Agent for treating high-risk impaired glucose tolerance

Details Agent for treating high-risk impaired glucose tolerance Agent for treating high-risk impaired glucose tolerance

1999-07-02

2001-03-13

Spivack, Phyllis G. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

Reexamination Certificate

active

06200958

ABSTRACT:

TECHNICAL FIELD
The present invention relates to an agent for treating high-risk impaired glucose tolerance, especially to an agent for prevention of transition from high-risk impaired glucose tolerance to diabetes mellitus. The present agent is useful in therapeutic fields of the diabetes mellitus or high-risk impaired glucose tolerance.
BACKGROUND ART
According to the criteria issued by WHO (World Health Organization) based on a glucose tolerance test, diabetes mellitus and impaired glucose tolerance (hereinafter sometimes referred to as IGT) are distinguished by the fasting blood glucose level and the blood glucose level 2 hours after glucose loading. Patients with IGT have high blood glucose levels compared to those of patients with diabetes mellitus, and are reported to be at increased risk of developing diabetes mellitus and complications of arteriosclerotic diseases. In particular, it is known that patients with IGT who have blood glucose levels of 170 mg/dl or above at 2 hours following glucose loading, i.e., patients with high-risk IGT, may develop diabetes mellitus at a high rate [Diabetes Frontier, p. 136, 1992].
With regard to voglibose which is an &agr;-glucosidase inhibitor, there are reports of studies on effects of voglibose for insulin-resistant IGT and diabetes [Yakuri-to-Chiryo (Japanese Pharmacology & Therapeutics), 24 (5):213 (1996); Metabol. Exp. Clin., 45:731, 1996].
Voglibose (AO-128) is also known to have effects of lowering blood glucose level and improving glucose tolerance in rats [Yakuri-to-Chiryo (Japanese Pharmacology & Therapeutics), 19 (11):161 (1991); Journal of Nutrition Science and Vitaminology, 45 (1): 33 (1992)]. On the contrary, it has also been reported that the effect of voglibose in improving glucose tolerance could not be verified in human [Rinsho-Seijinbyo, 22 (4): 109 (1992)].
For the above-mentioned high-risk IGT, in particular, there have been no report so far about research for preventing its transition to diabetes mellitus or about its treatment to recover the normal condition.
DISCLOSURE OF INVENTION
The present invention aims to develop an agent for prevention of transition from high-risk IGT to diabetes mellitus, used as a prophylaxis for diabetes mellitus, as well as an agent for treating high-risk IGT.
The present invention relates to:
(1) An agent for prevention of transition from high-risk impaired glucose tolerance to diabetes mellitus comprising an &agr;-glucosidase inhibitor;
(2) An agent for treating high-risk impaired glucose tolerance comprising an &agr;-glucosidase inhibitor;
(3) The agent of the above items (1) or (2) wherein &agr;-glucosidase inhibitor is voglibose.
(4) The agent of the above items (1), (2) or (3) wherein the high-risk impaired glucose tolerance exhibits a blood glucose level between 170 and 199 mg/dl at 2 hours in a 75 g oral glucose tolerance test;
(5) The agent of the above item (2) or (3) which is administered until the blood glucose level at 2 hours in a 75 g oral glucose tolerance test decreases to the normal range;
(6) The agent of the above items (1), (2) or (3) for administering for 13 weeks or longer;
(7) The agent of the above item (1) or (3) wherein the diabetes mellitus is non-insulin-dependent diabetes mellitus;
(8) The agent of the above items (1), (2) or (3) which is in the form of preparation for oral administration;
(9) The agent of the above item (1), (2) or (3) which is administered at a dose of 0.15 to 15 mg per day;
(10) The agent of the above item (1), (2) or (3) which is administered within 60 minutes before meals.
(11) A method of treatment of IGT or prevention of IGT from progressing to diabetes mellitus which comprises administering the agent of item (1) to (10).
