US Patent # RE39,113. Utilization of derivatives of tetrahydropyridines(or 4-hydroxypiperidines)-butylazols in the preparation of a medicament for the treatment of pain

United States Patent	RE39,113
Merce-Vidal , et al.	May 30, 2006

Utilization of derivatives of tetrahydropyridines(or 4-hydroxypiperidines)-butylazols in the preparation of a medicament for the treatment of pain

Abstract

Derivatives of tetrahydropyridines (or 4-hydroxypiperidines)-butylazols of formula (I), wherein R.sub.1, R.sub.2 and R.sub.3, which are similar or different, represent each of them hydrogen, halogen, alkyl C.sub.1-C.sub.4, 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; Z.sub.1 is N or CR4; Z.sub.2 is N or CR.sub.5; Z.sub.4 is N or CR.sub.7; and R.sub.4, R.sub.5, R.sub.6 and R.sub.7, which different, represent hydrogen, halogen, alkyl C.sub.3-C.sub.4, 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.

Inventors:	Merce-Vidal; Ramon (Barcelona, ES), Frigola-Constansa; Jordi (Baracelona, ES)
Assignee:	Laboratories Del Dr. Esteve, S.A. (Barcelona, ES)
Appl. No.:	10/355,216
Filed:	July 9, 1999
PCT Filed:	July 09, 1999
PCT No.:	PCT/ES99/00222
371(c)(1),(2),(4) Date:	February 13, 2001
PCT Pub. No.:	WO00/02519
PCT Pub. Date:	January 20, 2000

Related U.S. Patent Documents


	Application Number	Filing Date	Patent Number	Issue Date
Reissue of:	09743085	Feb., 2001	06384055	May., 2002

Foreign Application Priority Data


Jul 10, 1998 [ES]			9801467

Current U.S. Class:	514/326 ; 514/340; 514/341; 514/343; 546/205; 546/208; 546/210; 546/268.4; 546/272.7
Current International Class:	A61K 31/445 (20060101); A61K 31/44 (20060101); C07D 211/06 (20060101); C07D 401/00 (20060101)
Field of Search:	514/326,340,341,343 546/205,208,210,268.4,272.7

References Cited

U.S. Patent Documents


5731331	March 1998	Merci-Vidal et al.

Foreign Patent Documents


9604287	Feb., 1996	WO
9735584	Oct., 1997	WO

Other References

Guitart et al. "The effect of E-5842 . . . " European J. Pharm. v.363, p. 127-130 (1998). cited by examiner .
Rossi et al. "Pharmacological characterization . . . " CA 127:200544 (1997). cited by examiner .
Kobayashi et al. "Effect o sigma ligands on the nociceptin/ . . . "CA 126:287948 (1997). cited by examiner .
Kest et al. "1,3-di-o-toylguanidin . . . "CA 123:140771 (1995). cited by examiner.

Primary Examiner: Chang; Celia
Attorney, Agent or Firm: Ladas and Parry LLP

Claims

What is claimed is:

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 R.sub.1, R.sub.2 and R.sub.3 are identical or different and are selected from hydrogen, .Iadd.halogen, .Iaddend.C.sub.1-C.sub.4 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; Z.sub.1, is a nitrogen atom or a substituted carbon atom represented by the formula C--R.sub.4; Z.sub.2 is a nitrogen atom or a substituted carbon atom represented by the formula C--R.sub.5; Z.sub.4 is a nitrogen atom or a substituted carbon atom represented by the formula C--R.sub.7; with the condition that Z.sub.1; Z.sub.2 and Z.sub.4 taken together can represent, at most, two nitrogen atoms; and R.sub.4, R.sub.5, R.sub.6 and R.sub.7, are identical or different and are selected from hydrogen, halogen, C.sub.1-C.sub.4 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 claim 1, wherein R.sub.1, R.sub.2 and R.sub.3 are selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, methoxyl, methyl, ethyl, propyl, isopropyl, sec-butyl and a tert-butyl radical.

