Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-05
2003-06-17
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S211150, C514S227800, C514S234200, C514S263200, C514S263220, C514S263300, C514S263400, C540S481000, C540S492000, C540S524000, C544S061000, C544S118000, C544S264000, C544S265000, C544S277000
Reexamination Certificate
active
06579868
ABSTRACT:
TECHNICAL FIELD TO WHICH THE INVENTION BELONGS
The present invention relates to a novel purine compound having an adenosine receptor antagonism and to a preventive or therapeutic agent for diabetes mellitus and diabetic complications comprising an adenosine receptor antagonist having a hypoglycemic action and a glucose tolerance improving action on the basis of an inhibiting action to saccharogenesis and a promoting action to saccharide utilization at the periphery. More particularly, it relates to a preventive or therapeutic agent for diabetes mellitus and diabetic complications in which an adenosine receptor antagonist is an adenosine A2 receptor antagonist.
PRIOR ART
With regard to therapeutic agents for diabetes mellitus, various biguanide compounds and sulfonylurea compounds have been used. However, the biguanide compounds induce a lactic acidosis and, therefore, their use is limited while the sulfonylurea compounds often result in a severe hypoglycemia due to their strong hypoglycemic action and, therefore, their use is to be careful.
An object of the present invention is to provide a preventive or therapeutic agent for diabetes mellitus and diabetic complications on the basis of a new action mechanism which is different from that of conventional biguanide compounds and sulfonylurea compounds having several limitations in actual use.
DISCLOSURE OF THE INVENTION
The present inventors have carried out various investigations and, as a result, they have found that antagonists to adenosine receptors can be preventive or therapeutic agents of a new type for diabetes mellitus. Thus, hyperglycemia of spontaneous diabetic mice was relieved by an adenosine receptor antagonist. Such an action is presumed to be the results of inhibition of the gluconeogenic action and the glycogenolytic action, promoted by endogenous adenosine, from liver by an antagonist. Based upon such a finding, the present inventors have carried out an investigation for the compounds having excellent hypoglycemic action and glucose tolerance improving action as a preventive or therapeutic agent and have found novel purine compounds represented by the following formula (I). As a result of further investigation of their action mechanism in detail, they have found that, among the adenosine receptor antagonistic action, the adenosine A2 receptor antagonistic action is the real substance for showing the hypoglycemic and glucose tolerance improving action and have accomplished the present invention where adenosine A2 receptor antagonist is a preventive or therapeutic agent of a new type for diabetes and diabetic complications.
The novel purine compound according to the present invention is represented by the following formula (I).
A purine compound represented by the formula (I), its pharmacologically acceptable salt or hydrates thereof.
In the formula R
1
means:
1) formula:
(in the formula, X represents hydrogen atom, hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted acyloxy group or an optionally substituted amino group; and R
5
and R
6
are the same as or different from each other and each represents hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted saturated or unsaturated C
3-8
cycloalkyl group, an optionally substituted C
3-8
cycloalkyl-C
2-6
alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally protected carboxyl group or an optionally substituted four to six membered ring having at least one hetero atom. Alternatively, R
5
and R
6
may represent an oxygen atom or a sulfur atom together or may represent a ring being formed together with the carbon atom to which they are bonded which may have a hetero atom. This ring may be substituted.); or
2) a five- or six-membered aromatic ring which may have substituent group and hetero atom.
W represents a formula —CH
2
CH
2
—, —CH═CH— or —C≡C—.
R
2
represents hydrogen atom, an optionally substituted lower alkyl group, hydroxyl group or a formula —NR
7
R
8
(in which R
7
and R
8
are the same as or different from each other and each represents hydrogen atom, hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted acyl group, an optionally substituted C
3-8
cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group. Alternatively, R
7
and R
8
may be a saturated ring which is formed together with a nitrogen atom to which they are bonded. This ring may further have a hetero atom or a substituent.).
R
3
represents hydrogen atom, an optionally substituted C
3-8
cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted C
2-6
alkenyl group.
R
4
represents hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted C
3-8
cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted C
2-6
alkenyl group, an optionally substituted C
2-6
alkynyl group or an optionally substituted cyclic ether.
However, the case where (1) W is —CH
2
CH
2
— and X is hydrogen atom and an alkyl group or where (2) W is —C≡C—, R
3
is hydrogen atom and R
4
is an optionally substituted cyclic ether is excluded.
There has been no report that an adenosine A2 receptor antagonist is effective for prevention and therapy of diabetes mellitus and diabetic complications.
The present invention provides a preventive or therapeutic agent for diabetes, a preventive or therapeutic agent for diabetic complications, a hypoglycemic agent, an improving agent for impaired glucose tolerance, a potentiating agent for insulin sensitivity or obesity which comprises a purine compound of the formula (I), its pharmacologically acceptable salt or hydrates thereof as an active ingredient.
The present invention provides a method or a use by administrating a pharmacologically or clinically effective amount of a purine compound of the formula (I), its pharmacologically acceptable salt or hydrates thereof to a patient for prevention or therapy of diabetes mellitus, for prevention or therapy of diabetic complications, for prevention or therapy of a disease against which a purine compound of the formula (I), its pharmacologically acceptable salt or hydrates thereof is effective for its prevention or therapy, for hypoglycemia, for improvement of impaired glucose tolerance, for potentiation of insulin sensitivity, or for prevention and therapy of obesity.
The present invention provides a pharmaceutical composition containing a pharmacologically or clinically effective amount of a purine compound of the formula (I), its pharmacologically acceptable salt or hydrates thereof.
Adenosine is a nucleoside widely existing in living body and has a physiological action to a cardiovascular system, a central nervous system, a respiratory system, kidney, an immune system, etc. The action of adenosine is achieved via at least four receptors—A1, A2a, A2b and A3—in which G protein is participated (Fredholm, B. B. et al., Pharmacol. Rev., 46, 143-156, 1994.). In 1979, adenosine receptor was at first classified into A1 and A2 on the basis of their pharmacological action and participation in adenylate cyclase (Van Calker, D. et al., J. Neurochem., 33, 999-1003, 1979.). Then A2 receptor has classified into the subtypes of A2a and A2b on the basis of high and low affinity to adenosine and to adenosine A2 agonists, i.e. NECA and CGS-21680 (Burns, R. F. et al., Mol. Pharmacol., 29, 331-346, 1986.; Wan, W. et al., J. Neurochem., 55, 1763-1771, 1990.). Although gradually, physiological and pathological significance of those receptors has been clarified in a central nervous system, a circulatory system, etc.
With regard to saccharometabolism, the following reports have been available. In an experiment usin
Asano Osamu
Harada Hitoshi
Horizoe Tatsuo
Hoshino Yorihisa
Inoue Takashi
Berch Mark L.
Eisai Co. Ltd.
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