Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-05
2003-05-13
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S181000
Reexamination Certificate
active
06562849
ABSTRACT:
TECHNICAL FIELD
The present invention relates to amine derivative compounds or their pharmacologically acceptable salts having superior insulin tolerance ameliorating effects, blood sugar lowering effects, anti-inflammatory effects, immunoregulatory effects, aldose reductase inhibitory effects, 5-lipoxygenase inhibitory effects, lipid peroxide formation inhibitory effects, PPAR activation effects, anti-osteoporosis effects, leukotriene antagonistic effects, fat cell promotion effects, cancer cell proliferation inhibitory effects and calcium antagonistic effects.
Moreover, the present invention relates to a preventing and/or therapeutic agent containing as an active ingredient the above-mentioned amine derivative compounds or their pharmacologically acceptable salts for diseases such as diabetes, hyperlipemia, obesity, glucose intolerance, hypertension, fatty liver, diabetic complications (including retinopathy, nephropathy, neuropathy, cataracts and coronary diseases), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (such as ischemic heart disease), cell injury induced by atherosclerosis or ischemic heart disease (such as brain injury induced by apoplexy), gout, inflammatory diseases (including arthritis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases and pancreatitis), cancer, osteoporosis and cataracts.
Moreover, the present invention relates to pharmaceutical compositions comprising a combination of the above amine derivative compounds or their pharmacologically acceptable salts and at least one kind of RXR activator, sulfonylurea agent, &agr;-glucosidase inhibitory agent, aldose reductase inhibitory agent, biguanide agent, statin compound, squalene synthesis inhibitory agent, fibrate compound, LDL disassimilation promoter, angiotensin II antagonist, angiotensin converting enzyme inhibitory agent, antitumor agent and FBPase inhibitory agent (and particularly preferably antitumor agents and preventing and/or therapeutic agents for diabetes or diabetic complications).
BACKGROUND ART
At present, thiazolidine compounds, oxazolidine compounds and the like are reported to be useful as preventing or therapeutic agents for various diseases such as diabetes and hyperlipemia.
For example, oxazolidinedione derivatives having blood sugar and blood lipid lowering effects are disclosed in (1) Japanese Patent Application (Kokai) No. Hei 7-101945 and (2) Japanese Patent Application (Kokai) No. Hei 7-165735. However, the compounds of the inventions as claimed in these publications have a structure that differs from the structure of the compounds of the present invention in that the oxazolidinedione has a comparatively long chain aliphatic hydrocarbon group (the compounds of the present invention have a thiazolidinedione- or oxazolidinedione-methyl group), and although it may have a benzimidazole or imidazopyridine group, each group only has comparatively small substituents such as hydrocarbon groups (the compounds of the present invention are required to have a benzimidazole or imidazopyridine structure, and its substituent is comparatively large and must include an amino group and an aryl group).
In addition, an azolidinedione derivative having anti-diabetes effects is disclosed in (3) U.S. Pat. No. 5,985,884. However, the compound of the invention as claimed in this publication also has a different structure from the compounds of the present invention in that it is unable to have a benzimidazole or imidazopyridine structure having an amino group as its substituent.
Moreover, a thiazolidinedione compound capable of satisfactorily controlling blood sugar values is disclosed in (4) Japanese Patent Application (Kokai) No. Hei 5-213913. However, the compound of the invention as claimed in this publication also has a different structure from the compounds of the present invention in that it also requires a piperidine structure in the case of having a benzimidazole structure, and in that its substituent is comparatively small.
DISCLOSURE OF THE INVENTION
As a result of extensive studies on the synthesis of a series of amine derivative compounds and their pharmacological activity over the course of many years, the inventors of the present invention have found that amine derivative compounds having a novel structure have superior insulin tolerance ameliorating effects, blood sugar lowering effects, anti-inflammatory effects, immunoregulatory effects, aldose reductase inhibitory effects, 5-lipoxygenase inhibitory effects, lipid peroxide formation inhibitory effects, PPAR activation effects, anti-osteoporosis effects, leukotriene antagonistic effects, fat cell promotion effects, cancer cell proliferation inhibitory effects and calcium antagonistic effects, have less side effects, and have a high degree of antitumor activity, thereby leading to completion of the present invention.
It is another object of the present invention to provide a preventing and/or therapeutic agent containing as an active ingredient the above-mentioned amine derivative compounds or their pharmacologically acceptable salts for diseases such as diabetes, hyperlipemia, obesity, glucose intolerance, hypertension, fatty liver, diabetic complications (including retinopathy, nephropathy, neuropathy, cataracts and coronary diseases), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (such as ischemic heart disease), cell injury induced by atherosclerosis or ischemic heart disease (such as brain injury induced by apoplexy), gout, inflammatory diseases (including arthritis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases and pancreatitis), cancer, osteoporosis and cataracts.
Further, it is another object of the present invention to provide pharmaceutical compositions comprising a combination of the above amine derivative compounds or their pharmacologically acceptable salts and at least one kind of RXR activator, sulfonylurea agent, &agr;-glucosidase inhibitory agent, aldose reductase inhibitory agent, biguanide agent, statin compound, squalene synthesis inhibitory agent, fibrate compound, LDL disassimilation promoter, angiotensin II antagonist, angiotensin converting enzyme inhibitory agent, antitumor agent and FBPase inhibitory agent (and particularly preferably antitumor agents and agents for treating and/or preventing diabetes or diabetic complications).
The present invention relates to an amine derivative compound of the formula (I):
wherein:
R
1
represents a carbamoyl group (which may have one or two substituents &agr; described later), a thiocarbamoyl group (which may have one or two substituents &agr; described later), a sulfonyl group (which has one substituent &agr; described later) or a carbonyl group (which has one substituent &agr; described later);
R
2
and R
3
are the same or different and each represent a hydrogen atom, a C
1
-C
10
alkyl group, a C
6
-C
10
aryl group (which may have from 1 to 3 substituents &bgr; described later) or a C
7
-C
16
aralkyl group (which may have from 1 to 3 substituents &bgr; described later on the aryl portion);
W
1
, W
2
and W
3
are the same or different and each represent a single bond or a C
1
-C
8
alkylene group;
X, Y and Q each represent an oxygen atom or a sulfur atom;
Z represents a ═CH— group or a nitrogen atom;
Ar represents a benzene ring or a naphthalene ring;
L represents from 1 to 4 substituents on the Ar ring and the or each substituent is a hydrogen atom, a C
1
-C
6
alkyl group, a C
6
-C
10
aryl group (which may have from 1 to 3 substituents &bgr; described later) or a C
7
-C
16
aralkyl group (which may have from 1 to 3 substituents &bgr; described later on the aryl portion);
the substituent &agr; represents (i) a C
1
-C
10
alkyl group, (ii) a C
1
-C
6
halogenoalkyl group, (iii) a C
3
-C
10
cycloalkyl group, (iv) a C
6
-C
10
aryl group (which may hav
Fujita Takashi
Fujiwara Toshihiko
Honma Hidehito
Oguchi Minoru
Wada Kunio
Frishauf Holtz Goodman & Chick P.C.
Gerstl Robert
Sankyo Company Limited
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