Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-07
2002-08-13
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S394000, C514S399000, C548S183000, C548S186000, C548S189000, C548S304700
Reexamination Certificate
active
06432993
ABSTRACT:
The present invention relates to a substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof having excellent insulin resistance improving action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, lipid peroxide production inhibitory action, peroxisome proliferator activated receptor (which will hereinafter be abbreviated as “PPAR”) activating action, anti-osteoporosis action, leukotrienes antagonism, fat-cell formation promoting action, cancer-cell proliferation inhibitory action and calcium antagonism; a pharmaceutical composition comprising, as an effective ingredient, the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof; use of the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof for the preparation of a pharmaceutical composition; a method for the prevention or treatment of diabetes or like diseases, which comprises administering an effective amount of the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof to a warm-blooded animal; or a pharmaceutical composition obtained by using, in combination, the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof and at least one compound selected from &agr;-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors.
BACKGROUND OF THE INVENTION
It is reported that thiazolidine compounds, oxazolidine compounds and the like are useful as preventive agents and/or remedies for various diseases such as diabetes and hyperlipidemia.
For example, a number of thiazolidine compounds having hypoglycemic action are disclosed in Chem. Pharm. Bull., 30, 3580-3600(1982), Prog. Clin. Biol. Res., 265, 177-192(1988), Diabetes, 37(11), 1549-1558(1988), Arzneim.-Forsch., 40(1), 37-42(1990), EP0441605A and the like.
The action of thiazolidine compounds on hyperlipidemia is reported in Diabetes, 40(12), 1669-1674(1991), Am. J. Physiol., 267(1 Pt 1), E95-E101(1994), Diabetes, 43(10), 1203-1210(1994) and the like.
The action of thiazolidine compounds on glucose tolerance insufficiency and insulin resistance is disclosed in Arzneim.-Forsch., 40(2 Pt 1), 156-162(1990), Metabolism, 40(10), 1025-1230(1991), Diabetes, 43(2), 204-211(1994) and the like.
It is recently reported in N. Engl. J. Med., 331(18), 1226-1227(1994) that a normal person having insulin resistance has developed diabetes without glucose tolerance insufficiency and also that a medicament for improving insulin resistance is useful as a preventive agent the onset of diabetes in such a normal person.
The action of thiazolidine compounds on hypertension is reported in Metabolism, 42(1), 75-80(1993), Am. J. Physiol., 265(4 Pt 2), R726-R732(1933), Diabetes, 43(2), 204-211(1994) and the like.
The action of thiazolidine compounds on coronary artery diseases is reported in Am. J. Physiol., 265(4 Pt 2), R726-R732(1933), Hypertension, 24(2), 170-175(1994) and the like.
The action of thiazolidine compounds on arteriosclerosis is reported in Am. J. Physiol., 265(4 Pt 2), R726-R732(1933) and the like.
The action of thiazolidine compounds on cachexia is reported in Endocrinology, 135(5), 2279-2282(1994), Endocrinology, 136(4), 1474-1481(1995) and the like.
Among thiazolidine compounds having hypoglycemic action, compounds containing a heterocyclic group are disclosed in WO92/07839A, WO92/07850A and EP00745600A.
In addition, oxazolidine-2,4-dione compounds having hypoglycemic action are disclosed in WO92/02520A and the like.
In WO92/03425A, it is disclosed that compounds containing a 3,5-dioxooxadiazolidin-2-ylmethylphenyl or a N-hydroxyureido group exhibit hypoglycemic action.
In EP00676398A, 5-{4-[5-(3,5-di-t-butyl-4-hydroxyphenylthio)-3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy]benzyl}thiazolidine-2,4-dione is disclosed only as one of the exemplified compounds.
DISCLOSURE OF THE INVENTION
As a result of investigation for many years on the synthesis of a series of substituted fused heterocyclic compounds and their pharmacological activity, the present inventors have found that a substituted condensed heterocyclic compound having a novel structure has excellent insulin-resistance improving action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, lipid-peroxide-production inhibitory action, PPAR activating action, anti-osteoporosis action, leukotrienes antagonism, fat-cell-formation promoting action, cancer-cell proliferation inhibitory action and calcium antagonism; has reduced side effects; and moreover has high fat solubility.
Another object of the present invention is to provide a preventive agent and/or remedy, which comprises as an effective ingredient the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof, for diseases alleviated by the above-described actions such as diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts and coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease and the like), cell injury (e.g. brain injury induced by strokes and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis and the like), cancer, osteoporosis and cataracts.
Another object of the present invention is to provide a pharmaceutical composition (particularly suited is a preventive agent and/or remedy for diabetes or diabetic complications) obtained by using, in combination, the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof and at least one compound selected from &agr;-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors.
The present invention thus provides (i) pharmaceutical compositions containing as an active ingredient, a substituted fused heterocyclic compound of the formula (I) or a pharmacologically acceptable salt or prodrug thereof and (ii) methods of treating by administering said active ingredient to a warm-blooded animal, particularly to a human.
In the present invention, a substituted fused heterocyclic compound is represented by the following formula (I):
wherein:
R
1
represents a group of the following formula:
or a group of the following formula:
[in which:
R
4
represents a phenyl group which is substituted with 1 to 5 substituents selected from Substituents &agr; or a pyridyl group which may be substituted with 1 to 4 substituents selected from Substituents &agr;,
R
5
represents a hydrogen atom or a substituent selected from Substituents &agr;
R
6
represents a hydrogen atom, a C
1-6
alkyl group, a C
6-10
aryl group which may be substituted with 1 to 3 substituents selected from Substituents &bgr; or a C
7-16
aralkyl group which may be substituted with 1 to 3 substituents selected from Substituents &bgr;,
D represents an oxygen or sulfur atom, and
E represents a CH group or nitrogen atom],
R
2
represents a hydrogen atom or a substituent selected from Substituents &agr;,
R
3
represents a group of the following formula:
A represents a C
1-6
alkylene group, and
B represents an oxygen or sulfur atom,
with the proviso that 5-{4-[5-(3,5-di-t-butyl-4-hydroxyphenylthio)-3-methyl-3H-im
Fujita Takashi
Fujiwara Toshihiko
Wada Kunio
Frishauf Holtz Goodman & Chick P.C.
Patel Sudhaker B.
Sankyo Company Limited
Shah Mukund J.
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