1.32(a.c., 4H); 2.16
2951, 2924, 2824,
(d, t, J=13.0Hz J′=4.4Hz, 2H); 2.37(s, 3H); 2.41-2.55
1406, 1247, 1146
(a.c., 5H); 2.79(d, J=11.3Hz, 2H); 3.88(t, J=7.5Hz,
762, 703 KBr
2H); 7.27(t, J=7.2Hz, 1H); 7.36(t, J=7.6Hz, 2H); 7.51
(d, J=7.3Hz, 2H) (CDCl3)
3
H
H
H
H
H
CH
N
CH═CH—CH═CH—C
122-123° C.
3180 (b.a., OH),
1.51(quin, J=7.4Hz, 2H); 1.73(d, J=12.7Hz, 2H); 1.87
2929, 2818, 1496,
(quin, J=7.6Hz, 2H); 2.10(dt, J=12.9Hz J′=4.1Hz, 2H);
1467, 1459, 1445,
2.36-2.50(a.c., 4H); 2.70(d, J=11.2Hz, 2H); 3.25(b.a.,
1286, 1219, 1143,
1H); 4.12(t, J=7.1Hz, 2H); 7.21-7.40(a.c., 6H); 7.51
769, 743, 707
(d, J=8.3Hz, 2H); 7.70-7.75(a.c., 2H) (CDCl3)
KBr
4
H
H
H
H
H
CH
N
H
N
123° C.
3180 (b.a., OH),
1.45(quin, J=7.5Hs, 2H); 1.69(d, J=12.9Hz, 2H); 1.85
2949, 2919, 2838,
quin, J=7.5Hz, 2H); 2.07(dt, J=13.0Hz J′=4.1Hz, 2H);
1276, 1145, 1135,
2.33-2.45(a.c., 4H); 2.69(d, J=11.2Hz, 2H); 2.93(b.a.,
1006, 770, 707,
1H); 4.10(t, J=6.9Hz, 2H); 7.18(t, J=7Hz, 1H); 7.27
676
(t, J=7.8Hz, 2H); 7.46(d, J=8.3Hz, 2H); 7.80(s, 1H);
KBr
7.91(s, 1H) (CDCl3)
5
H
H
Cl
H
H
N
CH
Cl
CH
106° C.
3145 (b.a., OH),
1.47(quin, J=7.5Hz, 2H); 1.69(d, J=11.9Hz, 2H); 1.84
2947, 2918, 2834,
(quin, J=7.6Hz, 2H); 2.05(dt, J=13Hz, J′=4.4Hz, 2H);
1318, 1147, 1083,
2.34-2.50(a.c., 5H); 2.72 (d, J=11.2Hz, 2H); 4.05
1112, 990, 817,
(t, J=7.0Hz, 2H); 7.29(AB system, J=8.6Hz, 2H); 7.36
612
(s, 2H); 7.42(AB system, J=8.6Hz, 2H) (CDCl3)
KBr
6
H
H
Cl
H
H
C—CH3
N
Cl
CCl
oil
3340 (b.a., OH),
1.54(m, 2H); 1.67-1.78(a.c., 4H); 2.06(dt, J=13Hz,
2946, 2820, 1537,
J′=4.2Hz, 2H); 2.32(s, 3H); 2.38-2.45(a.c., 5H); 2.73
1492, 1471, 1406,
(d, J=11.2Hz, 2H); 3.86(t, J=7.3Hz, 2H); 7.28(AB
1376, 1247, 1135,
system, J=8.6Hz, 2H); 7.43(AB system, J=8.6Hz, 2H)
1094, 1013, 828,
(CDCl3)
755
film
7
H
CF3
H
H
H
N
CH
Cl
CH
oil
3360 (b.a., OH),
1.48(quin, J=7.6Hz, 2H); 1.71(d, J=12.5Hz, 2H); 1.85
2948, 2823, 1438,
(quin, J=7.6Hz, 2H); 2.06-2.21(a.c., 3H); 2.36-2.43
1378, 1330, 1212,
(a.c., 4H); 2.76(d, J=11.5Hz, 2H); 4.06(t, J=7.1Hz,
1165, 1124, 1047,
2H); 7.35(s, 2H); 7.43-7.51(a.c., 2H); 7.66
972, 804, 704
(d, J=7.5Hz, 1H); 7.79(s, 1H) (CDCl3)
film
8
H
CF3
H
H
H
C—CH3
N
Cl
CCl
oil
3340 (b.a., OH),
1.57(quin, J=7.5Hz, 2H); 1.70-1.80(a.c., 4H); 2.15
2948, 2823, 1408,
(dt, J=12.9Hz J′=3.6Hz, 2H); 2.35(s, 3H); 2.40-2.52
1330, 1165, 1126,
(a.c., 4H); 2.80(d, J=11.7Hz, 2H); 3.88(t, J=7.0Hz,
1075, 789, 763,
2H); 7.42-7.57(a.c., 2H); 7.69(d, J=7.5Hz, 1H); 7.82
704
(s, 1H) (CDCl3)
film
9
H
H
F
H
H
C—CH3
N
Cl
CCl
oil
3330 (b.a., OH),
1.58(m, 2H); 1.64-1.81(a.c., 4H); 2.14(dt, J=12.9Hz
2946, 2818, 1509,
J′=3.6Hz 2H); 2.32(s, 3H); 2.43-2.60(a.c., 4H); 2.84
1406, 1247, 1222,
(d, J=11Hz, 2H); 3.87(t, J=7.1Hz, 2H); 4.18(b.a., 1H),
1160, 835
7.01(t, J=8.8Hz, 2H); 7.46(dd, J=8.8Hz J′=5.2Hz, 2H)
film
(CDCl3)
10
H
H
H
H
H
CH
CH
CH═CH—CH═CH—C
109-111° C.
3190 (b.a., OH),
1.57(m, 2H); 1.73(d, J=14Hz, 2H); 1.80(b.a., 1H);
2956, 2823, 1461,
1.90(m, 2H); 2.13(dt, J=13Hz J′=4Hz, 2H); 2.32-2.46
1446, 1319, 1303,
(a.c., 4H); 2.76(d, J=11.3Hz, 2H); 4.16(t, J=7.1Hz,
1218, 1142, 738,
2H); 6.50(d, J=3.1Hz, 1H); 7.05-7.14(a.c., 2H); 7.18-
703
7.40(a.c., 5H); 7.50(d, J=7.8Hz, 2H); 7.00
KBr
(d, J=7.3Hz, 1H) (CDCl3)
11
H
H
CH3
H
H
C—CH3
N
Cl
CCl
oil
3360 (b.a., OH),
1.53(m, 2H); 1.66-1.84(a.c., 4H); 2.09(dt, J=12.9Hz,
2946, 2818, 1535,
J′=3.6Hz, 2H); 2.33(s, 3H); 2.36(s, 3H); 2.39-2.50
1471, 1406, 1376,
(a.c., 4H); 2.77(d, J=11.2Hz, 2H); 3.87(t, J=7.0Hz,
1247, 1134, 817,
2H); 7.15(AB system, J=7.8Hz, 2H); 7.33(AB
755
system, J=7.8Hz, 2H) (CDCl3)
12
H
H
H
H
H
N
CH
H
CH
89-91° C.
3137 (b.a., OH),
1.51(quin, J=7.6Hz, 2H); 1.73(d, J=12.3Hz, 2H); 1.89
2947, 2532, 1396,
(quin, J=7.6Hz, 2H); 2.00-2.20(a.c., 3H); 2.35-2.45
1378, 1119, 1046,
(a.c., 4H); 2.76(d, J=10.2Hz, 2H); 4.13(t, J=7.1Hz,
756, 697
2H); 6.21(s, 1H); 7.21(m, 1H); 7.30-7.37(a.c., 3H);
KBr
7.44-7.52(a.c., 3H) (CDCl3)
13
H
H
H
H
H
N
CH
CH═CH—CH═CH—C
107-109° C.
3311 (b.a., OH),
1.53(m, 2H); 1.71(d, J=12.2Hz, 2H); 1.95(m, 2H);
2953, 2803, 1465,
2.10(m, 2H); 2.29(b.a., 1H); 2.35-2.47(a.c., 4H);
1375, 1133, 1117,
2.71(d, 2H); 4.39(t, J=7.1Hz, 2H); 7.13(t, 1H); 7.22-
1043, 1017, 761,
7.44(a.c., 5H); 7.50(d, J=8Hz, 2H); 7.71(d, J=8.3Hz,
744, 704
1H); 795(s, 1H) (CDCl3)
KBr
14
H
H
H
H
H
N
C—CH═CH—CH═CH
CH
120-122° C.
