Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-30
2003-03-04
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S311000, C514S350000, C546S156000, C546S146000, C546S316000, C546S323000
Reexamination Certificate
active
06528525
ABSTRACT:
The present invention relates to amidocarboxylic acid derivatives, or their pharmacologically acceptable salts or their pharmacologically acceptable esters. These compounds have some excellent effects of lowering blood glucose, reducing lipid, ameliorating insulin resistance, alleviating inflammatory diseases, immunoregulation, inhibiting aldose reductase, inhibiting 5-lipoxygenase, suppressing generation of lipid peroxide, activating PPAR (peroxysome proliferator activated receptor) and alleviating osteoporosis.
Furthermore, the present invention relates to a composition containing the above-mentioned amidocarboxylic acid derivatives, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof as an active ingredient useful in the treatment and prevention of the following diseases. They include diseases caused mainly by insulin resistance such as diabetes mellitus, hyperlipemia, obesity, impaired glucose tolerance (IGT), insulin resistant non-IGT (NGT), hypertension, fatty liver, diabetic complications (for example, retinopathy, nephropathy, neurosis, cataracts, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS) and cell injury caused by atherosclerosis (for example cerebral injury induced by apoplexy and the like); inflammatory diseases such as arthrosteitis, pain, pyrexia, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcers, cancer, cachexia, autoimmune diseases and pancreatitis; osteoporosis; cataracts; etc. The present invention relates to a use of these compounds, their salts and esters for producing a medicament for prevention or treatment of these diseases, or a method of treating or preventing these diseases by the administration of pharmacologically effective amounts of such compounds to warm-blooded animals.
BACKGROUND ART
While insulin and sulfonylurea compounds such as tolbutamide and Glipizide have conventionally been used as therapeutic agents for diabetes mellitus and hyperglycemia, and carboxylic acid derivatives have recently been reported to be useful insulin-nondependent diabetes therapeutic agents. These compounds are described, for example in:
(1-1) International Patent Publication No. WO91/19702 (Japanese PCT Application (Kokai) No. Hei 5-507920);
(1-2) International Patent Publication WO94/29285;
(1-3) International Patent Publication WO94/29302;
(1-4) International Patent Publication WO95/03288; and
(1-5) International Patent Publication WO96/04260.
However, the compounds described above are different from the compounds of the present invention to be described later in that the former compounds do not have the characteristics of the latter compounds which have an amide bond in the side chain of the carboxylic acid derivative.
Compounds having amide bonds in the side chains are described, for example in:
(2-1) Japanese Patent Application (Kokai) No. Hei 6-172339;
(2-2) International Patent Publication WO 92/07850 (=Japanese PCT Application (Kokai) No. Hei 6-502144); and
(2-3) U.S. Pat. No. 5,330,998.
However, these compounds are different from the compounds of the present invention to be described later in that the former compounds have thiazolidyl groups and the like at the terminal of the molecule.
Although carboxylic acid derivatives having amide bonds in the side chains are described, for example, in:
(3-1) Japanese Patent Application (Kokai) No. Hei 5-155828; and
(3-2) Japanese Patent Application (Kokai) No. Hei 5-279353, the compound (3-1) and the compound (3-2) are different from the present invention in pharmacological activity and chemical structure. The compound (3-1) has an effect of inhibiting aggregation and in the molecule of the compound (3-1) there is an amino group or the like at the 2- to 5-positions of the carboxylic acid and a heterocyclic group or the like at the terminal of the side chain. The compound (3-2) has an inhibitory action against damage of ischemic tissue and is an acetic acid derivative.
DISCLOSURE OF THE INVENTION
The present inventors made intensive studies on amidocarboxylic acid derivatives, and pharmacologically acceptable salts and esters thereof, which have strong effects of lowering blood glucose, reducing lipid, ameliorating insulin resistance, alleviating inflammatory diseases, immunoregulation, inhibiting aldose reductase, inhibiting 5-lipoxygenase, suppressing generation of lipid peroxide, activating PPAR (peroxysome proliferator activated receptor) and alleviating osteoporosis, and accomplished the present invention.
To describe it in detail, the present invention provides novel amidocarboxylic acid derivatives, pharmacologically acceptable salts thereof and pharmacologically acceptable esters thereof which are useful as therapeutic or preventive agents for diseases caused mainly by insulin resistance such as diabetes mellitus, hyperlipemia, obesity, impaired glucose tolerance, insulin resistant non-IGT, hypertension, fatty liver, diabetic complications (e.g., retinopathy, nephropathy, neurosis, cataracts, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome and cell injury caused by atherosclerosis (for example, cerebral injury induced by apoplexy and the like); inflammatory diseases such as arthrosteitis, pain, pyrexia, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcers, cancer, cachexia, autoimmune diseases (e.g. systemic lupus erythematosus, juvenile rheumatoid arthritis, Sjogren's syndrome, diffuse scleroderma, mixed connective tissue disease, dermatomyositis, Hashimoto's disease, primary myxoma, thyrotoxia, pernicious anemia, ulcerative colitis, autoimmune atrophic gastritis, idiopathic Addison disease, male sterility, Goodpasture's syndrome, acute progressive glomerulonephritis, myasthenia gravis, polymyositis, pemphigus vulgaris, bullous pemphigoid, sympathetic ophthalmitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, rheumatic fever, lupoid hepatitis, primary biliary cirrhosis, Behcet's disease, CREST syndrome, etc.) and pancreatitis; osteoporosis; and cataracts.
Further, the present invention provides (i) pharmaceutical compositions containing as an active ingredient the novel amidocarboxylic acid derivatives, the pharmacologically acceptable salts thereof or the pharmacologically acceptable esters thereof and (ii) methods of treating by administering said active ingredient to a warm blooded animal, and particularly to a human.
The present invention relates to an amidocarboxylic acid derivative of the formula (I):
a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
In the formula,
R
1
represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 6 carbon atoms or an aralkyl group having from 7 to 12 carbon atoms;
R
2
represents a straight or branched chain alkylene group having from 1 to 6 carbon atoms;
R
3
represents (i) a hydrogen atom, (ii) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (iii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iv) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (v) a halogen atom, (vi) a nitro group, (vii) a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (viii) an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents &agr; described later, (ix) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents &agr; described later on the aryl moiety, (x) a hydroxyl group or (xi) a straight or branched chain aliphatic acyl group having from 1 to 5 carbon atoms;
R
4
represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms;
Z represents a straight or branched chain alkylene group
Fujiwara Toshihiko
Sakurai Mitsuya
Takamura Makoto
Yanagisawa Hiroaki
Frishauf Holtz Goodman & Chick P.C.
Robinson Benta
Rotman Alan L.
Sankyo Company Limited
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