Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-04-08
2004-08-17
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S338000, C514S375000, C544S137000, C546S271100, C548S216000, C548S217000, C548S224000
Reexamination Certificate
active
06777410
ABSTRACT:
TECHNICAL FIELD
Blood glucose levels in normal subjects are maintained at constant levels by insulin action. Diabetes mellitus is characterized by chronic hyperglycemia due to lost in the control of blood glucose level.
Basically, diabetes therapy aims to correct hyperglycemia, that is by decreasing blood glucose into normal level. Accordingly, the importance of therapeutic control on postprandial hyperglycemia without affecting fasting glucose level is getting a great deal of attention.
Currently, besides insulin injection, major drugs for diabetes treatment are classified into three: First group of drugs is called insulin secretagogues, and is represented by sulfonylureas. These drugs directly induce insulin secretion from pancreas. Insulin then reduces blood glucose level. Drugs from the second group are called insulin sensitizers, which were launched recently. These drugs do not directly stimulate insulin release but enhance glucose uptake in the peripheral tissues. The third group of drugs is called &agr;-glucosidase inhibitors, which are able to prevent from rapid increase in postprandial glucose. These drug's action is to suppress the transient rise in glucose level occurring during meal by delaying digestion and absorption of dietary carbohydrate.
On the other hand, it is known that glucagon-like peptide-1 (hereinafter, referred to as GLP-1) is a hormone secreted from L-cells, which are endocrine cells existing in the intestinal epithelium of small intestine. GLP-1 lowers blood glucose level by inducing insulin secretion from &bgr;-cells existing in the pancreatic islet of Langerhans (Eur. J. Clin. Invest, volume 22, page 154, 1992). Importantly, it is reported that the effect of GLP-1 on insulin secretion is dependent on glucose, that is GLP-1 induces insulin secretion only when blood glucose level is high and does not induce it during normoglycemia (Lancet, volume 2, page 1300, 1987). GLP-1 also enhances insulin biosynthesis (Endocrinology, volume 130, page 159, 1992) and accelerates proliferation of &bgr;-cells (Diabetologia, volume 42, page 856, 1999). Therefore GLP-1 is not only stimulating insulin secretion but also is a very important hormone for the maintenance of pancreatic &bgr;-cells.
The efficacy of GLP-1 has been confirmed in patients with Type-II diabetes. The administration and maintaining high blood level of GLP-1 significantly reduces hyperglycemia (Diabetologia, volume 36, page 741, 1994 or ibid., volume 39, page 1546, 1996).
In addition, GLP-1 induces glucose utilization in peripheral tissues (Endocrinology, volume 135, page 2070, 1994 or Diabetologia, volume 37, page 1163, 1994). Intracerebroventricular injection of GLP-1 induces feeding behavior (Digestion, volume 54, page 360, 1993). It is also reported that GLP-1 reduced gastrointestinal motility (Dig. Dis. Sci., volume 43, page 1113, 1998).
Compounds closest to the compounds of the present invention in structure are described in U.S. Pat. No. 4,717,414 (hereinafter, referred to as Reference A) and J. Chem. Soc., Perkin Trans. 1, page 1547, 1979 (hereinafter, referred to as Reference B).
The compounds of Reference A have an imidazoisoindole-dione skeleton having an oxo group at the imidazo part condensing to the isoindole skeleton.
However, although the imidazoisoindole-dione skeleton is common to the compounds of the invention and the compounds of Reference A, the compounds of the invention have a functional group such as, for example, an aryl group at the substituent part at the 9-position on the skeleton and in that point are utterly different from the compounds of Reference A having a substituted alkyl group (R
4
C(Z)R
5
) such as, specifically for example, a nitromethyl group or a 1-nitro-1-ethylmethyl group, in structure. Further, the use in Reference A is herbicides and is utterly different from the invention in industrially applicable fields. Further, the preparation process in Reference A utilizes nucleophilic reaction of alkyl carbon anions, etc. onto dihydroimidazoisoindole-dione, etc., and is utterly different from the preparation process of the invention utilizing cyclization reaction.
Reference B discloses a compound having an oxazoloisoindole-dione skeleton which has an oxo group at the oxazolo part condensing to the isoindole skeleton.
However, Reference B mainly discloses novel preparation processes of isoindolobenzazepine derivatives, and merely discloses that, in the reaction step, only one compound having an oxazoloisoindole-dione skeleton is formed as a reaction by-product. The oxazoloisoindole-dione skeleton is common to the compounds of the invention and the compound of Reference B, but the compounds of the invention having a functional group such as, for example, an aryl group at the substituent part at the 9-position on the skeleton and in that point are utterly different from the compound of Reference B which is Compounds (1 1) having an &agr;-bromobenzyl group as the substituent, in structure.
Further, Japanese Laid-open Patent Publication (Tokuhyo-hei) No. 507388/1994 (hereinafter, referred to as Reference C) and U.S. Pat. No. 3,507,863 (hereinafter, referred to as Reference D) disclose tricyclic heterocycles wherein a 6-membered ring, a 5-membered ring and a 5-membered ring are condensed.
Reference C discloses compounds having an oxazoloisoindole skeleton or an imidazoisoindole skeleton wherein the oxazolo part or the imidazo part is condensed to the isoindole skeleton, respectively.
However, although the oxazoloisoindole skeleton or the imidazoisoindole skeleton are common to the compounds of the invention and the compounds of Reference C, the compounds of the invention have a functional group such as, for example, an oxo group or a thioxo group at the the oxazolo part or the imidazo part condensed to the isoindole skeleton and in that point are utterly different from the compounds of Reference C not having the oxo group or the like, in structure. Further, the use in Reference C is antiviral drugs and is the same in the industrially applicable field, but is an use having no relation to the use in the invention.
Reference D discloses compounds having an oxazoloisoindole skeleton, an imidazoisoindole skeleton or a thiazoloisoindole skeleton wherein the oxazolo part, the imidazo part or the thiazolo part is condensed to the isoindole skeleton, respectively.
However, although the oxazoloisoindole skeleton, the imidazoisoindole skeleton and the thiazoloisoindole skeleton are common to the compounds of the invention and the compounds of Reference D, the compounds of the invention have a functional group such as, for example, an oxo group or a thioxo group at the the oxazolo part, the imidazo part or the thiazolo part condensed to the isoindole skeleton and in that point are utterly different from the compounds of Reference D not having the oxo group or the like, in structure. Further, the use in Reference D is antiinflammatories or anticonvulsants and the same in the industrially applicable field, but is an use having no relation to the use in the invention.
As background art disclosing an invention having relation to the use in the present invention, there can be mentioned U.S. Pat. No. 3,928,597 (hereinafter, referred to as Reference E). Reference E discloses an invention of a method of treating hyperglycemia comprising orally or parenterally administering a 2,3-dihydroimidazoisoindolol compound wherein a lower alkyl group is substituted at the imidazo part condensed to the isoindole skeleton, and an imidazolylphenyl phenyl ketone compound.
However, although the imidazoisoindolone skeleton is common to the compounds of the invention and the compounds of Reference E, the compounds of the invention have a functional group such as, for example, an oxo group or a thioxo group at the imidazo part condensed to the isoindole skeleton and in that point are utterly different from the compounds of Reference E not having the oxo group or the like, in structure. Moreover, the invention of Reference E is a use invention which was attained by administering both of the 2,3-dihydr
Eiki Jun-ichi
Iino Tomoharu
Nagase Toshio
Nishimura Teruyuki
Sato Yoshiyuki
Banyu Pharmaceutical Co. Ltd.
Nixon & Vanderhye P.C.
Stockton Laura L.
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