Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-14
1999-10-26
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514259, 514247, 514252, 5483111, 5483124, 5483164, 5483265, A61K 31505
Patent
active
059729465
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel acetamide derivative selectively acting on the peripheral-type benzodiazepine receptors, more particularly, an acetamide derivative having 2-phenyl-4-pyrimidinylamino moiety or 2-phenyl-4-pyrimidinyloxy moiety, a process for preparing the same, and a pharmaceutical composition containing the same.
BACKGROUND ART
In the central nervous system 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 (.omega..sub.1, .omega..sub.2) benzodiazepine receptors and a peripheral-type (.omega..sub.3) benzodiazepine receptor, respectively (hereinafter, occasionally referred to as BZ.omega..sub.1 -receptor, BZ.omega..sub.2 -receptor and BZ.omega..sub.3 -receptor, respectively). Among them, the peripheral-type BZ-receptor unevenly distributes in the peripheral tissues or organs such as kidney, liver, heart, etc., but 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 allopregnanolone, allotetrahydrodeoxycorticosterone (THDOC), 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 choride ion channel gating process by binding to the neurosteroid-specific recognition site on the .gamma.-aminobutyric acid-A-receptor (hereinafter, occasionally referred to as GABA.sub.A -receptor) [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 are disclosed in many literatures including patent applications. 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, in addition to the above, there have been known the compounds disclosed in Japanese Patent First Publication (Kokai) Nos. 5946/1987 and 32058/1990.
Japanese Patent First Publication (Kokai) No. 5946/1987 (EP-A-205375, U.S. Pat. No. 4,788,199) discloses amide compounds of the following formula, which are bound to the peripheral-type BZ-receptor, and are useful as anxiolytics, anticonvulsants and antiangina agents, and for the treatment of immuno-deficiency syndrome. ##STR2## wherein A is a nitrogen atom or .dbd.CH--; B is a nitrogen atom or .dbd.CH--; V and W are the same or different and each a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group both having 1 to 3 carbon atom, etc.; Z is bound in the ortho- or para-position with respect to the B, and is a phenyl group, a thienyl group, a pyridyl group, or a phenyl group substituted by 1 to 2 groups selected from a halogen atom, an alkyl group or an alkoxy group both having 1 to 4 carbon atoms, trifluoromethyl group and a nitro group; a chain of --X--(CH.sub.2).sub.n --(CHR).sub.m --CONR.sub.1 R.sub.2 is bound in the ortho- or para-position with respect to the B; R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; R.sub.1 and R.sub.2 are the same or different and each a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a phenyl
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Romeo et al., "2-Aryl-3-Indoleacetamides(FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR)" J.Pharmacol.Exp. Ther. 262:971-978 (1992).
derivatives Pharmazie 43:537-537 (1988).
Furukawa Kiyoshi
Hino Katsuhiko
Itoh Mari
Murata Teruya
Oka Makoto
Dainippon Pharmaceutical Co., Ltd.
Reamer James H.
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