Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-01
2001-08-28
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S245000, C544S247000, C548S301700, C548S420000, C514S224500, C514S257000, C514S387000, C514S410000, C549S024000
Reexamination Certificate
active
06281355
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compounds having a high affinity for mitochondrial diazepam binding inhibitor receptor (MDR).
BACKGROUND ART
Benzodiazepine (BZ) receptors which are an acting site of anti-anxiety drugs are classified into 2 subtypes of central benzodiazepine receptor (CBR) located on GABA
A
receptor/chloride channel complex and MDR located on the central nervous system (glial cells) or adrenal glands (Clin. Neuropharmacol., 16, 401-417 (1993)). Recently, CBR agonists of which representative is diazepam are widely used as anti-anxiety drugs. However, since CBR agonists act directly on GABA
A
receptor/chloride channel complex, they cause an anti-anxiety action together with side-effects such as excessive sedation or psychic dependence. On the other hand, since MDR agonists act indirectly on GABA
A
receptor/chloride channel complex via synthesis of neurosteroids such as endogenous neuroactive steroids (endogenous anti-anxiety substances), they cause an anti-anxiety action, but do not cause side-effects such as psychic dependency or excessive sedation (J. Pharmacol. Exp. Ther., 267, 462-471, 1993; ibid., 265, 649-656, 1993).
Accordingly, there is a need of the development of therapeutic agents for diseases (obsessive disorders, panic disorders) on which the previous BZs do not have a satisfactorily therapeutic effect, and development of MDR agonists as anti-anxiety drugs which alleviate the side-effects as recognized in the previous BZs.
Furthermore, the compounds which act on MDR, in view of acting on GABA
A
receptors, have a possibility of use as therapeutical agents of sleeping disorders, epilepsy, dyskinesia accompanied by muscle rigidity, feeding disorders, circulation disorders, recognition and learning disability or drug dependence (Progress in Neurobiology, 38, 379-395, 1992, ibid., 49, 73-97, 1996; J. Neurochem., 58, 1589-1601; Neuropharmacol., 30, 1435-1440, 1991). In addition, these compounds, in view of the physiological functions of MDR, have a possibility of use as therapeutic agents of cancer (Biochimica et Biophysica Acta, 1241, 453-470, 1995), lipid metabolism abnormality (Eur. J. Pharmacol., 294, 601-607, 1995), schizophrenia (Neuropharmacology, 35, 1075-1079, 1996), cerebral infarction (J. Neurosci., 15, 5263-5274, 1995), AIDS (Abstracts of the fifth international conference on AIDS, p. 458, 1989), Alzheimer's disease (Alzheimer Dis. Assoc. Disotd., 2, 331-336, 1988) or Huntington chorea (Brain Res., 248, 396-401, 1982).
Among the compounds having affinity for MDR, there are indole compounds disclosed in Japanese Translation of PCT publication (Kohyo) No.6-501030.
DISCLOSURE OF THE INVENTION
As a result of extensive researches about compounds having a high affinity for MDR, the present inventors have found that the specific nitrogen-containing tetracyclic compounds meet the above object, thus the present invention has been accomplished. As stated above, while the indole compounds having an affinity for MDR are known, there are not reported nitrogen-containing tetracyclic compounds which have an affinity for MDR.