3295 (b.a., OH),
1.58(m, 2H); 1.73(d, J=13.5Hz, 2H); 1.90-2.20(a.c.,
2946, 2817, 1377,
4H); 2.38-2.47(a.c., 4H); 2.75(d, J=10.5Hz, 2H); 4.42
1126, 786, 735,
(t, J=6.Hz, 2H); 7.06(t, J=7.5Hz, 1H); 7.22-7.37(a.c.,
700
4H); 7.49(d, J=7.8Hz, 2H); 7.61-7.71(a.c., 2H); 7.90
KBr
(s, 1H) (CDCl3)
15
H
H
CH3
H
H
N
CH
Cl
CH
81-82° C.
3122 (b.a., OH),
1.51(quin, J=7.6Hz, 2H); 1.73(d, J=11.7Hs, 2H); 1.87
2936, 1475,
(quin, J=7.6Hz, 2H); 2.12(dt, J=12.8Hz J′=4.4Hz, 2H),
1434, 1378, 1319,
2.33(s, 3H); 2.35-2.48(a.c., 5H); 2.74(d, J=11.2Hz,
898, 973, 814
2H); 4.07(t, J=7.1Hz, 2H); 7.15(d, J=8Hz, 2H); 7.25-
KBr
7.40(a.c., 4H) (CDCl3)
16
H
H
CH3O
H
H
N
CH
Cl
CH
122-123° C.
3190 (b.a., OH),
1.49(quin, J=7.6Hz, 2H); 1.72(d, J=11.8Hz, 2H); 1.84
2954, 2823, 2827,
(quin J=7.4Hz, 2H); 2.00-2.14(a.c.(dt+b.a.), 3H);
1509, 1314, 1243,
2.34-2.47(a.c., 4H); 2.72(d, J=11Hz, 2H); 3.77(s,
1178, 971
3H); 4.05(t, J=7.1Hz, 2H); 6.85(d, J=9Hz, 2H); 7.24-
KBr
7.42(a.c., 4H) (CDCl3)
17
H
H
H
H
H
CPh
N
H
CH
108-110° C.
3220 (b.a., OH),
1.45(quin, J=7.6Hz, 2H); 1.68-1.82(a.c., 4H); 2.08
2944, 2817, 1473,
(dt, J=13.0Hz J′=4.1Hz, 2H); 2.29-2.42(a.c., 4H); 2.5
1446, 1421, 1136,
(b.a., 1H); 2.67(d, J=11.2Hz, 2H); 4.01 m(t, J=7.3Hz,
1046, 787, 773,
2H); 7.01(s, 1H); 7.08(s, 1H); 7.20-7.56(a.c., 10H)
761, 700
(CDCl3)
KBr
18
H
H
CH3
H
H
CH
N
CH═CH—CH═CH—C
oil
3260 (b.a., OH),
1.58(quin, J=7.6Hz, 2H); 1.74(d, J=12Hz, 2H); 1.82
2944, 2817, 1497,
(b.a., 1H); 1.95(quin, J=7.6Hz, 2H); 2.11(dt, 2H);
1459, 1381, 1287,
2.33(s, 3H); 2.40-2.50(a.c., 4H); 2.74(d, J=11.5Hz,
1135, 1046, 817,
2H); 4.20(t, J=7.1Hz, 2H); 7.15(d, J=8.3Hz, 2H);
745
7.22-7.35(a.c., 3H); 7.37-7.43(a.c., 2H); 7.79(m,
film
1H); 7.87(s, 1H) (CDCl3)
19
H
H
H
H
H
CH
N
Ph
CPh
138-139° C.
3194 (b.a., OH),
1.38(m,2H); 1.56(m, 2H); 1.72(d, J=12.4Hz, 2H);
2939, 2806, 1509,
2.09(dt, 2H); 2.25(t, J=7.4Hz, 2H); 2.39(m, 2H); 2.66
1446, 773, 766,
(m, 2H); 3.10(b.a., 1H); 3.78(t, J=7.2Hz, 2H); 7.10-
758, 696
7.52(a.c., 16H);
KBr
20
CH═CH—CH═CH
H
H
H
N
CH
Cl
CH
oil
3357 (b.a., OH),
1.44(quin, J=7.3Hz, 2H); 1.77(quin, J=7.5Hz, 2H);
2946, 2833, 1434,
2.15-2.30(a.c., 5H); 2.34(t, J=7.5Hz, 2H); 2.57(m, 2H);
1379, 1315, 1140,
2.73(d, J=11.3Hz, 2H); 3.99(t, J=7.1Hz, 2H); 7.26-7.46
1123, 972, 781,
(a.c., 6H); 7.73(d, J=8.1Hz, 1H); 7.82(m, 1H); 8.91
613
(m, 1H) (CDCl3)
KBr
21
H
CH═CH—CH═CH
H
H
N
CH
Cl
CH
142-143° C.
3131 (b.a., OH),
1.55(quin, J=7.5Hz, 2H); 1.70-1.97(a.c., 5H); 2.29
2950, 2820, 1377,
(dt, J=12.7Hz, J′=4.1Hz, 2H); 2.41-2.55(a.c., 4H); 2.83
1311, 971, 829,
(d, J=11.7Hz, 2H); 4.11(t, J=7.0Hz, 2H); 7.39-7.50
761, 613
(a.c., 4H); 7.64(dd, J=9.1Hz, J′=1.5Hz, 1H); 7.81-7.85
KBr
(a.c., 3H); 7.95(s, 1H) (CDCl3)
22
H
H
H
H
H
N
CH
C6HCl
CH
137-140° C.
3347, 2944, 2810,
1.56(m, 2H); 1.74(m, 2H); 1.80(b.a., 1H); 1.94(m,
1562, 1492, 1376,
2H); 2.40(dt, J=13.1Hz, J′=4.0Hz, 2H); 2.40-2.50(a.c.,
1127, 1094, 1002,
4H); 2.77(m, 2H); 4.15(t, J=7.0Hz, 2H); 7.25-7.40
952, 828, 760, 699
(a.c., 7H); 7.50(d, J=8.3Hz, 2H); 7.61(s, 1H); 7.72
KBr
(s, 1H) (CDCl3)
23
H
H
F
H
H
CH
N
CH═CH—CH═CH—C
120-122° C.
3230, 2947, 2915,
1.58(m, 2H); 1.70(m, 2H); 1.93(m, 2H); 2.12(m, 2H);
1504, 1219, 1135,
2.40-2.55(a.c., 4H); 2.76(m, 2H); 4.19(t, J=7.0Hz,
835, 746
2H); 7.02(m, 2H); 7.26(m, 2H); 7.30-7.50(a.c., 3H);
KBr
7.74(m, 1H); 7.83(s, 1H) (CDCl3)
24
H
CF3
H
H
H
N
CH
Cl
CH
HCl
3259, 2465, 2420,
1.62-1.84(a.c., 6H); 2.53(m, 2H); 3.09-3.40(a.c., 6H);
147-148° C.
2365, 1328, 1108,
4.12(t, J=6.8Hz, 2H); 5.76(s, 1H); 7.51(s, 1H); 7.52-
1073
7.82(a.c., 4H); 8.02(s, 1H); 10.96(b.a., 1H);
KBr
(DMSO-d6)
25
H
H
F
H
H
N
CH
CH═CH—CH═CH—C
136-137° C.
3303, 2951, 2805,
1.54(m, 2H); 1.60-1.80(a.c., 3H); 1.97(m, 2H); 2.06
1506, 1464, 1376,
(dt, J=13.0Hz, J′=4.3Hz, 2H); 2.30-2.43(a.c., 4H, 2.72
1218, 1162, 1118,
(m, 2H); 4.40(t, J=7.0Hz, 2H); 6.99(t, J=8.8Hz, 2H),
832, 741
7.12(m, 1H); 7.32-7.47(a.c., 4H); 7.71(d, J=8.1Hz,
KBr
1H); 7.96(s, 1H) (CDCl3—CD3OD [1:1])
26
H
H
F
H
H
N
C—CH═CH—CH═CH
CH
148-150° C.
3325, 2950, 2923,
1.57(m, 2H); 1.70-1.77(a.c., 3H); 1.98-2.19(a.c., 4H);
2812, 1509, 1377,
2.35-2.49(a.c., 4H); 2.77(d, J=11.2Hz, 2H); 4.45
1218, 1131, 834,
(t, J=7.0Hz, 2H); 6.98-7.15(a.c., 3H); 7.25-7.49(a.c.,
758
3H); 7.63(d, J=8.3Hz, 1H); 7.69(d, J=7.8Hz, 1H); 7.91
KBr
(s, 1H) (CDCl3—CD3OD [1:1])
27
H
H
F
H
N
N
C—CH═CH—CH═CH
N
109-110° C.