3. The method as claimed in claim 1, wherein R.sub.1, R.sub.2 and R.sub.3 are selected so that two adjacent radicals can form part of a six-membered aromatic ring.

4. The method as claimed in claim 1, wherein R.sub.4, R.sub.5, R.sub.6 and R7 are selected from hydrogen, fluorine, chlorine, bromine, .[.trifluoromethyl, hydroxyl, methoxyl,.]. methyl, ethyl, propyl, isopropyl, .Iadd.butyl, isobutyl, .Iaddend.sec-butyl, tert-butyl, unsubstituted phenyl, or a substituted phenyl wherein the substituent is selected .[.front halogen atoms.]. .Iadd.from fluorine, chlorine and bromine.Iaddend..

5. The method as claimed in claim 1, wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are selected so wt two adjacent radicals form part of a six-membered aromatic ring.

6. The method as claimed in claim 1, further comprising an analgesic used for the treatment of pain.

.[.7. The method as claimed in claim 1, wherein the compound of formula (I) is selected from the group consisting of: 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-imidazol- e; 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-met- hyl-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]-b- utyl}-2H-imidazole; 4,5-dichloro-1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperdinyl]butyl}-2H-me- thyl-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-pyr- azole; 4-chloro-1-{4-[4-hydroxy-4-(4-methoxyphenyl)-1-(piperidinyl)]-buty- l}-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-pyraz- ole; 1-{4-[4phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazol- e; 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)]but- yl-}-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-(1,2,3,6tetahyd- ropyridinyl)]-butyl}-1H-imidazole; 4-chloro-1-{4-[4-(1-naphthyl)-1-(1,2,3,6-tetrahydropyridinyl]butyl}-1H-py- razole; 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-benzimi- dazole; 1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benz- imidazole hydrochloride; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzim- idazole; 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-tetrahy- dropyridinyl)]-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-triazo- le hydrochloride; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazo- le; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-met- hyl-1H-benzimidazole; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidaz- ole; 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-i- midazole; 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-benzot- riazole; 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-benzot- riazole; 4chloro-1-{4-[4(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl]b- utyl}-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-pyrazol- e; 1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-benzimidazo- le; 4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]bu- tyl}-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-imida- zole; 3-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-i- midazole 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-triazo- le citrate; 1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazol- e; 1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-tria- zole hydrochloride; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazo- le; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-tr- iazole 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)]but- yl}-1H-pyrrole; 2,5-dimethyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]but- yl}-1H-pyrrole hydrochloride; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrol- e; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyr- role hydrochloride; 1-{4-[4-(4-chlorophenyl)-1-1(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-trizo- le hydrochloride..].

.Iadd.8. The method as claimed in claim 1, wherein the compound of formula 1 is selected from the group consisting of: 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-im- idazole; 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-pyrazo- le; 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]-bu- tyl}-2-methyl-1H-imidazole; 4,5-dichloro-1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperdinyl]butyl}-2-met- hyl-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-methy- l-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-pyraz- ole; 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-pyraz- ole; 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazo- le; 1-{4-[4-phenyl-1(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-1,2,4-triazol- e; 4-chloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]buty- l}-1H-pyrazole; 4,5-dichloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-bu- tyl-}-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-tetahy- dropyridinyl)]-butyl}-1H-imidazole; 4-chloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]-1H-pyr- azole; 4,5-dichloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridin- yl)]-butyl}-2-methyl-1H-imidazole; 4,5-dichloro-1-{4-[4-[phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-2-me- thyl-1H-imidazole; 4,5-dichloro-1-{4-[4-[phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-2-me- thyl-1H-imidazole hydrochloride; 4,5-dichloro-1-{4-[4-[phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-butyl}-2-me- thyl-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-tetrahydropyrid- inyl)]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-pyrazo- le; 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-imidazo- le; 1-{4-[4-(4-methylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-ben- zimidazole; 4,5-diphenyl-1-{4-[4-[phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-imi- dazole; 4-chloro-1-{4-[4-(1-naphthyl)-1-(1,2,3,6-tetrahydropyridinyl]buty- l}-1H-pyrazole; 4-chloro-1-{4-[4-(2-naphthyl)-1-(1,2,3,6-tetrahydropyridinyl]butyl}-1H-py- razole; 1-{2-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]ethyl}-1- H-benzimidazole; 1-{4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazol- e hydrochloride; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzim- idazole; 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-tetrah- ydropyridinyl)]-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)]but- yl}-1H-imidazole hydrochloride; 4-(4-chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1- H-pyrazole hydrochloride; 4-(4-chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1- H-pyrazole; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-triazol- e hydrochloride; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazo- le; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-met- hyl-1H-benzimidazole; 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazo- le; 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-in- dazole; 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2- H-benzotriazole hydrochloride; 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-benzot- riazole; 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-benzot- riazole; 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-pyrazol- e; 1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-benzimidazo- le; 4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]bu- tyl}-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-indaz- ole; 3-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-in- dazole 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)]buty- l}-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-triazo- le citrate; 1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazol- e; 1-{4-[4-(4-bromophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-tria- zole hydrochloride; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazo- le; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-tr- iazole 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)]but- yl}-1H-pyrrole; 2,5-dimethyl-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]but- yl}-1H-pyrrole hydrochloride; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrol- e; 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyr- role hydrochloride; and 1-{4-[4-(4-chlorophenyl)-1-1(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triaz- ole citrate, in the preparation of a medicament for the treatment of acute pain, neuropathic pain or nociceptive pain in mammals, including man..Iaddend.

