Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-23
2002-06-18
Shah, Mukund J. (Department: 1629)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S373000, C514S339000, C514S307000, C514S301000, C514S292000, C546S276700, C546S148000, C546S114000, C546S085000
Reexamination Certificate
active
06407112
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an optically active tetrahydrobenzindole derivative and a pharmaceutical composition containing the same. It also relates to an optically active intermediate suitable for producing the optically active compound, and a method for producing the optically active compound.
BACKGROUND ART
Since the function of serotonin (5-HT) in the central nervous system has been suggested, the classification and distribution of the serotonin receptor have been gradually clarified. According to a detailed analysis of the serotonin receptor using a recent molecular biological method, 5-HT
1
and the subtype thereof, 5-HT
2
and the subtype thereof, 5-HT
3
, 5-HT
4
, 5-HT
6
, 5-HT
7
and the like have been specified, and fourteen kinds of serotonin receptors have been proposed (refer to R. D. Ward et al., Neuroscience, 64, 1105 to 1111, 1995).
Of these serotonin receptors, 5-HT
7
abundantly present in a brain is considered to have an important function on the circadian rhythm regulation, both in human and animals (refer to T. W. Lovenberg et al., Neuron, 11, 449 to 458, 1993). It is also considered that 5-HT
7
is present not only in a brain of human and animals, but also in a smooth muscle tissue, i.e., spleen, stomach, ileum, small intestine, coronary vessel or the like of human and animals (refer to A. J. Sleight, DN&P, 214 to 223, 1997), and performs various physiological functions. Accordingly, the creation of compounds acting on 5-HT
7
receptor is extremely useful for the research of physiological functions in these organs, and also useful for treatment or prevention of diseases caused by an abnormality in a function in these organs.
The present inventors have already found a substance having a strong binding affinity for 5-HT
7
receptor in an organism. Namely, according to the inventions by the present inventors (WO98/00400, and Japanese Patent Applications Nos. 9-358380, 9-358381 and 10-85913, corresponding to WO99/33804), there are provided a novel tetrahydrobenzindole derivatives which have strong affinity on cloned 5-HT
7
receptor and a pharmaceutical composition characterized by containing the same.
By the above-described inventions, compounds which showed strong affinity on cloned 5-HT
7
receptor could have been newly provided. However, details regarding an optically active compound present in the tetrahydrobenzindole derivative were still not clear. Now, it is widely known that an active substance to be bound with a receptor in an organism is one having a stereostructure desirably fitting in a compound binding site of the receptor. It is strongly desired to obtain a single optical isomer in view of clarification of physiological properties of a receptor and also the creation of a pharmaceutical composition. Accordingly, the object of the present invention is to obtain an optically active compound having a high selectivity on 5-HT
7
receptor.
DISCLOSURE OF THE INVENTION
The present inventors have conducted investigations regarding tetrahydrobenzindole derivative from various points. Namely, regarding mutual separation of optically active compounds, conventionally, have been known methods, i.e., fractional crystallization and a utilization of a salt formation comprising an optically active acid and base. Recently, so-called chiral chromatography using an optically active carrier is known. However, in any method as described above, respective conditions of separation and fractionation of a compound must be selected. Further, these methods cannot necessarily be applied to all related compounds.
The present inventors could have solved the above-described problem by developing a novel synthesis route comprising an optical resolution in the stage of a raw material for synthesis and utilization of an optically active raw material. Specifically, according to the present invention, there are provided an optically active tetrahydrobenzindole derivative and a pharmaceutical composition containing the optically active compound, an optical intermediate suitable for producing the optically active compound, and a method for producing the optically active compound.
Accordingly, the present invention comprises the following construction.