3400, 2931, 2812,
1.47-1.80(a.c., 4H); 1.90-2.25(a.c., 5H); 2.25-2.55
1509, 1229, 1101,
(a.c., 4H); 2.70(m, 2H); 4.78(t, J=6.9Hz, 2H); 7.01
831, 745
(t, J=8.7Hz, 2H); 7.26-7.54(a.c., 4H); 7.85(dd, J=6.7Hz,
KBr
J′=3.0Hz, 2H) (CDCl3—CD3OD [1:1])
28
H
H
F
H
H
N
N
CH═CH—CH═CH—C
102-103° C.
3430, 2952, 2925,
1.45-1.80(a.c., 4H); 1.85-2.25(a.c., 5H); 2.25-2.55
1508, 1223, 1140,
(a.c., 4H); 2.77(m, 2H); 4.69(t, J=6.9Hz, 2H); 7.01
833, 744
(t, J=8.7Hz, 2H); 7.26-7.53(a.c., 5H); 8.06(d, J=7.3Hz,
KBr
1H) (CDCl3—CD3OD [1:1])
29
H
H
F
H
H
CH
N
H
N
oil
3350 (b.a., OH),
1.55(m, 2H); 1.74(d, J=12.6Hz, 2H); 1.94(m, 2H);
2947, 2818, 1509,
2.13(m, 2H); 2.40-2.55(a.c., 4H); 2.79(m, 2H); 4.20
1222, 1138, 836,
(t, J=6.9Hz, 2H); 7.02(t, J=8.4Hz, 2H); 7.46(m, 2H);
681
7.91(s, 1H); 8.04(s, 1H) (CDCl3)
film
30
H
H
Cl
H
H
CH
N
H
N
89-91° C.
3119 (b.a., OH),
1.46(m, 2H); 1.71(m, 2H); 1.90(quin, J=7.4Hz, 2H);
2956, 2829, 1509,
2.05(m, 2H); 2.33-2.50(a.c., 4H); 2.54(b.a., 1H); 2.72
1379, 1277, 1145,
(m, 2H); 4.16(t, J=7.1Hz, 2H); 7.28(m, 2H); 7.42(m,
1007, 824, 685
2H); 7.86(s, 1H); 7.99(s, 1H) (CDCl3)
KBr
TABLE 2
##STR00004##
Ex.
R1
R2
R3
R4
R5
Z1
Z2
R6
Z4
Salt/m.p.
IR cm−1
1H-RMN (300 MHz), δ (solvent)
1a
H
H
H
H
H
N
CH
Cl
CH
62-64° C.
3113, 2920, 2745,
1.56(quin, J=7.6Hz, 2H); 1.91(quin, J=7.6Hz,
1375, 1325, 1138,
2H); 2.47(t, J=7.4Hz, 2H); 2.58(m, 2H); 2.65
965, 837, 742,
(t, J=5.6Hz, 2H); 3.14(m, 2H); 4.11(t, J=7.1Hz,
688
2H); 6.06(m, 1H); 7.23-7.42(a.c., 7H) (CDCl3)
2a
H
H
H
H
H
CH
N
CH═CH—CH═CH—C
66-69° C.
2933, 1495, 745,
1.55(quin, J=7.6Hz, 2H); 1.92(quin, J=7.6Hz,
694, 665
2H); 2.43(t, J=7.3Hz, 2H); 2.52(m, 2H); 2.61
film
(t, J=5.6Hz, 2H); 3.07(m, 2H); 4.14(t, J=7.1Hz,
2H); 6.02(m, 1H); 7.20-7.40(a.c., 8H); 7.80(m,
1H); 7.86(s, 1H) (CDCl3)
3a
H
H
H
H
H
CH
N
H
N
63-64° C.
2942, 1438, 1381,
1.56(m, 2H); 1.95(m, 2H); 2.47(t, J=7.1Hz,
1271, 1142, 1006,
2H); 2.56(m, 2H); 2.66(t, J=5.3Hz, 2H); 3.11
753, 697, 681,
(m, 2H); 4.19(t, J=7.0Hz, 2H); 6.05(s, 1H); 7.21
KBr
(m, 1H); 7.30(t, J=7.6Hz, 2H); 7.36(d, J=7.8Hz,
2H); 7.94(s, 1H); 8.06(s, 1H) (CDCl3)
4a
H
H
Cl
H
H
N
CH
Cl
CH
103-104° C.
2939, 1493, 1436,
1.54(m, 2H); 1.90(m, 2H); 2.45(t, J=7.4Hz,
1381, 1306, 1122,
2H); 2.51(m, 2H); 2.65(t, J=5.6Hz, 2H); 3.10
1097, 973, 843,
(m, 2H); 4.10(t, J=7.0Hz, 2H); 6.03(m, 1H);
824, 730
7.26(AB system, J=8.6Hz, 2H); 7.29(AB
KBr
system, J=8.6Hz, 2H); 7.37(s, 1H); 7.41(s, 1H)
(CDCl3)
5a
H
H
Cl
H
H
C—CH3
N
Cl
CCl
119-120° C.
2922, 1531, 1494,
1.59(m, 2H); 1.76(m, 2H); 2.36(s, 3H); 2.42-
1469, 1403, 1380,
2.53(a.c., 4H); 2.67(t, J=5.3Hz, 2H); 3.12(m,
1366, 1245, 1094,
2H); 3.88(t, J=7.4Hz, 2H); 6.04(m, 1H); 7.27
1010
(AB system, J=9.1Hz, 2H); 7.30(AB
KBr
system, J=9.1Hz, 2H) (CDCl3)
6a
H
CF3
H
H
H
N
CH
Cl
CH
oil
2944, 1434, 1375,
1.53,(quin, J=7.5Hz, 2H); 1.89(quin, J=7.7Hz,
1331, 1247, 1165,
2H); 2.45(t, J=7.3Hz, 2H); 2.54(m, 2H); 2.66
1126, 1076, 972,
(t, J=5.5Hz, 2H); 3.10(m, 2H); 4.08(t, J=7.1Hz,
800, 698
2H); 6.10(m, 1H); 7.35-7.56(a.c., 5H); 7.59(s,
film
1H) (CDCl3)
7a
H
CF3
H
H
H
C—CH3
N
Cl
CCl
oil
2931, 2815, 1533,
1.62(quin, J=6.6Hz, 2H); 1.77(quin, J=7.6Hz,
1405, 1331, 1246,
2H); 2.37(s, 3H); 2.51(t, J=7.2Hz, 2H); 2.60(m,
1165, 1125, 1076,
2H); 2.71(t, J=5.6Hz, 2H); 3.17(m, 2H); 3.89
797, 699
(t, J=7.3Hz, 2H); 6.14(m, 1H); 7.40-7.50(a.c.,
film
2H); 7.55(d, J=7.5Hz, 1H); 7.62(s, 1H) (CDCl3)
8a
H
H
F
H
H
N
CH
Cl
CH
86-87° C.
2936, 1512, 1378,
1.60(quin, J=7.5Hz, 2H); 1.91(quin, J=7.5Hz,
1326, 1229, 988,
2H); 2.50-2.82(a.c., 4H); 2.76(t, J=5.6Hz, 2H);
967
3.19(m, 2H); 4.11(t, J=6.9Hz, 2H); 5.97(s, 1H);
KBr
6.99(t, J=8.8Hz, 2H); 7.32(dd, J=8.8Hz J′ =5.4Hz,
2H); 7.38(s, 1H); 7.40(s, 1H) (CDCl3)
9a
H
H
F
H
H
C—CH3
N
Cl
CCl
79-82° C.
2934, 1531, 1512,
1.74(m, 4H); 2.35(s, 3H); 2.60-2.72(a.c., 4H);
1408, 1247, 1225,
2.90(m, 2H); 3.33(m, 2H); 3.88(m, 2H); 5.95(s,
1167, 818
1H); 6.99(t, J=8.6Hz, 2H); 7.31(aa.c., 2H)
KBr
(CDCl3)
10a
H
H
H
H
H
C—CH3
N
Cl
CCl
oil
2929, 1533, 1405,
1.59(m, 2H); 1.76(m, 2H); 2.37(s, 3H); 2.49
1246, 748
(t, J=7.3Hz, 2H); 2.58(m, 2H); 2.69(t, J=5.4Hz,
film
2H); 3.14(m, 2H); 3.89(t, J=7.4Hz, 2H); 6.06
(m, 1H); 7.22-7.40(a.c., 5H) (CDCl3)
11a
H
H
H
H
H
C—CH3
N
Cl
CCl
.HCl
2930, 2576, 1407,
1.69(m, 2H); 1.81(m, 2H); 2.35(s, 3H); 2.71
203-204° C.