Description

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

In our patent application WO 96/04287 compounds of general formula (I) are disclosed ##STR00001## that have an affinity for the cry and 5HT.sub.1A 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.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of derivatives of tetrahydropyridines (or 4-hydroxypyperidine)butylazoles of general formula: ##STR00002## where R.sub.1, R.sub.2 and R.sub.3 are either identical or different and represent a hydrogen atom, .Iadd.a halogen atom, .Iaddend.a C.sub.1-C.sub.4 alkyl group, a trifluoromethyl radical, a hydroxyl or alkoxyl radical, and furthermore, two adjacent radicals can form part of an six-member aromatic ring; A represents a carbon atom and the dotted line represents an additional bond, or A represents a carbon atom bound to a hydroxyl group (C--OH) and the dotted line represents the lack of an additional bond; Z.sub.1 represents a nitrogen atom or a substituted carbon atom that can be represented by C--R.sub.4; Z.sub.2 represents a nitrogen atom or a substituted carbon atom that can be represented by C--R.sub.5; Z.sub.4 represents a nitrogen atom or a substituted carbon atom that can be represented by C--R.sub.7; with the condition that Z.sub.1, Z.sub.2 and Z.sub.4 taken together can represent, at most, two nitrogen atoms; and R.sub.4, R.sub.5, R.sub.6 and R.sub.7, are identical or different and represent a hydrogen atom, a halogen atom, a C.sub.1-C.sub.4 alkyl group, an aryl or substituted aryl group, or two adjacent radicals can form part of a six-member aromatic ring; or one of their physiologically acceptable salts, in the elaboration of a medicament for the treatment of acute pain, neuropatic pain or nocipeptive pain in mammals, including man.

