Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-21
2004-06-29
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S226500, C514S228800, C514S255030, C514S257000, C514S307000, C514S314000, C514S317000, C514S326000, C544S008000, C544S047000, C544S058100, C544S072000, C544S171000, C544S357000, C549S315000, C549S315000, C549S315000, C549S315000, C549S315000, C549S315000, C549S315000, C549S207000, C549S213000
Reexamination Certificate
active
06756370
ABSTRACT:
The invention relates to compounds of the formula I
in which
R
1
, R
2
in each case independently of one another are aryl or Het,
aryl is phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, CN, A, OA or OH,
Het is a mono- or binuclear unsaturated heterocyclic ring system which is unsubstituted or mono-, di- or trisubstituted by Hal, CN, A, OA or OH and which contains one, two or three identical or different heteroatoms such as nitrogen, oxygen and sulfur,
A is alkyl having 1-6 C atoms,
Hal is F, Cl, Br or I,
and their physiologically acceptable salts and solvates.
The invention was based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their physiologically acceptable salts and solvates have valuable pharmacological properties together with good tolerability, as they have actions on the central nervous system. The compounds have a strong affinity for 5-HT
2A
receptors; they furthermore exhibit 5-HT
2A
receptor-antagonistic properties.
Other compounds which also show 5-HT
2A
-antagonistic actions are described, for example, in EP 0320983 or in WO 99/11641. 1-Phenylethyl-4-piperidinemethanol derivatives are described in EP 0208235 and in EP 0531410.
For the in-vitro detection of the affinity for 5-HT
2A
receptors, it is possible to use, for example, the following test (Example A1). The 5-HT
2A
receptors are exposed to both [
3
H]ketanserin (a substance known for its affinity for the receptor) and the test compound. The decrease in the binding of [
3
H]ketanserin to the receptor is a sign of the affinity of the test substance for the 5-HT
2A
receptor. Detection is carried out analogously to the description of J. E. Leysen et al., Molecular Pharmacology, 1982, 21: 301-314 or as also described, for example, in EP 0320983.
The experimental proof that the compounds according to the invention have affinity for the 5-HT
2A
receptor is demonstrated experimentally in vitro, as described above, for some representative compounds of the formula I. The pharmacological test data are summarized in Example A1, Table A. As a comparison, the compound (+)-&agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol, which is disclosed in EP 0531410, is additionally listed.
The efficacy of the compounds according to the invention as 5-HT
2A
receptor antagonists can be measured in vitro analogously to W. Feniuk et al., Mechanisms of 5-hydroxytryptamine-induced vasoconstriction, in: The Peripheral Actions of 5-Hydroxytryptamine, ed. Fozard JR, Oxford University Press, New York, 1989, p. 110. Thus the contractility of the rat tail artery, caused by 5-hydroxytryptamine, is mediated by 5-HT
2A
receptors. For the test system, vessel rings, prepared from the ventral rat tail artery, are subjected to perfusion with an oxygen-saturated solution in an organ bath. By introduction of increasing concentrations of 5-hydroxy-tryptamine into the solution, a response to the cumulative concentration of 5-HT is obtained. The test compound is then added to the organ bath in suitable concentrations and a second concentration curve is measured for 5-HT. The strength of the test compound on the shift of the 5-HT-induced concentration curve to higher 5-HT concentrations is a measure of the 5-HT
2A
receptor-antagonistic property in vitro.
The 5-HT
2A
-antagonistic property can be determined in vivo analogously to M. D. Serdar et al., Psychopharmacology, 1996, 128: 198-205.