1376, 1245, 750,
(d, J=7.2Hz, 1H); 2.91(m, 1H); 3.17(a.c., 3H);
KBr
3.56(m, 1H); 3.75(m, 1H); 3.90-3.97(a.c., 3H);
6.17(s, 1H); 7.25-7.40(a.c., 3H); 7.47
(d, J=7.6Hz, 2H); 11.30(b.a., 1H) (DMSO-d6)
12a
H
H
H
H
H
C—CH3
N
Cl
CCl
.2HCl
3569, 2941, 2692,
1.67(m, 2H); 1.76(m, 2H); 2.36(s, 3H); 2.69
192-194° C.
2556, 1601, 1446,
(d, J=18.0Hz, 1H); 2.88(m, 1H); 3.15(a.c., 3H);
769, 753, 698
3.54(m, 1H); 3.72(m, 1H); 3.85-398(a.c., 3H);
KBr
6.15(s, 1H); 7.22-7.38(a.c., 3H); 7.45
(d, J=7.3Hz, 2H); 9.93(b.a., 1H); 11.36(b.a., 1H)
(DMSO-d6)
13a
H
H
F
H
H
CH
CH
CH═CH—CH═CH—C
oil
2937, 1510, 1464,
1.61(quin, J=7.7Hz, 2H); 1.93(quin, J=7.6Hz,
1230, 1161, 816,
2H); 2.42-2.58(a.c., 4H); 2.66(t, J=5.6Hz, 2H);
742
3.11(m, 2H); 4.17(t, J=7.0Hz, 2H); 5.98(m,
film
1H); 6.51(d, J=3.9Hz, 1H); 6.95-7.39(a.c., 8H);
7.65(d, J=7.8Hz, 1H) (CDCl3)
14a
H
H
H
H
H
CH
CH
CH═CH—CH═CH—C
oil
2938, 1510, 1485,
1.63(quin, J=7.4Hz,2H); 1.949quin, J=7.4Hz,
1463, 1446, 1376,
2H); 2.49(t, J=7.6Hz, 2H); 2.60(m, 2H); 2.69
1336, 1315, 763,
(t, J=5.3Hz, 2H); 3.14(m, 2H); 4.19(t, J=7.1Hz,
740, 695
2H); 6.08(m, 1H); 6.53(m, 1H); 7.08-7.44(a.c.,
film
9H); 7.67(d, J=8.1Hz, 1H) (CDCl3)
15a
H
H
CH3
H
H
C—CH3
N
Cl
CCl
87-88° C.
2939, 2916, 1529,
1.59(m, 2H); 1.75(m, 2H); 2.32(s, 3H); 2.36(s,
1404, 1378, 1243,
3H); 2.47(t, J=7.2Hz, 2H); 2.54(m, 2H); 2.67
1166, 1131, 1016
(t, J=5.2Hz, 2H); 3.11(m, 2H); 3.87(t, J=7.3Hz,
film
2H); 6.01(s, 1H); 7.11(AB system, J=8.1Hz,
2H); 7.27(AB system, J=8.1Hz, 2H) (CDCl3)
16a
H
H
H
H
H
N
CH
H
CH
36-38° C.
2941, 1396, 748,
1.54(quin, J=7.6Hz, 2H); 1.91(quin, J=7.6Hz,
695
2H); 2.45(t, J=7.6Hz, 2H); 2.55(m, 2H); 2.65
film
(t, J=5.6Hz, 2H); 3.11(m, 2H); 4.14(t, J=7.1Hz,
2H); 6.03(m, 1H); 6.21(m, 1H); 7.20-7.39(a.c.,
6H); 7.49(m, 1H) (CDCl3)
17a
H
H
H
H
H
N
CH
CH═CH—CH═CH—C
50-52° C.
2942, 1465, 1158,
1.61(quin, 2H); 2.00(quin, J=7.5Hz, 2H); 2.43-
832, 740, 691
2.58(a.c., 4H); 2.68(m, 2H); 3.14(s, 2H); 4.43
film
(t, J=6.6Hz, 2H); 6.02(s, 1H); 7.13(t, J=7.3Hz,
1H); 7.20-7.51(a.c., 7H); 7.73(d, J=7.9Hz, 1H);
7.99(s, 1H) (CDCl3)
18a
H
H
H
H
H
N
C—CH═CH—CH═CH
CH
73-75° C.
3049, 2940, 2778,
1.60(quin, J=7.6Hz, 2H); 2.09(quin, J=7.4Hz,
1467, 1371, 1158,
2H); 2.48(t, J=7.4Hz, 2H); 2.55(m, 2H); 2.66
1143, 1131, 757,
(t, J=5.6Hz, 2H); 3.11(d, J=2.9Hz, 2H); 4.45
742, 692
(t, J=7.1Hz, 2H); 6.03(s, 1H); 7.07(t, J=7.5Hz,
KBr
1H); 7.20-739(a.c., 6H); 7.63(d, J=4.3Hz, 1H);
7.70(d, J=8Hz, 1H); 7.91(s, 1H) (CDCl3)
19a
H
H
CH3
H
H
N
CH
Cl
CH
72-73° C.
3115, 2938, 2740,
1.55(quin, 2H); 1.90(quin, J=7.5Hz, 2H); 2.33
1376, 1328, 1137,
(s, 3H); 2.46(t, J=7.5Hz, 2H); 2.55(m, 2H); 2.66
986, 966, 844,
(t, J=6.4Hz, 2H); 3.11(m, 2H); 4.10(t, J=7.0Hz,
824, 797
2H); 6.01(s, 1H); 7.12(AB system, J=8Hz, 2H);
KBr
7.27(AB system, J=8Hz, 2H); 7.37(s, 1H); 7.41
(s, 1H) (CDCl3)
20a
H
H
CH3O
H
H
N
CH
Cl
CH
104-105° C.
2923, 1533, 1405,
1.54(quin, 2H); 1.89(quin, J=7.6Hz, 2H); 2.44
1379, 1246, 749
(t, J=7.4Hz, 2H); 2.52(m, 2H); 2.65(t, J=5.3Hz,
KBr
2H); 3.10(m, 2H); 3.78(s, 3H); 4.09(t, J=7.0Hz,
2H); 5.95(s, 1H); 6.84(AB system, J=8.5Hz,
2H); 7.31(AB system, J=8.5Hz, 2H); 7.36(s,
1H); 7.40(s, 1H) (CDCl3)
21a
H
H
H
H
H
N
CH
Cl
CH
oil
2948, 223, 2811,
2.08(quin, J=7.0Hz, 2H); 2.42(t, J=7.0Hz, 2H);
2774, 1446, 1382,
2.58(m, 2H); 2.67(t, J=5.6Hz, 2H); 3.13(m,
1316, 971, 748,
2H); 4.17(t, J=6.9Hz, 2H); 6.07(m, 1H); 7.23-
695
7.45(a.c., 7H) (CDCl3)
film
22a
H
H
H
H
H
CCH3
N
Cl
CCl
oil
2923, 1533, 1405,
1.95(quin, J=7.2Hz, 2H); 2.39(s, 3H); 2.46
1379, 1246, 749
(t, J=7.0Hz, 2H); 2.58(m, 2H); 2.69(t, J=4.9Hz,
film
2H); 3.13(m, 2H); 3.96(t, J=7.3Hz, 2H); 6.07
(m, 1H); 7.20-7.41(a.c., 5H) (CDCl3)
23a
H
H
H
H
H
CPh
N
H
CH
oil
2940, 1496, 1474,
1.51(m, 2H); 1.81(m, 2H); 2.40(t, J=7.4Hz,
1445, 1379, 1275,
2H); 2.56(m, 2H); 2.63(t, J=4.9Hz, 2H); 3.09
774, 698
(m, 2H); 4.04(t, J=7.2Hz, 2H); 6.03(m, 1H);
film
7.03(m, 1H); 7.13(m, 1H); 7.22-7.48(a.c., 8H);
7.58(m, 2H) (CDCl3)
24a
H
H
CH3
H
H
CH
N
CH═CH—CH═CH—C
90-91° C.
2939, 2915, 1500,
1.59(m, 2H); 1.95(m, 2H); 2.32(s, 3H); 2.46
1461, 1377, 1365,
(t, J=7.3Hz, 2H); 2.53(m, 2H); 2.63(t, J=5.5Hz,
750
2H); 3.08(m, 2H); 4.20(t, J=6.95Hz, 2H); 6.00
KBr
(s, 1H); 7.11(d, J=7.8Hz, 2H); 7.27(a.c., 4H);
7.40(m, 1H); 7.80(m, 1H); 7.8(s, 1H) (CDCl3)
25a
H
H
H
H
H
CH
N
Ph
CPh
100-101° C.