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 "G.sub.1-G.sub.4 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-US-00001 TABLE 1 ##STR00003## Ex. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Z.sub.1 Z.sub.2 R.sub.6 Z.sub.- 4 m.p. IR cm.sup.-1 .sup.1H-RMN (300 MHz), .delta. (solvent) 1 H H H H H N CH Cl CH 102-103.degree. 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) (CDCl.sub.3) 2 H H H H H C--CH.sub.3 N Cl CCl 86-89.degree. 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) (CDCl.sub.3) 3 H H H H H CH N CH.dbd.CH--CH.dbd.CH--C 122-123.degree. 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) (CDCl.sub.3) KBr 4 H H H H H CH N H N 123.degree. 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) (CDCl.sub.3) 5 H H Cl H H N CH Cl CH 106.degree. 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) (CDCl.sub.3) KBr 6 H H Cl H H C--CH.sub.3 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, (CDCl.sub.3) 755 film 7 H CF.sub.3 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) (CDCl.sub.3) film 8 H CF.sub.3 H H H C--CH.sub.3 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) (CDCl.sub.3) film 9 H H F H H C--CH.sub.3 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 (CDCl.sub.3) 10 H H H H H CH CH CH.dbd.CH--CH.dbd.CH--C 109-111.degree. 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) (CDCl.sub.3) 11 H H CH.sub.3 H H C--CH.sub.3 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) (CDCl.sub.3) 12 H H H H H N CH H CH 89-91.degree. 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) (CDCl.sub.3) 13 H H H H H N CH CH.dbd.CH--CH.dbd.CH--C 107-109.degree. 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) (CDCl.sub.3) KBr 14 H H H H H N C--CH.dbd.CH--CH.dbd.CH CH 120-122.degree. 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) (CDCl.sub.3) 15 H H CH.sub.3 H H N CH Cl CH 81-82.degree. 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) (CDCl.sub.3) 16 H H CH.sub.3O H H N CH Cl CH 122-123.degree. 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) (CDCl.sub.3) 17 H H H H H CPh N H CH 108-110.degree. 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 (CDCl.sub.3) KBr 18 H H CH.sub.3 H H CH N CH.dbd.CH--CH.dbd.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) (CDCl.sub.3) 19 H H H H H CH N Ph CPh 138-139.degree. 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.dbd.CH--CH.dbd.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) (CDCl.sub.3) KBr 21 H CH.dbd.CH--CH.dbd.CH H H N CH Cl CH 142-143.degree. 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) (CDCl.sub.3) 22 H H H H H N CH C.sub.6HCl CH 137-140.degree. 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) (CDCl.sub.3) 23 H H F H H CH N CH.dbd.CH--CH.dbd.CH--C 120-122.degree. 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) (CDCl.sub.3) 24 H CF.sub.3 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.degree. 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-d.sub.6) 25 H H F H H N CH CH.dbd.CH--CH.dbd.CH--C 136-137.degree. 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) (CDCl.sub.3--CD.sub.3OD [1:1]) 26 H H F H H N C--CH.dbd.CH--CH.dbd.CH CH 148-150.degree. 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) (CDCl.sub.3--CD.sub.3OD [1:1]) 27 H H F H N N C--CH.dbd.CH--CH.dbd.CH N 109-110.degree. 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) (CDCl.sub.3--CD.sub.3OD [1:1]) 28 H H F H H N N CH.dbd.CH--CH.dbd.CH--C 102-103.degree. 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) (CDCl.sub.3--CD.sub.3OD [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) (CDCl.sub.3) film 30 H H Cl H H CH N H N 89-91.degree. 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) (CDCl.sub.3) KBr

