Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-01
2002-04-16
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S262100, C544S118000, C544S265000, C544S276000, C544S322000, C544S324000
Reexamination Certificate
active
06372740
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel 2-aryl-8-oxodihydro-purine derivative selectively acting on the peripheral-type benzo-diazepine receptors, more particularly, a 2-aryl-8-oxodihydropurine derivative having an acetamide moiety at the 7-position or the 9-position of the purine nucleus, a process for the preparation thereof, a pharmaceutical composition containing the same, and an intermediate therefor.
BACKGROUND ART
In the tissues of the mammals including human, there are three kinds of benzodiazepine (hereinafter, occasionally referred to as BZ) recognition sites, and each is named as central-type (&ohgr;
1
,&ohgr;
2
) benzodiazepine receptors and a peripheral-type (&ohgr;
3
) benzodiazepine receptor, respectively (hereinafter, occasionally referred to as BZ&ohgr;
1
-receptor, BZ&ohgr;
2
-receptor and BZ&ohgr;
3
-receptor, respectively). Among them, the central-type BZ-receptors are the binding sites for BZ-compounds, and are present on the &ggr;-aminobutyric acid (hereinafter, occasionally referred to as “GABA”)
A
-BZ-receptor-Cl
−
ion channel complexes. On the other hand, the peripheral-type BZ-receptor widely distributes in the central or peripheral tissues or organs such as brain, kidney, liver, heart, etc., and it especially distributes with high density in the cells of the endocrinium organs such as adrenal glands, testicles, etc., or in the cells deeply participating in the inflammation-immune system in whole body such as mast cells, lymphocytes, macrophages, blood platelets, etc., so that the physiological roles of the peripheral-type BZ-receptor have recently been drawing attention. On the other hand, the peripheral-type BZ-receptor is present a lot in the mitochondrial membrane of glial cells in the brain, and it participates in cholesterol influx into the mitochondrial membrane, and hence, it is thought to act on the biosynthesis pathway of cholesterol into neurosteroids such as progesterone, allopregnanolone, etc., via pregnenolone. Thus, it is considered that stimulation of the peripheral-type BZ-receptor accelerates the synthesis of neurosteroids in the brain which affect the chloride ion channel gating process by binding to the neurosteroid-specific recognition site (which is a different site from the benzodiazepine receptor) on the GABA
A
-BZ receptor-Cl
−
ion channel complexes [cf. Romeo, E., et al., J. Pharmacol. Exp. Ther., 262, 971-978 (1992)].
A compound having a non-BZ nucleus and selectively showing an affinity for the peripheral-type BZ-receptor has been disclosed in Japanese Patent First Publication (Kokai) No. 201756/1983 (=EP-A-94271), and since then, various compounds have been disclosed in many patent publications, etc., however, there is no compound which has actually been used as a medicament.
As a compound having a non-BZ nucleus and selectively showing an affinity for the peripheral-type BZ-receptors, the following compounds have been known.
Japanese Patent First Publication (Kokai) No. 5946/1987 (=U.S. Pat. No. 4,788,199, EP-A-205375 (patent family)) discloses that amide compounds of the following formula are bound to the peripheral-type BZ-receptor, and are useful as anxiolytics, anticonvulsants and drugs for treatment of angina pectoris, and in the treatment of immuno-deficiency syndrome.
Japanese Patent First Publication (Kokai) No. 32058/1990 (=EP-A-346208, U.S. Pat. No. 5,026,711) discloses that 4-amino-3-carboxyquinoline compounds of the following formula show an affinity for the peripheral-type BZ-receptor both in vitro and in vivo, and can be used in the prophylaxis or treatment of human cardiovascular diseases, or as an antiallergic agent, or in the prophylaxis or treatment of infectious diseases, or in the treatment of anxiety.
WO 96-32383 publication discloses that the acetamide derivative of the following formula selectively acts on BZ&ohgr;
3
-receptor, and has anxiolytic activity and anti-rheumatoid activity so that it can be used in the treatment of anxiety-relating diseases or immune diseases.
wherein X is —O— or —NR
4
—; R
1
is a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a cycloalkyl-lower alkyl group; R
2
is a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl-lower alkyl group, etc.; R
3
is a hydrogen atom, a lower alkyl group, or a hydroxy-lower alkyl group; R
4
is a hydrogen atom, a lower alkyl group, etc.; R
5
is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxy-lower alkyl group, a substituted or unsubstituted benzyloxy-lower alkyl group, an acyloxy-lower alkyl group, a lower alkoxy-lower alkyl group, an amino group, a mono- or di-lower alkylamino group, an acylamino group, an amino-lower alkyl group, a nitro group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, a carboxyl group, a protected carboxyl group, a carboxy-lower alkyl group, or a protected carboxy-lower alkyl group; R
6
is a hydrogen atom, a lower alkyl group, a trifluoromethyl group, or a substituted or unsubstituted phenyl group, or R
5
and R
6
may optionally combine to form —(CH
2
)
n
—(n is 3, 4, 5 or 6); R
7
is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group, or a nitro group; and R
8
is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group.
DISCLOSURE OF INVENTION
The present inventors have intensively studied in order to prepare a compound acting selectively and potently on BZ&ohgr;
3
-receptor, and have found the 2-aryl-8-oxodihydropurine derivatives of the following formula (I), and finally have accomplished the present invention.
An object of the present invention is to provide a novel 2-aryl-8-oxodihydropurine derivative acting selectively and potently on BZ&ohgr;
3
-receptor, more particularly, to provide a 2-aryl-8-oxodihydropurine derivative having an acetamide moiety on the 7-position or the 9-position of the purine nucleus. Especially, the present invention provides a useful compound having an anti-anxiety activity. Another object of the present invention is to provide a process for preparing said compound. Still further object of the present invention is to provide a pharmaceutical composition containing said compound. Further object of the present invention is to provide an intermediate for preparing said compound. These and other objects and advantages of the present invention are obvious to any person skilled in the art from the following disclosure.
The present invention provides a 2-aryl-8-oxodihydropurine derivative of the following formula (I), a pharmaceutically acceptable acid addition salt thereof, a process for the same, and a pharmaceutical composition containing the same:
wherein
W is a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, or a substituted or unsubstituted phenyl group;
X is a hydrogen atom, a lower alkyl group, a cycloalkyl-lower alkyl group, a substituted or unsubstituted phenyl-lower alkyl group, a lower alkenyl group, a carbamoyl group, a di-lower alkylcarbamoyl group, or a group of the formula (Q):
—CH(R
3
)CON(R
1
)(R
2
) (Q)
(wherein R
1
is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, or a hydroxy-lower alkyl group, R
2
is a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl-lower alkyl group, or a substituted or unsubstituted heteroaryl group, or R
1
and R
2
may combine together with the adjacent nitrogen atom to form a piperidine ring, a pyrrolidine ring, a morpholine ring, or a piperazine ring, and these rings may optionally be substituted by one or two lower alkyl groups, and R
3
is a hydrogen atom, a lower alkyl group, or a hydroxy-lower alkyl group);
Y is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkyl-lowe
Furukawa Kiyoshi
Kondo Katsunori
Masumoto Kaoru
Murata Teruya
Oka Makoto
Berch Mark L.
Dainippon Pharmaceutical Co., Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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