3130, 2939, 2770,
1.46(quin, J=7.5Hz, 2H); 1.65(quin, J=7.6Hz,
1600, 1506, 1443,
2H); 2.33(t, J=7.3Hz, 2H); 2.53(m, 2H); 2.60
1259, 954, 780,
(m, 2H); 3.05(m, 2H); 3.84(t, J=7.2Hz, 2H);
774, 750, 696,
6.02(m, 1H); 7.05-7.50(a.c., 15H); 7.61(s, 1H)
649
(CDCl3)
KBr
26a
CH═CH—CH═CH
H
H
H
N
CH
Cl
CH
oil
3057, 3043, 2942,
1.61(quin, J=7.5Hz, 2H); 1.95(quin, J=7.6Hz, 2H);
2806, 2768, 1378,
2.51-2.57(a.c., 4H); 2.76(t, J=5.6Hz, 2H); 3.20(m, 2H);
1365, 971, 801,
4.14(t, J=7.1Hz, 2H); 5.74(m, 1H); 7.26-7.50(a.c., 6H);
778
7.75(d, J=8Hz, 1H); 7.84(m, 1H); 8.02(m, 1H);
film
(CDCl3)
27a
H
CH═CH—CH═CH
H
H
N
CH
Cl
CH
95-96° C.
3111, 2920, 2806,
1.57(m, 2H); 1.92(m, 2H); 2.48(m, 2H); 2.71
1374, 1326, 966,
(a.c., 4H); 3.18(m, 2H); 4.11(m, 2H); 6.22(m, 1H);
826, 749, 612,
7.38-7.50(a.c., 4H); 7.61(m, 1H); 7.75-7.84(a.c., 4H)
KBr
(CDCl3)
28a
H
H
F
H
H
CH
N
CH═CH—CH═CH—C
135-136° C.
3050, 2920,
2.54(m, 2H); 2.74t, J=5.6Hz, 2H); 2.92(t, J=6.7Hz,
2780, 2760,
2H); 3.24(m, 2H); 4.35(t, J=6.7Hz, 2H); 5.98(m, 1H);
1510, 1492,
7.00(t, J=8.7Hz); 7.26-7.40(a.c., 4H); 7.42(m, 1H);
1459, 1224,
7.81(m, 1H); 8.01(s, 1H) (CDCl3)
1202, 1161,
771, 751
KBr
29a
H
H
H
H
H
CH
N
CH═CH—CH═CH—C
HCl
2940, 2488,
1.70-1.90(a.c., 4H); 2.78(m, 2H); 3.17(m, 2H);
177-178° C.
1500,
3.20-3.50(b.a., 2H); 3.79(m, 2H); 4.30(t, J=6.6Hz, 2H);
1420, 1390, 742
6.15(s, 1H); 7.17-7.40(a.c., 5H); 7.45(d, J=7.3Hz, 2H);
KBr
7.65(m, 2H); 8.35(s, 1H) (DMSO-d6)
30a
H
H
F
H
H
CH
N
CH═CH—CH═CH—C
106-108° C.
2942, 1512,
1.59(quin, J=7.5Hz, 2H); 1.96(quin, J=7.5Hz, 2H); 2.40-
1498,
2.50(a.c., 4H); 2.63(t, J=5.5Hz, 2H); 3.09(m, 2H); 4.21
1460, 1376,
(t, J=7.1Hz, 2H); 5.97(m, 1H); 6.98(t, J=8.1Hz, 2H);
1221, 756
7.20-7.35(a.c., 4H); 7.40(m, 1H); 7.80(m, 1H); 7.89(s,
KBr
1H) (CDCl3)
31a
H
H
F
H
H
CH
N
CH═CH—CH═CH—C
HCl
2930, 1600,
1.70-2.00(a.c., 4H); 2.78(m, 2H); 3.20(m, 2H); 3.20-
1510,
3.60(b.a., 2H); 3.81(m, 2H); 4.38(t, J=6.6Hz, 2H); 6.13
1275
(s, 1H); 7.19(t, J=8.7Hz, 2H); 7.33(m, 2H); 7.49(m,
KBr
2H); 7.71(d, J=7.8Hz, 1H); 7.77(d, J=7.6Hz, 1H); 8.79
(s, 1H); 11.20(b.a., 1H) (DMSO-d6)
32a
H
CF3
H
H
H
CCH3
N
Cl
CCl
HCl
2930, 2490,
1.67(m, 2H); 1.79(m, 2H); 2.33(s, 3H); 2.79(m, 1H);
205-206° C.
1330,
2.91(m, 1H); 3.10-3.20(a.c., 3H); 3.55(m, 1H); 3.77
1243, 1164,
(m, 1H); 3.91-4.00(a.c., 3H); 6.33(s, 1H); 7.58-7.80
1119,
(a.c., 4H); 11.32(b.a., 1H) (DMSO-d6)
33a
H
H
F
H
H
N
CH
Cl
CH
HCl
2543, 1512,
1.71-1.85(a.c., 4H); 2.68(m, 1H); 2.86(m, 1H); 3.10-
191-192° C.
1232,
3.20(a.c., 3H); 3.55(m, 1H); 3.72(m, 1H); 3.90(m,
967, 807
1H); 4.12(t, J=6.5Hz, 2H); 6.14(s, 1H); 7.20(t, J=8.7Hz,
KBr
2H); 7.40-7.55(a.c., 3H); 8.06(s, 1H); 11.20(b.a., 1H)
(DMSO-d6)
34a
H
H
H
H
H
N
CH
CH═CH—CH═CH—C
HCl
2931, 2566, 742
1.80(m, 2H); 1.91(m, 2H); 2.67(m, 1H); 2.88(m, 1H);
193-194° C.
KBr
3.10-3.20(a.c., 3H); 3.52(m, 1H); 3.71(m, 1H); 3.90
(m, 1H); 4.46(t, J=6.7Hz, 2H); 6.15(s, 1H); 7.14
(t, J=7.5Hz, 1H); 7.25-7.41(a.c., 4H); 7.46(d, J=8.6Hz,
2H); 7.71(d, J=8.6Hz, 1H); 7.75(d, J=8.3Hz, 1H); 8.08
(s, 1H); 11.18(b.a., 1H) (DMSO-d6)
35a
H
H
F
H
H
CCH3
N
Cl
CCl
HCl
2930, 2590,
1.67(m, 2H); 1.79(m, 2H); 2.33(s, 3H); 2.67(m, 1H);
160-161° C.
1512,
2.90(m, 1H); 3.10-3.25(a.c., 3H); 3.54(m, 1H); 3.72
1409, 1241, 827,
(m, 1H); 3.85-3.98(a.c., 3H); 6.13(s, 1H); 7.19(m,
KBr
2H); 7.50(m, 2H); 11.28(b.a., 1H) (DMSO-d6)
36a
H
H
H
H
H
N
CH
4-ClPh
CH
HCl
2472, 1560,
1.77(m, 2H); 1.87(m, 2H); 2.70(m, 1H); 2.86(m, 1H);
198-199° C.
1450,
3.16(a.c., 3H); 3.55(m, 1H); 3.73(m, 1H); 3.90(m,
1095, 955, 810,
1H); 4.17(t, J=6.6Hz, 2H); 6.15(m, 1H); 7.25-7.47(a.c.,
745
7H); 7.59(m, 2H); 7.90(s, 1H); 8.27(s, 1H); 10.91
KBr
(b.a., 1H) (DMSO-d6)
37a
H
H
H
H
H
N
CH
4-ClPh
CH
126-127° C.
2935, 1570,
1.60(m, 2H); 1.97(m, 2H); 2.48(t, J=7.3Hz, 2H); 2.56
1493, 1455,
(m, 2H); 2.67(t, J=5.1Hz, 2H); 3.13(m, 2H); 4.18
1379, 1091,
(t, J=7.1Hz, 2H); 6.05(m, 1H); 7.23-7.40(a.c., 9H); 7.61
953, 815, 746
(s, 1H); 7.74(s, 1H) (CDCl3)
KBr
38a
H
H
F
H
H
CH
N
H
N
HCl
3450, 2429,
1.74(m,2H); 1.86(m, 2H); 2.68(m, 1H); 2.84(m, 1H);
166-168° C.