TABLE-US-00002 TABLE 2 ##STR00004## Ex. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 Z.sub.1 Z.sub.2 R.sub.6 Z.sub.- 4 Salt/m.p. IR cm.sup.-1 .sup.1H-RMN (300 MHz), .delta. (solvent) 1a H H H H H N CH Cl CH 62-64.degree. 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) (CDCl.sub.3) 2a H H H H H CH N CH.dbd.CH--CH.dbd.CH--C 66-69.degree. 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) (CDCl.sub.3) 3a H H H H H CH N H N 63-64.degree. 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) (CDCl.sub.3) 4a H H Cl H H N CH Cl CH 103-104.degree. 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) (CDCl.sub.3) 5a H H Cl H H C--CH.sub.3 N Cl CCl 119-120.degree. 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) (CDCl.sub.3) 6a H CF.sub.3 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) (CDCl.sub.3) 7a H CF.sub.3 H H H C--CH.sub.3 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) (CDCl.sub.3) 8a H H F H H N CH Cl CH 86-87.degree. 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) (CDCl.sub.3) 9a H H F H H C--CH.sub.3 N Cl CCl 79-82.degree. 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 (CDCl.sub.3) 10a H H H H H C--CH.sub.3 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) (CDCl.sub.3) 11a H H H H H C--CH.sub.3 N Cl CCl .HCl 2930, 2576, 1407, 1.69(m, 2H); 1.81(m, 2H); 2.35(s, 3H); 2.71 203-204.degree. 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-d.sub.6) 12a H H H H H C--CH.sub.3 N Cl CCl .2HCl 3569, 2941, 2692, 1.67(m, 2H); 1.76(m, 2H); 2.36(s, 3H); 2.69 192-194.degree. 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-d.sub.6) 13a H H F H H CH CH CH.dbd.CH--CH.dbd.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) (CDCl.sub.3) 14a H H H H H CH CH CH.dbd.CH--CH.dbd.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) (CDCl.sub.3) 15a H H CH.sub.3 H H C--CH.sub.3 N Cl CCl 87-88.degree. 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) (CDCl.sub.3) 16a H H H H H N CH H CH 36-38.degree. 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) (CDCl.sub.3) 17a H H H H H N CH CH.dbd.CH--CH.dbd.CH--C 50-52.degree. 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) (CDCl.sub.3) 18a H H H H H N C--CH.dbd.CH--CH.dbd.CH CH 73-75.degree. 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) (CDCl.sub.3) 19a H H CH.sub.3 H H N CH Cl CH 72-73.degree. 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) (CDCl.sub.3) 20a H H CH.sub.3O H H N CH Cl CH 104-105.degree. 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) (CDCl.sub.3) 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) (CDCl.sub.3) film 22a H H H H H CCH.sub.3 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) (CDCl.sub.3) 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) (CDCl.sub.3) 24a H H CH.sub.3 H H CH N CH.dbd.CH--CH.dbd.CH--C 90-91.degree. 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) (CDCl.sub.3) 25a H H H H H CH N Ph CPh 100-101.degree. 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 (CDCl.sub.3) KBr 26a CH.dbd.CH--CH.dbd.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 (CDCl.sub.3) 27a H CH.dbd.CH--CH.dbd.CH H H N CH Cl CH 95-96.degree. 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 (CDCl.sub.3) 28a H H F H H CH N CH.dbd.CH--CH.dbd.CH--C 135-136.degree. 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) (CDCl.sub.3) 1202, 1161, 771, 751 KBr 29a H H H H H CH N CH.dbd.CH--CH.dbd.CH--C HCl 2940, 2488, 1.70-1.90(a.c., 4H); 2.78(m, 2H); 3.17(m, 2H); 177-178.degree. 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-d.sub.6) 30a H H F H H CH N CH.dbd.CH--CH.dbd.CH--C 106-108.degree. 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) (CDCl.sub.3) 31a H H F H H CH N CH.dbd.CH--CH.dbd.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-d.sub.6) 32a H CF.sub.3 H H H CCH.sub.3 N Cl CCl HCl 2930, 2490, 1.67(m, 2H); 1.79(m, 2H); 2.33(s, 3H); 2.79(m, 1H); 205-206.degree. 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-d.sub.6) 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.degree. 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-d.sub.6) 34a H H H H H N CH CH.dbd.CH--CH.dbd.CH--C HCl 2931, 2566, 742 1.80(m, 2H); 1.91(m, 2H); 2.67(m, 1H); 2.88(m, 1H); 193-194.degree. 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-d.sub.6) 35a H H F H H CCH.sub.3 N Cl CCl HCl 2930, 2590, 1.67(m, 2H); 1.79(m, 2H); 2.33(s, 3H); 2.67(m, 1H); 160-161.degree. 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-d.sub.6) 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.degree. 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-d.sub.6) 37a H H H H H N CH 4-ClPh CH 126-127.degree. 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) (CDCl.sub.3) 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.degree. 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-d.sub.6) 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) (CDCl.sub.3) 1227, 1161, 1140, 846, 824, 681 film 40a H H F H H CCH.sub.3 N CH.dbd.CH--CH.dbd.