Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-22
2004-04-20
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S373000
Reexamination Certificate
active
06723725
ABSTRACT:
The invention relates to compounds of the formula I
in which
R
1
is a phenyl radical which is unsubstituted or substituted by R
2
and/or R
4
or is Het
1
,
R
2
, R
4
,
R
5
, R
6
in each case independently of one another are Hal, A, OA, OH, CN or acyl,
R
3
is a phenyl radical which is unsubstituted or substituted by R
5
and/or R
6
or is Het
2
,
Het
1
is a mono- or binuclear unsaturated heterocyclic ring system, which is unsubstituted or mono- or disubstituted by Hal, A, OA or OH and contains one, two or three identical or different heteroatoms such as nitrogen, oxygen and sulfur,
Het
2
is an unsaturated heterocyclic ring system which is unsubstituted or mono- or disubstituted by Hal, A, OA and contains one or two 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.
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 affinity of [
3
H]ketanserin for 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 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-hydroxytryptamine 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.
Other compounds which likewise exhibit 5-HT
2
-antagonistic actions are described, for example, in EP 0320983. Similar piperazine derivatives having antiarrhythmic properties are disclosed, for example, in EP 0431945. Other indolecarbonyl derivatives having analgesic properties are described in EP 0599240. EP 0624584 describes piperazine derivatives as calmodolin [sic] inhibitors. The compounds according to the invention are to be considered as a selection invention with respect to the last-mentioned document. WO 99/11641 describes phenylindole derivatives having 5-HT
2
-antagonistic properties.
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; e.g. WO 9524194), anxiety states and also physiological changes which accompany anxiety states such as, for example, tachycardia, tremors or sweating (e.g. EP 319962), panic attacks, psychoses, schizophrenia, anorexia, delusional obsessions, agoraphobia, migraine, Alzheimer's disease, sleep disorders and also sleep apnoea, tardive dyskinesias, learning disorders, age-dependent memory disorders, eating disorders such as bulimia, drug abuse such as, for example, of alcohol, opiates, nicotine, psychostimulants such as, for example, cocaine or amphetamines (e.g. U.S. Pat. No. 6,004,980), sexual functional disorders, states of pain of all types and fibromyalgia (e.g. WO 9946245). The compounds of the formula I are suitable for the treatment of extrapyramidal side effects (EPS) in neuroleptic drug therapy. EPS is characterized by Parkinson-like syndromes, acathisia and dystonic reactions (e.g. EP 337136). They are further suitable for the treatment of anorexia nervosa, angina, Reynaud's phenomenon, coronary vasospasms, in the prophylaxis of migraine (e.g. EP 208235), pain and neuralgia (e.g. EP 320983), for the treatment of the Rett syndrome with autistic traits, of the Asperger syndrome, or autism and autistic disorders, in concentration deficiency states, developmental diseases, hyperactivity states with mental underdevelopment and stereotypic behavioural states (e.g. WO 9524194).
In addition, they are suitable for the treatment of endocrine disorders such as hyperprolactinaemia, furthermore in vasospasms, thrombotic disorders (e.g. WO 9946245), hypertension and gastrointestinal 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 N-(indolecarbonyl)-piperazine derivatives 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 compounds.
The invention accordingly relates to the compounds of the formula I and a process for the preparation of compounds of the formula I.
The process for the preparation of compounds of the formula I is characterized in that
a) a compound of the formula II
in which L is Cl, Br, I or a free or reactively functionally modified OH group, and R
3
has the meaning indicated previously, is reacted with a compound of the formula III
in which R
1
has the meaning indicated previously, or
b) a compound of the formula IV
in which R
3
has the meaning indi
Bartoszyk Gerd
Böttcher Henning
Greiner Hartmut
Harting Jürgen
März Joachim
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
Raymond Richard L.
LandOfFree
Indole derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Indole derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indole derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3252913