Tetrahydrobenzindole compounds

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S253090, C514S254080, C514S323000, C514S339000, C514S411000, C544S295000, C544S364000, C544S372000, C546S200000, C546S276700, C548S437000

Reexamination Certificate

active

06355642

ABSTRACT:

TECHNICAL FIELD
This invention relates to a tetrahydrobenzindole compound. Since this tetrahydrobenzindole compound binds to serotonin receptors in the living body, it also relates to the treatment and prevention of diseases which are induced by the abnormality of serotonin controlling functions, such as manic-depressive psychosis, anxiety, schizophrenia, sleep disorders, jet lag, gastrointestinal disease, cardiovascular disease and the like.
BACKGROUND ART
In the present society, the environment which surrounds us is sharply changing, and adaptation for it is becoming more and more difficult. Thus, a part which is too much for adaptation for the social environment is accumulated in our bodies as stress and sometimes causes abnormality of not only physical functions but also mental functions. In the treatment of abnormal mental functions, importance of drug therapy has been increasing more and more in addition to psychological therapy, so that development of effective drugs has been put forward.
Since the indication about the action of serotonin (5-HT) in the central nervous system, classification and distribution of serotonin receptors have been revealed gradually. By the detailed analysis of serotonin receptors using molecular biological technique in recent years, 5-HT
1
and its subtypes, 5-HT
2
and its subtypes, 5-HT
3
, 5-HT
4
, 5-HT
6
, 5-HT
7
and the like have been specified and a total of 14 different serotonin receptors have been proposed [R. D. Ward et al., Neuroscience, Vol. 64, pp. 1105-1111 (1995)]. Studies on the physiological functions of serotonin receptors have also been making progress, and not only their relation to appetite, body temperature regulation, blood pressure regulation and the like body functions but also their relation to depression, anxiety, schizophrenia, sleep disorders and the like mental functions have been revealed [P. L. Bonate et al.,
Clinical Neuropharmacology
, 14, pp. 1-16 (1991)]. Actually, 5-HT
1A
receptor agonists, 5-HT
2
receptor inhibitors and 5-HT re-uptake inhibitors are now used in the clinical field.
It has been reported also that, since serotonin receptor 5-HT
6
has the affinity particularly for a drug group classified as atypical among already known schizophrenia treating drugs, the serotonin receptor 5-HT
6
is closely related to the efficacy of these drugs [R. D. Ward et al.,
Neuroscience
, Vol. 64, pp. 1105-1111 (1995)].
Roth B. L. et al. [
J. Pharmacol
. Exp. Ther., 1994, 268 (3), 163-170] have reported that several atypical schizophrenia treating drugs including clozapine have strong affinity for the 5HT
6
receptor, and several typical schizophrenia treating drugs show high affinity for both of the 5HT
6
and 5HT
7
receptors.
Also, Tollefson G. D. et al [
Psychopharmacol. Bull
., 1991, 27, 163-170] have reported that a 5HT
1A
partial agonist, buspirone, has high therapeutic effect for patients having both symptoms of depression and anxiety.
In addition, L. M. Caster et al. [
J. Med. Chem
., Vol. 38, 4760-4763 (1994)] have reported that certain N-butylpiperidines inhibit serotonin receptor 5-HT
4
selectively and are useful for the treatment of irritable digestive organ syndrome, and T. W. Lovenberg et al. [
Neuron
, Vol. 11, 449-458 (1993)] have assumed that serotonin receptor 5-HT
7
exerts an important function in the human circadian rhythm regulation.
As has been described in the above, functions of serotonin receptors are being revealed, so that great concern is directed toward the creation of a chemical substance which exerts its function upon one of these serotonin receptors or simultaneously upon a plurality of these serotonin receptors, because it will provide pharmaceutical preparations which are useful not only for the physiological studies on the function of central and peripheral nervous systems but also for the treatment and prevention of various diseases which are considered to be induced by the abnormality of intracerebral and peripheral serotonin controlling functions, such as schizophrenia, manic-depressive psychosis, anxiety, sleep disorders, jet lag, gastrointestinal disease, migraine and abnormal blood pressure and the like cardiovascular disease.
DISCLOSURE OF THE INVENTION
The present invention comprises the following constructions.
1. A compound represented by formula (I):
[wherein A represents N, CH, C having a double bond or CR
5
; each of B and Z independently represents N or CR
1
, with the proviso that A is N when B and/or Z is N; R
1
represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyano group, a trihalomethyl group, a hydroxy group, an alkoxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkoxycarbonyl group, a sulfamoyl group, an amino group, a substituted amino group, a carbamoyl group, an alkylcarbamoyl group, an acyl group or a carboxy group; R
2
represents a hydrogen atom or a lower alkyl group; R
3
represents a hydrogen atom, a lower alkyl group or an aralkyl group; R
4
represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, a nitro group, an amino group, a substituted amino group, a carbamoyl group, an alkylcarbamoyl group or an acyloxy group; R
5
represents a lower alkyl group, a cyano group, a carbamoyl group, a carboxy group, an acyl group, an acyloxy group, an alkoxy group, an alkoxycarbonyl group, a trihalomethyl group or a hydroxy group; and n is an integer of 2 to 6] or a pharmaceutically acceptable salt thereof.
2. A compound according to the aforementioned item 1, which is represented by formula (II):
[wherein Y represents N or CH; and R
1
, R
2
, R
3
, R
4
and n are as defined in the foregoing] or a pharmaceutically acceptable salt thereof.
3. A compound according to the aforementioned item 1, which is represented by formula (III):
[wherein R
1
, R
3
, R
4
and n are as defined in the foregoing] or a pharmaceutically acceptable salt thereof.
4. A compound according to the aforementioned item 1, which is represented by formula (IV):
[wherein R
1
, R
2
, R
3
, R
4
, R
5
and n are as defined in the foregoing] or a pharmaceutically acceptable salt thereof.
5. A compound according to the aforementioned item 1, which is represented by formula (V):
[wherein R
1
, R
3
, R
4
, Z and n are as defined in the foregoing; and R
1
is preferably a hydrogen atom, a lower alkyl group, a trihalomethyl group or an alkoxy group] or a pharmaceutically acceptable salt thereof.
6. A compound represented by formula (a-1):
[wherein X represents a halogen atom, a methanesulfonyloxy, ethanesulfonyloxy or the like alkylsulfonic acid ester residue or a benzenesulfonyloxy group, p-toluenesulfonyloxy or the like arylsulfonic acid ester residue; and R
3
, R
4
and n are as defined in the foregoing].
7. A pharmaceutical composition for use in the treatment or prevention of mental diseases, which contains any one of the compounds of the aforementioned items 1 to 5 or a pharmaceutically acceptable salt thereof.
The compounds which are provided by the present invention can be produced by the chemical synthesis methods described below. In the following descriptions concerning the chemical substances of the present invention and production methods thereof, the term “halogen atom” means fluorine, chlorine, bromine or iodine atom, the term “lower alkyl” means a methyl, ethyl or the like straight chain alkyl group having 1 to 4 carbon atoms, an isopropyl, isobutyl, t-butyl or the like branched-chain alkyl group or their halogen-substituted alkyl group, and the term “base to be used as a catalyst” means sodium hydroxide, potassium carbonate, triethylamine or the like.
In the formula (I), R
1
represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyano group, a trihalomethyl group (wherein the three halogen atoms are as defined in the foregoing and may be the same or different from one another, and a trifluoromethyl group

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