Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-03-08
2002-12-24
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S373000, C514S339000, C514S307000, C514S301000, C514S292000, C546S276700, C546S148000, C546S114000, C546S085000
Reexamination Certificate
active
06498251
ABSTRACT:
TECHNICAL FIELD
This invention relates to a tetrahydrobenzindole derivative or an intermediate thereof. Since this tetrahydrobenzindole derivative has the ability to bind to serotonin receptors in the living body, it also relates to the treatment and prevention of various diseases which are induced by the abnormality of serotonin controlling functions.
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 body functions but also mental functions. Under such circumstances, importance of drug therapy has been increasing more and more, 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 means 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
, 64, 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, 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 a drug group classified as atypical among already known schizophrenia treating drugs has the affinity particularly for serotonin receptor 5-HT
6
, the serotonin receptor 5-HT
6
is closely related to the efficacy of these drugs [R. D. Ward et al.,
Neuroscience
, 64, 1105-1111 (1995)].
It has been 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 [B. L. Roth et al.,
J. Pharmacol. Exp. Ther
., 268 (3), 1403-1410, 1994]. Also, it has been reported that a 5HT
1A
partial agonist, buspirone, has high therapeutic effect for patients having both symptoms of depression and anxiety [Tollefson G. D. et al.,
Psychopharmacol. Bull
., 27, 163-170, 1991]. In addition, the importance of serotonin receptors in various physiological functions was been reported in a large number, for example, it has been reported that certain N-butylpiperidines inhibit serotonin receptor 5-HT
4
selectively and are useful for the treatment of irritable bowel syndrome [L. M. Gaster et al., J. Med. Chem., 38, 4760-4763, 1995], and it has been assumed that 5-HT
7
exerts an important function in the human circadian rhythm regulation [T. W. Lovenberg et al.,
Neuron
, 11, 449-458, 1993].
In addition, it is considered that they are exerting various physiological functions by distributing not only in human and animal brains but also broadly in smooth muscle tissues such as the spleen, stomach, ileum, small intestines, coronary vessel and the like [A. J. Sleight,
DN
&
P
, 214-223, 1997]. In consequence, creation of a substance which acts upon 5-HT
7
receptor is considerably profitable for the studies of physiological functions in these organs and the treatment and prevention of diseases induced by functional abnormality in these organs.
The present inventors have already found a substance which has strong ability to bind to the 5-HT
7
receptor in the living body. That is, according to the inventions by the present inventors (WO 98/00400, Japanese Patent Application No. 9-358380, Japanese Patent Application No. 9-358381, Japanese Patent Application No. 10-85913, Japanese Patent Application No. 10-136872, Japanese Patent Application No. 10-229709 and Japanese Patent Application No. 10-319336), there are provided novel tetrahydrobenzindole derivatives which strongly bind to 5-HT
7
receptor in the living body and pharmaceutical compositions which comprise these compounds.
As described above, novel tetrahydrobenzindole derivatives which strongly bind to 5-HT
7
receptor in the living body have been provided, but creation of a compound which selectively binds to the 5-HT
7
receptor will be useful for the treatment and prevention of various diseases which are considered to be induced by the abnormality of central and peripheral serotonin controlling functions, such as mental diseases (manic-depressive psychosis, anxiety, schizophrenia, epilepsy, sleep disorders, biological rhythm disorders, migraine and the like), cardiovascular diseases (hypertension and the like) and gastrointestinal disorders, and will also provide medicaments having high safety that can prevent generation of unexpected side effects. It will also provide compounds which have high utility value in studies on the elucidation of physiological functions of 5-HT
7
receptor whose functions are not clear yet.
Thus, the object of the invention is to provide a compound which has strong affinity for the 5-HT
7
receptor in the living body and binds selectively to the 5-HT
7
receptor.
DISCLOSURE OF THE INVENTION
In order to solve these problems, the present inventors have examined on various compounds. As a result, it was found that certain tetrahydrobenzindole derivatives have strong affinity for 5-HT
7
receptor in the living body and selectively bind to 5-HT
7
receptor, thereby resulting in the accomplishment of the invention. That is, according to the invention, novel tetrahydrobenzindole derivatives and pharmaceutical compositions which comprise these compounds are provided, and intermediates useful in producing these compounds are also provided. Accordingly, the invention comprises the following constructions.
1. A compound represented by formula (1):
wherein R
1
represents a hydrogen atom, a lower alkyl group or an aralkyl group; R
2
represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, an acyloxy group, an alkoxycarbonyl group, a nitro group, an amino group, a substituted amino group, a carbamoyl group or an alkylcarbamoyl group, and n is an integer of from 2 to 6; and &agr; represents the following formula (a), (b), (c), (d) or (e):
wherein
in formulae (a) and (b), R
3
represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group or an alkoxy group, X represents NR
10
, NCONR
11
R
12
, S, SO, SO
2
or O, R
10
represents a hydrogen atom, a lower alkyl group, an alkenyl group, an oxoalkyl group, an aralkyl group, a cyanoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a substituted aminoalkyl group, an alkoxycarbonylalkyl group, a carbamoylalkyl group, an alkylcarbamoylalkyl group, an acyl group or an alkoxycarbonyl, R
11
and R
12
independently represent a hydrogen atom or a lower alkyl group, and Y represents a methylene group or a carbonyl group,
in formula (c), R
4
represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a cyano group, a trihalomethyl group, an alkoxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkoxycarbonyl, a sulfamoyl group, an amino group, a substituted amino group, a carbamoyl group, an alkylcarbamoyl group, an acyl group or a carboxy group, R
5
represents a hydrogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, a phenyl group or a substituted phenyl group, k is 0 or an integer of from 1 to 3, m is 0 or an integer of from 1 to 3, a
Ando Takashi
Fuji Kazuyuki
Hiranuma Toyokazu
Imai Masako
Kikuchi Chika
Liu Hong
Meiji Seika Kaisha Ltd.
Shah Mukund J.
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