2707, 2593,
3.16(a.c., 3H); 3.53(m, 1H); 3.70(m, 1H); 3.91(m,
1512, 1437,
1H); 4.27(t, J=6.7Hz, 2H); 6.12(s, 1H); 7.19(t, J=8.9Hz,
1230, 816, 626
2H); 7.50(d, J=8.9Hz,, J′ =5.5Hz, 2H); 8.23(s, 1H); 8.93
KBr
9s, 1H); 11.02(b.a., 1H) (DMSO-d6)
39a
H
H
F
H
H
CH
N
H
N
oil
2944, 2808,
1.60(m, 2H); 1.97(m, 2H); 2.40-2.70(a.c., 6H); 3.12
2773, 1602,
(m, 2H); 4.22(t, J=6.9Hz, 2H); 5.99(m, 1H); 6.98(m,
1510, 1273,
2H); 7.35(m, 2H); 7.95(s, 1H); 8.07*s, 1H) (CDCl3)
1227, 1161,
1140, 846,
824, 681
film
40a
H
H
F
H
H
CCH3
N
CH═CH—CH═CH—C
oil
2932, 1512,
1.63(m, 2H); 1.88(m, 2H); 2.42-2.55(a.c., 4H); 2.61
1456,
(s, 3H); 2.65(t, J=5.5Hz, 2H); 3.09(m, 2H); 4.14
1404, 1231, 744
(t, J=7.3Hz, 2H); 5.97(m, 1H); 6.99(m, 2H); 7.19-7.35
film
(a.c., 5H); 7.68(m, 1H); (CDCl3)
41a
H
H
F
H
H
N
CH
CH═CH—CH═CH—C
oil
2932, 2805,
1.57(m, 2H); 1.99(m, 2H); 2.42-2.50(a.c., 4H); 2.62
1511, 1465,
(t, J=5.6Hz, 2H); 3.06(m, 2H); 4.42(t, J=6.9Hz, 2H);
1230, 1160,
5.95(m, 1H); 6.97(t, J=8.8Hz, 2H); 7.12(m, 1H); 7.25-
825, 752, 741
7.41(a.c., 4H); 7.71(d, J=8Hz, 1H); 7.99(s, 1H)
film
(CDCl3)
42a
H
H
F
H
H
N
C—CH═CH—CH═CH
CH
102-103° C.
2941, 1510,
1.59(quin, J=7.0Hz, 2H); 2.09(quin, J=7.5Hz, 2H);
1374,
2.40-2.50(a.c., 4H); 2.64(t, J=6.2Hz, 2H); 3.10(m, 2H);
1226, 1162, 806,
4.45(t, J=7.1Hz, 2H); 5.96(m, 1H); 6.98(t, J=8.8Hz,
759, 741
2H); 7.07(t, J=7.6Hz, 1H); 7.20-7.35(a.c., 3H); 7.63
KBr
(d, J=8.5Hz, 1H); 7.71(d, J=8.6Hz, 1H); 7.90(s, 1H)
(CDCl3)
43a
H
H
F
H
H
N
C—CH═CH—CH═CH
N
HCl
2574, 2482,
1.80(m, 2H); 2.11(quin, J=7.2Hz, 2H); 2.69(m, 1H);
208-209° C.
1510,
2.83(m, 1H); 3.10-3.20(a.c., 3H); 3.52(m, 1H); 3.71
1231, 745
(m, 1H); 3.88(m, 1H); 4.80(t, J=6.3Hz, 2H); 6.11(s,
KBr
1H); 7.19(m, 2H); 7.41(m, 2H); 7.50(m, 2H); 7.91(m,
2H); 11.07(b.a., 1H) (DMSO-d6)
44a
H
H
F
H
H
N
C—CH═CH—CH═CH
N
76-77° C.
2931, 1511,
1.60(quin, J=7.5Hz, 2H); 2.19(quin, J=8.2Hz, 2H);
1470,
2.41-2.59(q.c., 4H); 2.64(t, J=5.7Hz, 2H); 3.08(m, 2H);
1380, 1327,
4.77(t, 7.0Hz, 2H); 5.95(m, 1H); 6.97(t, J=8.8Hz,
1224, 1172,
2H); 7.25-7.40(a.c., 4H); 7.85(m, 2H) (CDCl3)
1132, 851,
826, 757
KBr
45a
H
H
F
H
H
N
N
CH═CH—CH═CH—C
HCl
2928, 2680,
1.81(m, 2H); 1.99(m, 2H); 2.67(m, 1H); 2.48(m, 1H);
204-205° C.
2573, 2559,
3.10-3.20(a.c., 3H); 3.53(m, 1H); 3.72(m, 1H); 3.90
1515, 1454,
(m, 1H); 4.76(t, J=6.9Hz, 2H); 6.12(s, 1H); 7.19
1272, 1242,
(t, J=8.8Hz, 2H); 7.39(t, J=7.6Hz, 1H); 7.45-7.60(a.c.,
1224, 1166,
3H); 7.94(d, J=8.3Hz, 2H); 8.03(d, J=8.3Hz, 2H); 11.04
819, 745
(b.a., 1H) (CDCl3)
KBr
46a
H
H
F
H
H
N
N
CH═CH—CH═CH—C
88-90° C.
2939, 1510,
1.58(quin, J=7.5Hz, 2H); 2.07(quin, J=7.5Hz, 2H);
1229, 1209,
2.40-2.50(a.c., 4H); 2.61(m, 2H); 3.05(m, 2H); 4.66
1164, 744
(t, J=7.0Hz, 2H); 5.95(m, 1H); 6.96(t, J=8.8Hz, 2H);
KBr
7.23-7.38(a.c., 3H); 7.44(m, 1H); 7.52(m, 1H); 8.04
(d, J=8.3Hz, 1H) (CDCl3)
47a
H
H
Cl
H
H
N
CH
Cl
CH
HCl
3068, 2948,
1.71(m, 2H); 1.80(m, 2H); 2.70(m, 1H); 2.83(m, 1H);
172-173° C.
1491,
3.15-3.30(a.c., 3H); 3.44(m, 1H); 3.72(m, 1H); 3.89
1445, 1320,
(m, 1H); 4.11(t, J=6.5Hz, 2H); 6.20(s, 1H); 7.41(sys.
1308,
AB, JAB=8.8Hz, 2H); 7.48(Syst. AB, jAB=8.8Hz, 2H);
1096, 968, 809,
7.52(s, 1H); 8.04(s, 1H); 10.98(b.a., 1H) (DMSO-d6)
48a
H
H
H
H
H
N
CH
H
CH
HCl
2955, 2929,
1.70-1.90(a.c., 4H); 2.69(m, 1H); 2.89(m, 1H); 3.10-
180-181° C.
2530,
3.20(a.c., 3H); 3.53(m, 1H); 3.70(m, 1H); 3.91(m,
1445, 965, 761,
1H); 4.15(t, J=6.5Hz, 2H); 6.16(m, 1H); 6.23(m, 1H);
745
7.28-7.50(a.c., 6H); 7.78(m, 1H); 11.26(b.a., 1H)
KBr
(DMSO-d6)
49a
H
H
H
H
H
CH
N
H
N
HCl
2937, 2370,
1.74(m, 2H); 1.84(m, 2H); 2.72(m, 1H); 2.87(m, 1H);
122-123° C.
1503,
3.10-3.20(a.c., 3H); 3.54(m, 1H); 3.73(m, 1H); 3.88
1276, 1142, 774,
(m, 1H); 4.22(t, J=6.6Hz, 2H); 6.15(s, 1H); 7.27-7.70
755
(a.c., 3H); 7.47(m, 2H); 7.97(s, 1H); 8.59(s, 1H);
KBr
11.20(b.a., 1H) (DMSO-d6)
50a
H
H
H
H
H
CPh
N
H
CH
HCl
2930, 2554,
1.62-1.78(a.c., 4H); 2.75(m, 2H); 3.00(m, 2H); 3.25
170-171° C.
1469, 1459,
(m, 2H); 3.69(m, 2H); 4.08(t, J=6.7Hz, 2H); 6.13(s,
1444, 1278,
1H); 7.07(s, 1H); 7.24-7.40(a.c., 3H); 7.42-7.52(a.c.,
1075, 774, 762,
6H); 7.62(Syst. ab, J=7.6Hz, 2H) (DMSO-d6)
749, 732, 711,
702, 690
KBr
51a
H
H
H
H
H
CH
CH
H
CH
HCl
2930, 2482,
1.60-1.80(a.c., 4H); 2.70(m, 1H); 2.84(m, 1H); 3.08-
197-199° C.
1448, 1280,
3.22(a.c., 3H); 3.50(m, 1H); 3.71(m, 1H); 3.86-3.96
1090, 732
(a.c., 3H); 5.97(t, J=2.1Hz, 2H); 6.16(m, 1H); 6.76
KBr
(t, J=2.1Hz, 2H); 7.25-7.50(a.c., 5H); 10.47(b.a., 1H)
(DMSO-d6)
52a
H
H
H
H
H
CH
CH
H
CH
58-60° C.
