Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-26
2001-04-17
Lambkin, Deborah C. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S432000, C549S405000, C549S402000, C549S023000
Reexamination Certificate
active
06218427
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of prior PCT International Application No. PCT/JP97/02916 which has an International filing date of Aug. 22, 1997 which designated the United States of America.
TECHNICAL FIELD
The present invention relates to compounds useful as medicines and use of the compound. Specifically, the present invention relates to pharmaceutical compositions containing a chromen-3-carboxylic acid derivative, pharmaceutical compositions for use as an endothelin receptor antagonist containing the same, pharmaceutical compositions for use as a peripheral circulation insufficiency-improving agent containing the same and an novel chromen-3-carboxylic acid derivative. Further, the present invention relates to a pharmaceutical composition for use as a macrophage foam cell formation inhibitor containing an endothelin antagonist.
BACKGROUND ART
Endothelins are vasoactive peptides comprising 21 amino acid residues, are isolated from endothelial cells, and associates with homeostasis of a circulatory system. Endothelins act as aggravation factors of cardiovascular diseases such as hypertension, pulmonary hypertension, stroke, cerebrovascular spasm, acute renal insufficiency, acute proliferative nephropathy, acute myocardial infarction, chronic heart failure, vascular intimal thickness and the like by the medium of endothelin receptors.
Two kinds of receptor subtypes, an endothelin A and an endothelin B receptors, are known and three types of receptor antagonists, A-selective, B-selective and A & B non-selective antagonists, have been presumed to exist. Although there remain many unknown matters about what kind of diseases are associated with any type of receptors, they have been gradually made clear. For example, an endothelin A receptor is considered to be associated with acute and chronic diseases such as hypertension, pulmonary hypertension, cerebral stroke, cerebrovascular spasm, cerebral edema, acute renal insufficiency, myocardial infarction, chronic heat insufficiency, asthma and the like and therefore, the antagonists have been expected to be useful for treatment of these diseases. There is a possibility that an endothelin B receptor is associated with the appearance and progression of cardiovascular disease and further, it is considered to associate with metabolism of endothelin in blood, the vascular intimal thickness and development and differentiation of a certain kind of cells.
Peptide-type antagonists have been developed as endothelin receptor antagonists but there are many problems for application as a medicament of chronic diseases. For example, they tend to be readily metabolized in the living body, the duration of action is short, and they are not effective in oral administration and the like. Endothelin is associated with diverse diseases, the effect is potent and the mechanism of action is complicated. Accordingly, development of a non-peptide type endothelin antagonist having a long duration of action and a superior oral availability has been desired.
Indan and inden derivatives are disclosed in JP-A 7-501322 and WO 94/25013 as an endothelin receptor antagonist but the data of pharmacological activities indicating effectiveness of these derivatives as medicaments have not been disclosed.
Arteriosclerosis is caused by a combination of many risk factors and injury factors and one of the examples of risk factors is cholesterol. Law density cholesterol (hereinafter referred to as LDL) is oxidized after accumulation on artery walls, taken in macrophages and the macrophages turn foam cells. It is considered that accumulation of foam cell forming-macrophages accelerates the proliferation of smooth muscle cells and cell intimal fibrous thickness and finally leads up to an atherosclerotic lesion. According to these knowledge, a macrophage foam cell formation inhibitor is expected to be effective for treating and/or preventing the atherosclerosis.
The endothelin antagonists are generally supposed to have an anti-arteriosclerosis activity and the mechanism has been considered to be related to a thrombus formation caused by vasoconstriction or to a proliferation promoting effect on a vascular smooth muscle cell. With regard to an inhibition of macrophage foam cell formation, only BMS-182874 has been disclosed to reduce the number and size of foam cells (American Journal of Pathology vol. 146, No.4, 819-826 (1995)).
Compounds having similar structure have been disclosed in JP-A 60-149580 and JP-A 60-149581 but their endothelin antagonistic activity is not suggested at all.
DISCLOSURE OF INVENTION
These inventors discovered that compounds of the following formula (I&agr;) have a potent and orally available endothelin receptor antagonistic activity and accomplished the present invention. The present invention provides pharmaceutical compositions for use as an endothelin receptor antagonist comprising a compound of the formula (I&agr;):
wherein R
1
, R
2
, R
3
and R
4
are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, hydroxy, halogen, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted cycloalkoxy, optionally substituted acyloxy or optionally substituted amino,
R
5
is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl optionally substituted aryl, optionally substituted heterocyclic or optionally substituted cycloalkyl,
R
6
is hydrogen, optionally substituted alkyl or optionally substituted aryl,
R
7
is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl halogen, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic, optionally substituted heterocyclooxy, optionally substituted acyloxy, optionally substituted alkylthio, optionally substituted alkenylthio, optionally substituted alkynylthio or optionally substituted amino,
A is S or O and a broken line represents the presence or absence of a bond, or pharmaceutically acceptable salt, hydrate or prodrug thereof (hereinafter referred to as a compound (I&agr;)) as an active ingredient. The present invention provides compounds of the formula (I):
wherein R
1
-R
6
, A and a broken line are the same as defined above, R
7
is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic, optionally substituted heterocyclooxy, optionally substituted acyloxy, optionally substituted alkylthio, optionally substituted alkenylthio, optionally substituted alkynylthio or optionally substituted amino, excluding a compound wherein R
2
is methyl, R
5
is optionally substituted alkyl, R
7
is phenyl and A is O, or
pharmaceutically acceptable salt or hydrate thereof (hereinafter referred to as compound (I)), or a compound of the formula (I′):
wherein R
1
′, R
2
′, R
3
and R
4
are each independently hydrogen, optionally substituted alkyl optionally substituted alkenyl, optionally substituted cycloalkyl, hydroxy, halogen, optionally substituted alkoxy, optionally substituted acyloxy or optionally substituted amino,
R
6
is hydrogen or alkyl,
Ar
1
and Ar
2
are each independently optionally substituted aryl or optionally substituted heteroaryl and
a broken line represents presence or absence of a bond, or
pharmaceutically acceptable salt or hydrate thereof (hereinafter referred to as compound (I′)). The present invention provides pharmaceutical compositions comprising one of compounds (1) and/or (I′) and pharmaceutical compositions for use as an endothelin receptor antagonist comprising the same.
As
Hara Seijiro
Ishizuka Natsuki
Konoike Toshiro
Matsumura Ken-ichi
Matsuo Yoshiyuki
Birch & Stewart Kolasch & Birch, LLP
Lambkin Deborah C.
Shionogi & Co. Ltd.
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