Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-09
2002-12-03
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S267000, C514S866000
Reexamination Certificate
active
06489331
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an enhancer of insulin secretion and a medicament for the treatment of diabetes, which comprise a condensed purine derivative as an active ingredient.
BACKGROUND ART
Diabetes is a metabolic abnormality mainly of glycometabolism, resulting from insufficient insulin secretion, decreased sensitivity of target cells of insulin and so forth, and principally characterized by noticeable hyperglycemia. If the hyperglycemia continues for a long period of time, serious complications arise in various organs and nerves such as retinopathy, nephropathy and neuropathy, which are caused mainly by vascular lesion. Therefore, for the treatment of diabetes, it is extremely important to control and maintain blood glucose level at a normal level, and methods for that purpose have been studied since old days.
For a type of diabetes where onset is gradual and insulin therapy is not necessarily required for life support (non-insulin dependent diabetes: NIDDM), blood glucose level can be controlled by combination of exercise therapy and drug therapy. As the drugs, insulin secretion enhancers, one of orally available hypoglycemic agents, have widely been used clinically. However, since currently available insulin secretion enhancers all promote insulin secretion non-dependently on glucose level, they cause problems of severe hypoglycemia or insufficient control of blood glucose if doses are not appropriate, and are not fully satisfactory drugs. If a hypoglycemic agent can be provided that is capable of enhancing insulin secretion dependently on a blood glucose level, the agent is expected to be extremely useful for blood glucose control of patients suffering from diabetes because the risk of hypoglycemia due to an excess dosage can be avoided.
As purine derivatives, the compounds of the following formula (I) having diuretic action, antiasthmatic action, anti-dementia action, bronchodilatation action, antiallergic action, antiulcer action and so forth are known (Japanese Patent Unexamined Publication (Kokai) No.3-204880/1991; Journal of Medicinal Chemistry, vol. 35, p.3578, 1992; Journal of Medicinal Chemistry, vol. 36, p.2508, 1993; International Publication WO98/15555). Journal of Medicinal Chemistry, vol. 23, p.1188, 1980 discloses that the compounds represented by the formula (A) have bronchodilatation action. Furthermore, Journal of Medicinal Chemistry, vol. 40, p.3248, 1997 discloses that the compounds represented by the formula (B) have inhibitory action against type IV phosphodiesterase (bronchodilatation action).
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a medicament useful for the therapeutic treatment of diabetes and the prophylactic and/or therapeutic treatment of complications of diabetes. More specifically, the object of the present invention is to provide a medicament having action of enhancing insulin secretion in a blood glucose level-dependent manner.
The inventors of the present invention conducted various studies to achieve the foregoing object. As a result, we found that the compounds represented by the following general formula (I) have insulin secretion enhancing action, and that the compounds are useful as an active ingredient of a medicament for the treatment of diabetes. The present invention was achieved on the basis of these findings.
The present invention thus provides medicaments for the therapeutic treatment of diabetes which comprise compound represented by the general formula (I) or a physiologically acceptable salt thereof as an active ingredient:
wherein R
1
represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group; R
2
represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group; R
3
represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group; X
1
and X
2
independently represent a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group; and n represents an integer of from 0 to 3. The invention also provides medicaments for the prophylactic and/or therapeutic treatment of a complication of diabetes which comprise the aforementioned compound or a physiologically acceptable salt thereof as an active ingredient.
According to other aspects of the present invention, there are provided hypoglycemic agents comprising a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof as an active ingredient, and insulin secretion enhancers comprising a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof as an active ingredient. These medicaments are preferably provided in the form of a pharmaceutical composition which comprises a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof and one or more of pharmaceutical additives.
According to other aspects of the present invention, there are provided use of a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof for the manufacture of the aforementioned medicaments; a method for the therapeutic treatment of diabetes which comprises the step of administering a therapeutically effective amount of a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof to a mammal including human; a method for enhancing insulin secretion which comprises the step of administering a therapeutically effective amount of a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof to a mammal including human; and a method for decreasing blood glucose level which comprises the step of administering a therapeutically effective amount of a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof to a mammal including human.
The compounds represented by the general formula (I) will be hereinafter referred to as Compound (I).
Meanings of terms used herein are as follows. As the lower alkyl group or a lower alkyl moiety of a functional group containing the lower alkyl moiety (for example, an aralkyl group), an alkyl group having about 1 to 10 carbon atoms can be used, and the term “alkyl group” includes linear, branched and cyclic alkyl groups as well as those consisting of a combination thereof. A cyclic alkyl group or a cyclic alkyl moiety of an alkyl group may have one or more rings, and may have, for example, a bicyclic ring or tricyclic ring system.
Examples of the linear or branched lower alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a neopentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group and so forth. Examples of the cyclic lower alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a noradamantyl group, an adamantyl group and so forth.
Preferred examples of the lower alkyl group represented by R
1
include a linear or branched lower alkyl group (for example, a tert-butyl group, etc.), a monocyclic to tricyclic lower cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 3-noradamantyl group, etc.) and a lower alkyl group substituted with a lower cycloalkyl group (for example, a cyclopropylmethyl group, a cyclopentylmethyl group, etc.). Among them, a 3-noradamantyl group and a cyclopentyl group are more preferred. As the lower alkyl group represented by R
2
, a linear or branched lower alkyl group (for example, a methyl group, an ethyl group, a n-propyl group, etc.), a monocyclic lower cycloalkyl group or a lower al
Kusaka Hideaki
Matsuda Yuzuru
Nakanishi Satoshi
Ohta Yoshihisa
Shimada Jun'ichi
Greenblum & Bernstein P.L.C.
Kyowa Hakko Kogyo Co. Ltd.
Weddington Kevin E.
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