Serotonin-2(5-HT
2
)agonists such as 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induce sterotypic behaviour patterns such as, for example, head-twitching or ear-scratching in various animals such as, for example, mice or rats (N. A. Darmani et al., Pharmacol. Biochem. Behav. 1989, 36: 901-906; N. A. Darmani et al., Pharmacol. Biochem. Behav. 1990, 37: 95-99; N. A. Darmani et al., Pharmacol. Biochem. Behav. 1994, 48: 383-396; D. L. Willins and H. Y. Meltzer, J. Pharmacol. Exp. Ther., 1997, 282: 699-706). The response of head-twitching is selectively prevented by 5-HT
2A
antagonists, however ear-scratching is sensitive to 5-HT
2c
antagonists (N. A. Darmani et al., Pharmacol. Biochem. Behav. 1990, 37: 95-99; N. A. Darmani and C. F. Gerdes, Pharmacol. Biochem. Behav. 1995, 50: 545-550; D. L. Willins and H. Y. Meltzer, J. Pharmacol. Exp. Ther., 1997, 282: 699-706).
DOI-induced head-twitching in mice is used in order to test compounds having 5-HT
2A
antagonistic properties. The test compound is orally administered to male mice. 30 minutes later, 3 mg/kg of DOI is [sic] are administered intraperitoneally. The animals are observed for 15 minutes and the number of head twitches is noted. Quantification of the in vivo antagonistic effect of the test compounds ensues by comparison with the number of head twitches from those investigations in which the animals were only DOI-treated.
Surprisingly, the compounds according to the invention have, in comparison to the prior art, an improved suppression of the behaviour elicited on oral administration. The pharmacological test data are summarized in Example A2 in Table B. As a comparison, the compound (+)-&agr;-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, which is disclosed in EP 0531410, is additionally listed.
The test results indicate an unexpectedly improved bioavailability of the compounds according to the invention in comparison to the prior art.
The compounds of the formula I are therefore suitable both in veterinary and in human medicine for the treatment of functional disorders of the central nervous system and also of inflammation. They can be used for the prophylaxis and for the control of the sequelae of cerebral infarcts (cerebral apoplexy) such as stroke and cerebral ischaemias and for the treatment of extrapyramidal motor side effects of neuroleptics and also of Parkinson's disease, for the acute and symptomatic therapy of Alzheimer's disease and the treatment of amyotrophic lateral sclerosis. They are likewise suitable as therapeutics for the treatment of brain and spinal cord traumata. In particular, however, they are suitable as pharmaceutical active compounds for anxiolytics, antidepressants, antipsychotics, neuroleptics, antihypertensives and/or for positively affecting compulsive behaviour (obsessive-compulsive disorder, OCD), anxiety states, panic attacks, psychoses, schizophrenia, anorexia, delusional obsessions, agoraphobia, migraine, Alzheimer's disease, sleep disorders, tardive dyskinesias, learning disorders, age-dependent memory disorders, eating disorders such as bulimia, drug abuse and/or sexual functional disorders.
In addition, they are suitable for the treatment of endocrine disorders such as hyperprolactinaemia, furthermore in vasospasms, hypertension and gastro-intestinal disorders.
They are furthermore suitable for the treatment of cardiovascular disorders and also extrapyramidal symptoms as described in WO 99/11641 on page 2, lines 24-30.
The compounds according to the invention are further suitable for decreasing intraocular pressure and for the treatment of glaucoma. They are also suitable in animals for the prophylaxis and treatment of symptoms of intoxication on the administration of ergovaline. The compounds are furthermore suitable for the treatment of disorders of the cardiovascular system (WO 99/11641, page 3, lines 14-15).
The compounds according to the invention can also be employed together with other active compounds in the treatment of schizophrenia. Possible other active compounds are the compounds mentioned in WO 99/11641 on page 13, lines 20-26.
They can furthermore be employed as intermediates for the production of further pharmaceutical active compounds.
The invention relates to the piperidine alcohols of the formula I and to their physiologically acceptable acid addition salts. The invention also relates to the solvates, e.g. hydrates or alcoholates, of these c
Ackermann Karl-August
Bartoszyk Gerd
Böttcher Henning
Gottschlich Rudolf
Greiner Hartmut
Covington Raymond
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
Seaman D. Margaret
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