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); (CDCl.sub.3) 41a H H F H H N CH CH.dbd.CH--CH.dbd.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 (CDCl.sub.3) 42a H H F H H N C--CH.dbd.CH--CH.dbd.CH CH 102-103.degree. 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) (CDCl.sub.3) 43a H H F H H N C--CH.dbd.CH--CH.dbd.CH N HCl 2574, 2482, 1.80(m, 2H); 2.11(quin, J=7.2Hz, 2H); 2.69(m, 1H); 208-209.degree. 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-d.sub.6) 44a H H F H H N C--CH.dbd.CH--CH.dbd.CH N 76-77.degree. 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) (CDCl.sub.3) 1132, 851, 826, 757 KBr 45a H H F H H N N CH.dbd.CH--CH.dbd.CH--C HCl 2928, 2680, 1.81(m, 2H); 1.99(m, 2H); 2.67(m, 1H); 2.48(m, 1H); 204-205.degree. 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) (CDCl.sub.3) KBr 46a H H F H H N N CH.dbd.CH--CH.dbd.CH--C 88-90.degree. 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) (CDCl.sub.3) 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.degree. 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, J.sub.AB=8.8Hz, 2H); 7.48(Syst. AB, j.sub.AB=8.8Hz, 2H); 1096, 968, 809, 7.52(s, 1H); 8.04(s, 1H); 10.98(b.a., 1H) (DMSO-d.sub.6) 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.degree. 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-d.sub.6) 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.degree. 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-d.sub.6) 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.degree. 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-d.sub.6) 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.degree. 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-d.sub.6) 52a H H H H H CH CH H CH 58-60.degree. 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) (CDCl.sub.3) 723, 691 KBr 53a H H H H H N CCl CH.dbd.CH--CH.dbd.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) (CDCl.sub.3) 54a H H H H H N CCl CH.dbd.CH--CH.dbd.CH--C HCl 3460, 2940, 1.80(m, 2H); 1.90(m, 2H); 2.70(m, 1H); 2.87(m, 1H); 164-165.degree. 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-d.sub.6) 55a H H OH H H CCH.sub.3 N Cl CCl HCl 3062, 2561, 1.69(m, 2H); 1.75(m, 2H); 2.33(s, 3H); 2.68(m, 1H); 216-217.degree. 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-d.sub.6) 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.degree. 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-d.sub.6) 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.degree. 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-d.sub.4) 58a H H Br H H CH N H N 113-115.degree. 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) (CDCl.sub.3) 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.degree. 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-d.sub.6) 60a H H Cl H H CH N H N 101-103.degree. 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) (CDCl.sub.3) 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.degree. 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-d.sub.6) 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) (CDCl.sub.3) 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.degree. 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-d.sub.6 + TFA) 64a H H H H H CCH.sub.3 CH H CCH.sub.3 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) (CDCl.sub.3) 65a H H H H H CCH.sub.3 CH H CCH.sub.3 HCl 3434, (b.a.), 2935, 1.56(m, 2H); 1.77(m, 2H); 2.15(s, 6H); 2.70(m, 1H); 178-180.degree. 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-d.sub.6) 66a H H Cl H H CCH.sub.3 CH H CCH.sub.3 86-88.degree. 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) (CDCl.sub.3) film 67a H H Cl H H CCH.sub.3 CH H CCH.sub.3 HCl 3432 (b.a.), 2936, 1.56(m, 2H); 1.76(m, 2H); 2.14(s, 6H); 2.70(m, 1H); 182-184.degree. 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-d.sub.6) 68a H H Cl H H CH CH H CH 102-104.degree. 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) (CDCl.sub.3) 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.degree. 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-d.sub.6) 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.degree. 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 d.sub.6)

EBIOLOGICAL ASSAYS

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.degree. C. or 55.degree. 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.degree. 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-US-00003 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-US-00004 TABLE 4 Analgesic activity in the hot-plate assay (55.degree. 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-US-00005 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-US-00006 TABLE 6 Analgesic activity in the hot plate assay in mouse. PRODUCT DOSE (mg/kg, ip) .DELTA. Latency (Seconds) Example 47a 40 5 Pentazocine 10 6 Example 47a 40 + + 20 Pentazocine 10

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