(12) Use of &agr;-glucosidase inhibitor for treatment of IGT or prevention of IGT from progressing to diabetes mellitus which comprises administering the agent of item (1) to (10).
(13) Use of &agr;-glucosidase inhibitor in the manufacture of medicament for the treatment of IGT or the prevention of IGT from progressing to diabetes mellitus which comprises administering the agent of item. (1) to (10).
&agr;-Glucosidase inhibitors used in the present invention are those agents which have effects of inhibiting digestive enzymes such as amylase, maltase, &agr;-dextrinase, and sucrase, and thereby retarding digestion of starch and sucrose.
As these types of pharmaceutical compounds are mentioned, for instance, valiolamine derivatives of the general formula;
wherein A stands for a C
1-10
acyclic hydrocarbon group which may be substituted by hydroxyl, phenoxy, thienyl, furyl, pyridyl, cyclohexyl or optionally substituted phenyl, a C
5-6
cyclic hydrocarbon group which may be substituted by hydroxyl, hydroxymethyl, methyl or amino, or a sugar residue. They are described in U.S. Pat. Nos. 4,701,559; 4,777,294; 4,595,678, and Japanese Patent Application KOKAI Nos. 200335/1982; 59946/1983; 162597/1983; 216145/1983; 73549/1984; 95297/1984.
Referring to the above general formula [I], A includes a C
1-10
straight chain or branched aliphatic hydrocarbon group which may be either saturated or unsaturated, and these may be substituted by hydroxy, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl which may be substituted. The substituents for the phenyl group which may be substituted includes lower alkyl (e.g., C
1-6
), lower alkoxy (e.g., C
1-6
), halogen (for example, fluorine, chlorine, bromine, iodine), phenyl and so on.
Furthermore, A stands for a C
5-6
cyclic hydrocarbon group or a sugar residue. These groups may be substituted with hydroxy, hydroxymethyl, methyl, or amino. The term ‘sugar residue’ means herein the remaining group on removal of one hydrogen atom from a saccharide molecule, and as such may stand for the residue derived from a monosaccharide or an oligosaccharide, for instance.
These derivatives may be used in the form of salts with inorganic acids, e.g. hydrochloric acid, or organic acids, e.g. citric acid.
The following is a partial list of valiolamine derivatives represented by the general formula [I].
(1) N-phenethylvaliolamine,
(2) N-(3-phenylallyl)valiolamine,
(3) N-furfurylvaliomine,
(4) N-thienylvaliolamine,
(5) N-(3-pyridylmethyl)valiolamine,
(6) N-(4-bromobenzyl)valiolamine,
(7) N-[(R)-&bgr;-hydroxyphenethyl]valiolamine,
(8) N-[(S)-&bgr;-hydroxyphenethyl]valiolamine,
(9) N-(&bgr;-hydroxy-2-methoxyphenethyl)valiolamine,
(10) N-(3,5-di-tert-butyl-4-hydroxybenzyl)valiolamine,
(11) N-(cyclohexylmethyl)valiolamine,
(12) N-geranylvaliolamine,
(13) N-(1,3-dihydroxy-2-propyl)valiolamine,
(14) N-(1,3-dihydroxy-1-phenyl-2-propyl)valiolamine,
(15) N-[(R)-&agr;-(hydroxymethyl)benzyl]valiolamine,
(16) N-cyclohexylvaliolamine,
(17) N-(2-hydroxycyclohexyl)valiolamine,
(18) N-[(1R,2R)-2-hydroxycyclohexyl]valiolamine,
(19) N-(2-hydroxycyclopentyl)valiolamine,
(20)methyl 4-[(1S,2S)-(2,4,5(OH)/3,5)-2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl]amino-4,6- dideoxy- &agr;-D-glucopyranoside,
(21)methyl 4-[(1S,2S)-(2,4,5(OH)/3,5)-2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl]amino-4-deoxy-&agr;-D-glucopyranoside,
(22) [(1S,2S)-(2,4,5(OH)/3,5)-2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl][(1R,2S)-(2,6/3,4)-4-amino-2,3-dihydroxy-6-(hydroxymethyl)cyclohexyl]amine,
(23) N-[(1R,2S)-(2,4/3,5)-2,3,4-trihydroxy-5-(hydroxymethyl)cyclohexyl]valiolamine,
(24) N-[(1R,2S)-(2,6/3,4)-4-amino-2,3-dihydroxy-6-methylcyclohexyl]valiolamine,
(25) N-[(1R,2S)-(2,6/3,4)-2,3,4-trihydroxy-6-methylcyclohexyl]valiolamine,
(26) N-[(1R,2S)-(2,4,6/3)-2,3,4-trihydroxy-6-methylcyclohexyl]valiolamine,
(27)4-O-&agr;-[4-[((1S)-(1,2,4,5(OH)/3,5)-2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-D-glucopyranosyl]-D-gluopyranose, and
(28)1,6-anhydro-4-O-&agr;-[4-[((1S)-(1,2,4,5(OH)/3,5)-2,3,4,5-tetrahydroxy-5-C-(hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-D-glucopyranosyl]-&bgr;-D-glucopyranose.
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