&agr;-substituted carboxylic acid derivatives

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C548S309700, C548S310100

Reexamination Certificate

active

06596751

ABSTRACT:

TECHNICAL FIELD
The present invention relates to &agr;-substituted carboxylic acid derivatives having excellent insulin resistance improving activity, hypoglycemic activity, anti-inflammatory activity, immunoregulatory activity, aldose reductase inhibiting activity, 5-lipoxygenase inhibiting activity, peroxidized lipid production suppressing activity, PPAR activating activity, anti-osteoporosis activity, leukotrienes antagonistic activity, adipose cell formation promoting activity, cancer cell proliferation suppressing activity or calcium antagonistic activity, to their pharmacologically acceptable esters, to their pharmacologically acceptable amides and to their pharmacologically acceptable salts.
Further, the present invention is directed to preventives and/or therapeutic agents for diseases such as diabetes mellitus, hyperlipemia, obesity, glucose tolerance insufficiency, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataract, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease, etc.), cell injury lesion (e.g. cerebral injury induced by stroke, etc.) caused by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, fervescence, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis, etc.), cancer, osteoporosis, cataract, and so on containing said &agr;-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides or their pharmacologically acceptable salts as an active ingredient.
Furthermore, this invention concerns a pharmaceutical composition (particularly, preventives and/or therapeutic agents for diabetes mellitus or diabetic complications) containing at least one of sulfonylureas, &agr;-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statin type compounds, squalene synthesis inhibitors, fibrate type compounds, LDL disassimilation promoters, angiotensin II antagonists, angiotensin converting enzyme inhibitors, anti-cancer agents, and RXR activators (RXR agonists) together with said &agr;-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides or their pharmacologically acceptable salts.
BACKGROUND TECHNOLOGY
Some of the &agr;-substituted carboxylic acid derivatives of the present application are disclosed in (1) JP Unexamined Pub. H8 (1996)-504194 Gazette, (2) JP Unexamined Pub. H10 (1998)-501222 Gazette, (3) JP Unexamined Pub. H10 (1998)-504808 Gazette, (4) JP Unexamined Pub. H10 (1998)-114751 Gazette, (5) WO 98/31359 Gazette. However, the activities of the compounds described in these Gazettes are as therapeutic agents for anti-platelet aggregation, osteoclast mediating bone resorption suppression, osteoporosis and the like, which are different from those of the present invention.
Further, compounds showing an effect in treating diabetes mellitus or hypoglycemic activity are disclosed in (6) WO 97/31907 Gazette. However, the compounds described in said Gazette may have a benzimidazole ring, one of the structural features of the compounds in the present application also have the same group, but on the benzene ring of said benzimidazole ring in said Gazette there is no substituent or, if any substituent is present there, said substituent is only a lower alkyl group. On the other hand, the compounds of the present invention have comparatively bulky substituent(s) on the benzene ring of the benzimidazole ring, so they are different from the compounds of said Gazette.
Moreover, compounds having an effect in treating diabetes mellitus are disclosed in (7) WO 99/29640 Gazette. However, the compounds described in said Gazette may be &agr;-carboxylic acids having a benzimidazole structure similar to the compounds of the present application, but they are different from the compounds of the present application, because in this case the &agr;-substituent is an amino group or a protecting group thereof such as an alkoxycarbonyl group or an alkoxycarbonyl group which is comparatively easily removable. In addition, the compounds described in said Gazette are different from those of the present application in the nature of their fibroblast proliferation factor antagonism effects.
DISCLOSURE OF THE INVENTION
As the result of investigations for a long time on the search of synthesis and pharmacology of a series of said &agr;-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides and their pharmacologically acceptable salts, the present inventors have found the features that said &agr;-substituted carboxylic acid derivatives have excellent insulin resistance improving activity, hypoglycemic activity, anti-inflammatory activity, immunoregulatory activity, aldose reductase inhibiting activity, 5-lipoxygenase inhibiting activity, peroxidized lipid production suppressing activity, PPAR activating activity, anti-osteoporosis activity, leukotrienes antagonistic activity, adipose cell formation promoting activity, cancer cell proliferation suppressing activity or calcium antagonistic activity, with less side effects and high lipophilic solubility. Thus, the present invention has been established.
The other object of the present invention is to provide preventives and/or therapeutic agents against diseases such as diabetes mellitus, hyperlipemia, obesity, glucose tolerance insufficiency, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataract, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease, etc.), cell injury lesion (e.g. cerebral injury induced by stroke, etc.) caused by aterosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, fervescence, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis, etc.), cancer, osteoporosis, cataract, and so on containing said &agr;-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides or their pharmacologically acceptable salts as an active ingredient. Further, another object of the present invention is to provide a pharmaceutical composition (particularly, preventives and/or therapeutic agents for diabetes mellitus or diabetic complications) containing at least one of sulfonylureas, &agr;-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statins type compounds, squalene synthesis inhibitors, fibrate type compounds, LDL disassimilation promotors, angiotensin II antagonists, angiotensin converting enzyme inhibitors, anti-cancer agents, and RXR activators (RXR agonists) together with said &agr;-substituted carboxylic acid derivatives, their pharmacologically acceptable esters, their pharmacologically acceptable amides or their pharmacologically acceptable salts. The present invention relates to &agr;-substituted carboxylic acid derivatives having the general formula (I):
[wherein R
1
, R
2
and R
3
are the same or different, and each is a (i) hydrogen atom, (ii) C
1
-C
6
alkyl group, (iii) C
6
-C
10
aryl group (optionally having 1-5 substituting moieties &agr;
1
hereafter described), (iv) C
7
-C
16
aralkyl group (optionally having 1-5 substituting moieties &agr;
1
hereafter described on the aryl moiety thereof), (v) C
1
-C
6
alkylsulfonyl group, (vi) C
1
-C
6
halogenoalkylsulfonyl group, (vii) C
6
-C
10
arylsulfonyl group (optionally having 1-5 substituting moieties &agr;
1
hereafter described) or (viii) C
7
-C
16
aralkylsulfonyl group (optionally having 1-5 substituting moieties &agr;
1
hereafter described on the aryl moiety thereof),
A is a nit

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