1. An optically active compound represented by the following general formula (I):
wherein D represents the following general formula (II), (IIIa), (IIIb), (IV), (V) or (VI):
R
1
and R
3
each independently represents (single or plural) a hydrogen atom, a halogen atom, a lower alkyl, a cyano, a trihalomethyl, a hydroxy, an alkoxy, an alkylthio, an alkylsulfinyl, an alkylsulfonyl, a carboxy, an alkoxycarbonyl, an acyl, an acyloxy, an acylthio, a sulfamoyl, a nitro, an amino, an alkylamino, a carbamoyl, an alkylcarbamoyl or a phenyl;
R
2
and R
4
each independently represents a hydrogen atom, a lower alkyl or an aralkyl;
n represents an integer of 2 to 4;
A represents N, CH, C having a double bond or CR
7
(R
7
represents a lower alkyl, a cyano, a carbamoyl, an alkylcarbamoyl, a carboxy, an acyl, an acyloxy, an alkoxy, an alkoxycarbonyl, trihalomethyl or a hydroxy;
represents a single bond or a double bond;
G represents a methylene or a carbonyl;
E
1
represents a group forming a benzene ring, a pyridine ring or a pyrimidine ring;
E
2
represents a group forming a benzene ring, a pyridine ring or a pyrimidine ring together with a carbon atom having a double bond in a condensed part;
J represents a group forming a benzene ring, a thiophene ring, a furan ring, an imidazole ring or a pyrazole ring together with a carbon atom having a double bond in a condensed part;
X represents NR
8
, NCONR
9
R
10
, S, SO, SO
2
or O (in which R
8
represents a hydrogen atom, a lower alkyl, an aralkyl, an oxoalkyl, an alkenyl, a cyanoalkyl, a hydroxyalkyl, an alkoxyalkyl, an aminoalkyl, an alkylaminoalkyl, an alkoxycarbonylalkyl, a carbamoylalkyl, an alkylcarbamoylalkyl, an acyl or an alkoxycarbonyl, R
9
and R
10
each independently represents a hydrogen atom or a lower alkyl);
Y represents CH
2
, S, O or CO;
R
5
and R
6
each independently represents a hydrogen atom, a lower alkyl, a hydroxy, an alkoxy, an acyl or a phenyl;
R
a
represents a hydrogen atom or an alkyl;
m represents an integer of 1 to 3;
p represents an integer of 0 or 1 to 3;
q represents an integer of 0 or 1 to 3, provided that p+q represents an integer of 1 to 3;
and the pharmacologically acceptable salt thereof.
2. An optically active compound as described in item 1 above, wherein n is 4, and the pharmacologically acceptable salt thereof.
3. An optically active compound as described in item 1 or 2 above represented by the following general formula (VII):
wherein R
1
, R
2
, R
3
, R
4
, A, E
1
, and n have the same definitions as those of the item 1 above, and the pharmacologically acceptable salt thereof.
4. An optically active compound as described in item 3 above, wherein E
1
represents a group forming a pyridine ring or a pyrimidine ring; and A represents N, and the pharmacologically acceptable salt thereof.
5. An optically active compound as described in item 1 above represented by the following general formula (VIIIa):
wherein R
1
, R
2
, R
3
, X and n have the same definitions as those of the item 1 above, and the pharmacologically acceptable salt thereof
6. An optically active compound as described in item 1 above represented by the following general formula (VIIIb):
wherein R
1
, R
2
, R
3
, X, G and n have the same definitions as those of the item 1 above, and the pharmacologically acceptable salt thereof.
7. An optically active compound as described in item 1 above represented by the following general formula (IX):
wherein R
1
, R
2
, R
3
A, E
2
, Y, m and n have the same definitions as those of the item 1 above, and the pharmacologically acceptable salt thereof.
8. An optically active compound as described in item 7 above, wherein E
2
represents a group forming a pyridine ring or a pyrimidine ring together with a double bond; and A represents N, and the pharmacologically acceptable salt thereof.
9. An optically active compound as descr
Ando Takashi
Hiranuma Toyokazu
Kikuchi Chika
Koyama Masao
Morita Eriko
Liu Hong
Meiji Seika Kaisha Ltd.
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