2928, 1498,
1.58(m, 2H); 1.84(m, 2H); 2.47(t, J=7.5Hz, 2H); 2.58
1280, 1262,
(m, 2H); 2.68(m, 2H); 3.13(m, 2H); 3.92(t, J=7.1Hz,
1137, 1087,
2H); 6.06(m, 1H); 6.15(t, J=2.2Hz, 2H); 6.67
1060, 747,
(t, J=2.2Hz, 2H); 7.24-7.42(a.c., 5H) (CDCl3)
723, 691
KBr
53a
H
H
H
H
H
N
CCl
CH═CH—CH═CH—C
oil
2939, 1495,
1.58(quin, J=7.6Hz, 2H); 1.99(quin, J=7.6Hz, 2H);
1467,
2.47(m, 2H); 2.55(m, 2H); 2.65(m, 2H); 3.10(m, 2H);
1338, 745
4.36(t, J=7.1Hz, 2H); 6.04(m, 1H); 7.18-7.42(a.c., 8H);
film
7.67(d, J=7.6Hz, 1H) (CDCl3)
54a
H
H
H
H
H
N
CCl
CH═CH—CH═CH—C
HCl
3460, 2940,
1.80(m, 2H); 1.90(m, 2H); 2.70(m, 1H); 2.87(m, 1H);
164-165° C.
2550,
3.07-3.22(a.c., 3H); 3.52(m, 1H); 3.72(m, 1H); 3.87
1338, 743
(m, 1H); 4.43(t, J=6.6Hz, 2H); 6.14(s, 1H); 7.20-7.52
KBr
(a.c., 7H); 7.65(m, 1H); 7.7(m, 1H); 11.16(b.a., 1H)
(DMSO-d6)
55a
H
H
OH
H
H
CCH3
N
Cl
CCl
HCl
3062, 2561,
1.69(m, 2H); 1.75(m, 2H); 2.33(s, 3H); 2.68(m, 1H);
216-217° C.
1516, 1248
2.79(m, 1H); 3.14(a.c., 3H); 3.55(m, 1H); 3.68(m,
KBr
1H); 3.87-4.00(a.c., 3H); 5.97(s, 1H); 6.77(Syst.
ab, J=8.8Hz, 2H); 7.28(Syst. ab, J=8.8Hz, 2H); 9.62
(s, 1H); 10.82(b.a., 1H) (DMSO-d6)
56a
H
H
H
H
H
CH
N
Cl
CCl
HCl
2336, 1254
1.75(a.c., 4H); 2.70(m, 1H); 2.87(m, 1H); 3.17(a.c.,
166-167° C.
KBr
3H); 3.56(m, 1H); 3.74(m, 1H); 3.87-4.15(a.c., 3H),
6.17(s, 1H); 7.27-7.40(a.c., 3H); 7.47(m, 2H); 7.91(s,
1H); 11.02(b.a., 1H) (DMSO-d6)
57a
H
H
F
H
H
CH
N
H
N
Citrate
1720, 1709,
1.90(m, 2H); 2.08(quint., J=7.5Hz, 2H); 2.86(AB,
132-133° C.
1513, 1225,
J=15.5Hz, 4H); 2.93(b.a., 2H); 3.29(m, 2H); 3.54(t,
1193, 1166, 1133
J=5.9Hz, 2H) 3.93(b.a., 2H); 4.43(t, J=6.6Hz, 2H);
KBr
6.17(b.a., 1H); 7.19(m, 2H); 7.59(m, 2H); 8.10(s, 1H);
8.60(s, 1H) (MeOH-d4)
58a
H
H
Br
H
H
CH
N
H
N
113-115° C.
2939, 2773,
1.55(m, 2H); 1.95(m, 2H); 2.40-2.55(a.c., 4H); 2.64
2736, 1509,
(m, 2H); 3.08(m, 2H); 4.20(t, J=7.1Hz, 2H); 6.03(m,
1490, 1380,
1H); 7.22(AB, J=8.5Hz, 2H); 7.40(AB, J
1271, 1140, 1071,
7.93(s, 1H); 8.05(s, 1H) (CDCl3)
1006, 961, 844,
827, 800, 680
KBr
59a
H
H
Br
H
H
CH
N
H
N
HCl
3066, 2937,
1.76(m, 2H); 1.84(m, 2H); 2.71(m, 1H); 2.85(m, 1H);
162-164° C.
2479 (b.a.) 1514,
3.17(a.c., 3H); 3.55(m, 1H); 3.74(m, 1H); 3.80(m,
1146, 1012, 802
1H); 4.23(t, J=6.6Hz, 2H); 6.22(s, 1H); 7.42(Syst.
KBr
AB, J=8.1Hz, 2H); 7.56(Syst. AB, J=8.1Hz, 2H); 7.98
(s, 1H); 8.60(s, 1H) (DMSO-d6)
60a
H
H
Cl
H
H
CH
N
H
N
101-103° C.
2930, 2775,
1.56(quint, J=7.5Hz, 2H); 1.97(quint, J=7.5Hz, 2H);
2737, 1509,
2.40-2.70(a.c., 4H); 2.66(t, J=5.7Hz, 2H); 3.10(d, J=3
1493, 1381,
Hz, 2H); 4.21(t, J=7.0Hz, 2H); 6.04(s, 1H); 7.20-7.35
1271, 1141, 1091,
(m, 4H); 7.94(s, 1H); 8.06(s, 1H) (CDCl3)
1010, 961, 847,
KBr
61a
H
H
Cl
H
H
CH
N
H
N
HCl
2951, 2505 (b.a.)
1.73(m, 2H); 1.83(m, 2H); 2.70(m, 1H); 2.85(m, 1H);
165-166° C.
1502, 1494,
3.10-3.20(a.c., 3H); 3.54(m, 1H); 3.73(m, 1H); 3.88
1275, 1136,
(m, 1H); 4.22(t, J=6.6Hz, 2H); 6.20(s, 1H); 7.42(Syst.
1098, 1013, 810,
AB, J=8.6Hz, 2H); 7.49(Syst. AB, J=8.6Hz, 2H); 7.97
686
(s, 1H); 8.59(s, 1H); 11.17(b.a., 1H) (DMSO-d6)
KBr
62a
H
H
Cl
H
H
CPh
N
H
CH
oil
1445, 1379,
1.48(m, 2H); 1.80(m, 2H); 2.36(t, J=7.4Hz, 2H); 2.47
1271,
(m, 2H); 2.59(m, 2H); 3.04(d, J=3Hz, 2H), 4.03(t,
774, 681
J=7.4Hz, 2H); 6.01(s, 1H); 7.01(d, J=1.2Hz, 1H);
film
7.11(d, J=1.2Hz, 1H); 7.27(m, 4H); 7.35-7.60(a.c.,
5H) (CDCl3)
63a
H
H
Cl
H
H
CPh
N
H
CH
HCl
2935, 2695,
1.65(m, 2H); 1.80(m, 2H); 2.67(m, 1H); 2.82(m, 1H);
70° C.
2591, 1493,
3.05-3.21(a.c., 3H); 3.55(m, 1H); 3.69(m, 1H); 3.88
(hygrosc.)
1094, 777, 702
(m, 1H), 4.20(t, 6.6Hz, 2H); 6.18(s, 1H); 7.40(Syst.
KBr
AB, J=8.7Hz, 2H); 7.47(Syst. AB, J=8.7Hz, 2H); 7.60-
7.88(a.c., 5H); 7.86(s, 1H); 7.96(s, 1H) (DMSO-d6 +
TFA)
64a
H
H
H
H
H
CCH3
CH
H
CCH3
oil
2929, 1408, 1299,
1.65(a.c., 4H); 2.23(s, 6H); 2.48(m, 2H); 2.58(m, 2H);
746, 693
2.69(m, 2H); 3.15(m, 2H); 3.76(t, J=7.2Hz, 2H); 5.76
film
(s, 2H); 6.06(s, 1H); 7.20-7.40(a.c., 5H) (CDCl3)
65a
H
H
H
H
H
CCH3
CH
H
CCH3
HCl
3434, (b.a.), 2935,
1.56(m, 2H); 1.77(m, 2H); 2.15(s, 6H); 2.70(m, 1H);
178-180° C.
2560, 1443,
2.84(m, 1H); 3.08-3.22(a.c., 3H); 3.59(m, 1H); 3.70-
1405, 1298, 748,
3.80(a.c., 3H); 3.93(m, 1H); ); 5.59(s, 2H); 6.17(s,
692
1H); 7.25-7.50(a.c., 5H); 10.72(b.a., 1H) (DMSO-d6)
66a
H
H
Cl
H
H
CCH3
CH
H
CCH3
86-88° C.