The present invention is directed to a nitrogen-containing tetracyclic compound represented by Formula [I]:
wherein Y
1
—Y
2
—Y
3
is N—C═N or a group represented by the formula: C═C—NR
3
(wherein R
3
is a hydrogen atom, a C
1-5
alkyl group or a nitrogen-containing C
2-10
alkyl group), Y
4
is S, SO, SO
2
, CH
2
or a group represented by the formula: NR
4
(wherein R
4
is a C
1-5
alkanoyl group or a C
1-5
alkyl group), R
1
and R
2
are the same or different, and are each a hydrogen atom, a C
1-10
alkyl group, a C
3-15
alkoxyalkyl group or a C
3-15
alkylaminoalkyl group, or R
1
and R
2
taken together with the nitrogen atom to which they are attached form a cyclic amino group, X
1
and X
2
are the same or different, and are each a hydrogen atom, a C
1-5
alkyl group, a C
1-5
alkoxy group or a halogen atom, and n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
In the present invention, the C
1-5
alkyl group for R
3
, R
4
, X
1
and X
2
refers to a straight, branched or cyclic alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, a pentyl group and an isopentyl group. Examples of the nitrogen-containing C
2-10
alkyl group for R
3
are a methylaminopropyl group, a dimethylaminoethyl group, a pyrrolidinoethyl group and a 4-methylpiperazinoethyl group. Examples of the C
1-5
alkanoyl group for R
4
are a formyl group, an acetyl group and a propionyl group. The C
1-10
alkyl group for R
1
and R
2
refers to a straight, branched or cyclic alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a cyclobutyl group, a cyclopropylmethyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a cyclobutylmethyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a cyclohexyl group, a cyclopentylmethyl group, a 1-ethylbutyl group, a heptyl group, an isoheptyl group, a cyclohexylmethyl group, an octyl group, a nonyl group and a decyl group. The C
3-15
alkoxyalkyl group for R
1
and R
2
refers to a straight, branched or cyclic C
1-13
alkoxy-C
2-14
alkyl group, and examples thereof are a methoxyethyl group, a methoxypropyl group, a methoxybutyl group, an ethoxyethyl group, an ethoxypropyl group, an ethoxybutyl group, an ethoxypentyl group, an ethoxyhexyl group, an ethoxyheptyl group, a propoxyethyl group, a propoxypropyl group, a propoxybutyl group, an isopropoxyethyl group and a cyclopropylmethoxyethyl group. The C
3-15
alkylaminoalkyl group for R
1
and R
2
refers to a straight, branched or cyclic C
1-13
alkylamino-C
2-14
alkyl group, and examples thereof are a methylaminoethyl group, a dimethylaminoethyl group, a methylaminopropyl group, a dimethylaminopropyl group, a methylaminobutyl group, an ethylaminoethyl group, an ethylaminopropyl group, an ethylaminobutyl group, an ethylaminopentyl group, an ethylaminohexyl group, an ethylaminoheptyl group, an ethylaminooctyl group, a propylaminoethyl group, a propylaminopropyl group, a propylaminobutyl group, an isopropylaminoethyl group, a cyclopropylmethylaminoethyl group and a pyrrolidinoethyl group. Examples of the cyclic amino group which is formed by R
1
, R
2
and the nitrogen atom to which they are attached are a pyrrolidino group, a piperidino group, a homopiperidino group, a morpholino group, a piperazino group, an N-methylpiperazino group and a 3,5-dimethylpiperazino group. The C
1-5
alkoxy group for X
1
and X
2
refers to a straight, branched or cyclic alkoxy group, and examples thereof are a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a cyclopropylmethoxy group, a pentoxy group and an isopentoxy group. The halogen atom for X
1
and X
2
refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
In addition, examples of the pharmaceutically acceptable salt in the present invention are salts with mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid, or salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid or benzenesulfonic acid.
The compound of Formula [I] can be prepared by the following general preparation methods 1 to 6. In the following reaction formulae, Y
1
, Y
2
, Y
3
, Y
4
, R
1
, R
2
, X
1
, X
2
and n are as defined above, R
5
is a hydrogen atom or a C
1-5
alkyl group, R
6
is a C
1-5
alkyl group or a nitrogen-containing C
2-10
alkyl group, R
7
and R
8
are the same or different, and are each a C
1-5
alkyl group or a benzyl group, X
3
is a chlorine atom, a bromine atom or an iodine atom, X
4
is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and Boc is a t-butoxycarbonyl group.
General Preparation Method 1
Step (A): A tetracyclic indole derivative (3)
Chaki Shigeyuki
Gotoh Makoto
Kondoh Kuniaki
Kumagai Toshihito
Nagamine Masashi
Balasubramanian Venkataraman
Lorusso & Loud
Shah Mukund J.
Taisho Pharmaceutical Co. Ltd.
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