Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-03-27
2002-02-12
Bernhardt, Emily (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06346620
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the novel compound 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)-butyl]-1-piperazinyl}-5-fluoropyrimidine, its preparation and its therapeutic use, its physiologically acceptable salts, the processes for their preparation and their application as medicaments in human and/or veterinary therapeutics, and the pharmaceutical compositions which comprise them.
BACKGROUND OF THE INVENTION
Patents EP 382,637 and EP 497,659 of the Applicant Company disclosed various pyrimidinyl-piperazinylalkylazole derivatives having anxiolytic and/or tranquilizing properties. Although Patent EP 382,637 claims pyrimidinylpiperazinylalkylazole derivatives substituted at the 5-positron of the pyrimidine by a halogen atom, only two examples of compounds of this type are disclosed and, in both cases, it is a bromine atom.
BRIEF SUMMARY OF THE INVENTION
The Applicant Company has now discovered that the introduction of a fluorine atom as substituent at the 5-position of the pyrimidine, in the special case where the azole is an imidazole trisubstituted by a methyl group at the 2-position and by two chlorine atoms at the 4- and 5-positions, gives rise to the compound which is the subject-matter of the present patent, which compound exhibits some advantageous biological properties which make it of particular use in its application in human and/or veterinary therapeutics. In particular, the compound which is the subject-matter of the present patent is of use as an antiemetic against seasickness (nausea caused by motion), as an antidepressant or anxiolytic, as an inhibitor of gastric acid secretion or obsessive-compulsive disorders, in panic attacks and in sleep apnea in mammals, including man.
It is possible to prepare the compound 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]-1-piperazinyl}-5-fluoropyrimidine and its physiologically acceptable salts according to the invention by one of the processes shown hereinbelow.
a) By reaction of 8-(5-fluoro-2-pyrimidinyl)-8-aza-5-azoniaspiro [4.5]decane with 4,5-dichloro-2-methyl-1H-imidazole in the presence of potassium carbonate and in a dipolar aprotic solvent, such as dimethylformamide. The reaction temperature can vary between 70° C. and the reflux temperature of the solvent, and the reaction time fluctuates between 3 and 48 hours.
b) By reaction of 5-fluoro-2-(piperazin-1-yl) pyrimidine with 1-(4-chlorobutyl)-4,5-dichloro-2-methyl-1H-imidazole in the presence of potassium carbonate and in a dipolar aprotic solvent, such as dimethylformamide. The reaction temperature can vary between 70° C. and the reflux temperature of the solvent, and the reaction time varies between 3 and 48 hours. This reaction can also be carried out under phase transfer conditions by using an aqueous sodium hydroxide solution, toluene and a catalyst, such as tetrabutylammonium bromide. Under these conditions, the temperature of the reaction can vary between 50° C. and 90° C., and the reaction time varies between 12 and 72 hours.
c) By the reaction of 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]piperazin-1-yl}-5-fluoropyrimidine and of a physiologically acceptable acid, such as citric acid, in a suitable solvent, such as ethanol.
REFERENCES:
patent: 5128343 (1992-07-01), Pinol et al.
patent: 5227486 (1993-07-01), Merce-Vidal et al.
patent: 5292739 (1994-03-01), Merce-Vidal et al.
patent: 5382586 (1995-01-01), Merce-Vidal et al.
patent: 5532234 (1996-07-01), Frigola-Constansa et al.
patent: WO 97/21439 (1997-06-01), None
Pramod R. Saxena, Serotonin Receptors: Subtypes, Functional Responses and Therapeutic Relevance,Pharmac. Ther., (1995), vol. 66. pp. 339-368.
Frigola-Constansa Jordi
Merce-Vidal Ramon
Bernhardt Emily
Laboratories del Dr. Esteve S.A.
Rockey Milnamow & Katz Ltd.
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