2933, 1493,
1.65(a.c., 4H); 2.24(s, 6H); 2.48(m, 2H); 2.54(m, 2H);
1412, 1376,
2.69(m, 2H); 3.15(m, 2H); 3.77(t, J=7.1Hz, 2H); 5.77
1300, 750
(s, 3H); 6.06(s, 1H); 7.30(m, 4H) (CDCl3)
film
67a
H
H
Cl
H
H
CCH3
CH
H
CCH3
HCl
3432 (b.a.), 2936,
1.56(m, 2H); 1.76(m, 2H); 2.14(s, 6H); 2.70(m, 1H);
182-184° C.
258-, 1495,
2.84(m, 1H); 3.00-3.28(a.c., 3H); 3.58(m, 1H); 3.69-
1410, 1298,
3.77(a.c., 3H); 3.92(m, 1H); 5.58(s, 2H); 6.22(s,
1097, 804, 752
1H); 7.42(AB, J=8.6, 2H); 7.50(AB, J=8.6, 2H); 10.65
KBr
(b.a., 1H) (DMSO-d6)
68a
H
H
Cl
H
H
CH
CH
H
CH
102-104° C.
2931, 1492,
1.59(t, J=7.5Hz, 2H); 1.84(t, J=7.4Hz, 2H); 2.46
1280, 1090, 967,
(t, J=7.5Hz, 2H); 2.53(m, 2H); 2.66(t, J=5.6Hz, 2H);
828, 727
3.12(m, 2H); 3.92(t, J=7.1Hz, 2H); 6.05(m, 1H); 6.15
KBr
(d, J=1.8Hz, 2H); 6.66(d, J=1.8Hz, 2H); 7.26ab, J=8.4,
2H); 7.30(AB, J=8.4, 2H) (CDCl3)
69a
H
H
Cl
H
H
CH
CH
H
CH
HCl
2937, 2479,
1.72(m, 4H); 2.65(m, 1H); 2.87(m, 1H); 3.08-3.22
194-195° C.
1492, 1282,
(a.c., 3H); 3.52(m, 1H); 3.70(m, 1H); 3.80-4.00(a.c.,
1096, 810, 737
3H); 5.96(t, J=2.1Hz, 2H); 6.19(s, 1H); 6.76(t, J=2.1Hz,
KBr
2H); 7.42(AB, J=8.6Hz, 2H); 7.48(AB, J=8.6Hz, 2H);
11.12(b.a., 1H) (DMSO-d6)
70a
H
H
Cl
H
H
CH
N
H
N
Citrate
3384 (b.a.), 3200-
1.54(m, 2H); 1.83(m, 2H); 2.54(Syst. AB, J=15Hz,
133° C.
2200 (b.a.) 1726,
2H); 2.63(Syst. AB, J=15Hz, 2H); 2.82(m, 2H); 3.03
1702, 1594,
(m, 2H); 3.20-3.50(a.c., 4H); 4.21(t, J=6.8Hz, 2H);
1432, 1221,
6.20(s, 1H); 7.40(Syst. AB, J=8.8Hz, 2H); 7.48(Syst.
1131, 802
AB, J=8.8Hz, 2H); 7.97(s, 1H) (DMSO-
KBr
d6)
The analgesic activity of the products object of the invention have been studied in several assays using the Swiss albino mice as the experimental animal. The assay of contortions induced by phenylbenzoquinone, the hot-plate assay and the hot-point assay are now described. The examples that are presented by way of illustration describe some of the pharmacological assays and should not limit the scope of the invention in any way.
The assay of contortions induced by phenylbenzoquinone was carried out following the method described by E. Siegmund et al. (Proc. Soc. Exp. Biol. Med. 95: 729-731, 1957). In this assay the mice received [th]e product orally or sub-cutaneously (s.c.) and after 60 minutes (after oral administration) or after 30 minutes (after s.c. administration) they received an intraperitoneal (i.p.) injection of an 0.02% aqueous solution of phenylbenzoquinone, at a dosage of 10 ml/kg. The degree of analgesic was expressed as a percentage of the contortions with respect to the control group at each one of the dosages assayed. Using the results tained the effective dose-50 (ED-50) was calculated, that is to say the dose able to inhibit by 50% the contortions induced by phenylbenzoquinone.
The hot-plate assay was carried out following the method described by M. Ocana et al. (Europ J. Pharmacol. 186: 377-378, 1990). The product under study was administered s.c. or i.p. and 30 minutes later the analgesic effect was registered. For this the animals were placed on a metallic surface kept at 50° C. or 55° C. and the time registered (latency) until the licked their hind legs and a jump. The analgesic activity was calculated at each dose, comparing the potency of the treated group with the control group. Using the results obtained the ED-50 was calculated.
The assay of withdrawal of the tail from a hot spot (tail flick) was carried out following the method described by M. Ocana et al. (Br. J. Pharmacol. 110: 1049-1054, 1993). The mice were introduced into an immobiliser and placed on the tail-flick apparatus (LI7100, Letica, S.A). A beam of light was focussed on the tail, at 4 cm from the tip, and the latency for withdrawal of the tail automatically registered. Ten minutes before administering the product of the study the basal latency was registered.
After the product had been administered s.c. the tail withdrawal latencies at 10, 20, 30, 40, 45, 60, 90 and 120 minutes were registered. For each animal the area below curve of the latency was calculated during the time period following the method described by R. J. Tallarida and R. B. Murray (Manual of pharmacologic calculations with computer programs, Springer-Verlag, Berlin, p. 297, 1987). The degree of analgesic of each dosage was calculated comparing the area under curve of latency of the group treated with the medicament with the control group. Using these data the ED-50 was calculated.
The products object of the invention have a notable analgesic activity in the assay of contortions induced by phenylbenzoquinone. Several products have activity of the same order as morphine and clearly better that the products that inhibit biosynthesis of prostaglandins, such as aspirin and dipirone (see table 3).
The analgesic activity has also been demonstrated in the hot-plate assay, considered as a demonstration of analgesic action at the central nervous system level (see table 4).
The analgesic activity has also been demonstrated in the hot-beam assay applied to the mouse's tail, finding a good correspondence between the results obtained in the assay of the hot-plate and the assay of the calorific beam (see table 5).
Furthermore, the capacity of the products object of the invention for exhibiting synergistic analgesic activity with other analgesics, for example, pentazocine, has also been demonstrated. This has been shown for the compound of example 47a (see table 6). Effectively, the latency time in responding licking of the paws when the mice were placed on the hot-plate at 55° C., is much greater after the combined treatment with the compound of example 47a and pentazocine than the sum of the latencies of each one of the treatments carried out separately.
In summary, the products object of the invention have shown a clear analgesic activity in different assays, such as phenylbenzoquinone, hot-plate and calorific beam applied to the tail of the mouse. The activity of these products has been clearly superior to that of the inhibitors of the biosynthesis of prostaglandins such as aspirin and dipirone, and the activity has been shown to of the order of that of morphine. Furthermore, 5 the capacity for forming synergistic combinations with other analgesics has been demonstrated, as can be seen for the case of the compound of example 47a administered along with pentazocine in the hot-plate assay for mice.
TABLE 3
Analgesic activity in the assay of contortions induced by
phenylbenzoquinone in mouses
ED-50 (mg/kg)
PRODUCT
Oral route
S.C. route
Example 5
20
28
Example 6
80
34
Example 33a
30
2
Example 35a
37
1
Example 38a
5
1
Example 41a
58
6
Example 47a
19
26
Example 48a
38
1
Example 49a
2
1
Example 50a
10
2
Example 51a
9
3
Example 59a
13
2
Example 61a
22
2
Example 63a
44
33
Morfine
4
1
Dipirone
223
24
Aspirin
100
80
TABLE 4
Analgesic activity in the hot-plate assay (55° C.) in mouses
PRODUCT
ED-50 (mg/kg, sc)
Example 38a
7
Example 47a
89
Example 48a
5
Example 49a
4
Example 50a
58
Example 51a
2
Example 59a
43
Example 61a
48
Morfine
2
TABLE 5
Analgesic activity in the calorific beam assay in mouse's tail.
PRODUCT
ED-50 (mg/kg, sc)
Example 51a
5
Example 59a
60
Example 63a
70
Morfine
4
TABLE 6
Analgesic activity in the hot plate assay in mouse.
PRODUCT
DOSE (mg/kg, ip)
Δ Latency (Seconds)
Example 47a
40
5
Pentazocine
10
6
Example 47a
40
+
+
20
Pentazocine
10
Frigola-Constansa, Jordi, Merce-Vidal, Ramon
| Patent | Priority | Assignee | Title |
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