Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-08-17
2003-07-22
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000, C536S017400, C536S017300, C536S017200, C536S123100, C536S022100
Reexamination Certificate
active
06596696
ABSTRACT:
This is a U.S. National Phase Application Under 35 USC 371 and applicant herewith claims the benefit of priority of PCT/JP00/00512 filed Jan. 31, 2000, in the Japanese Patent Office and Application No. 11-042695 filed in Japan on Feb. 22, 1999 each of whose contents are incorporated by reference.
TECHNICAL FIELD
The present invention relates to maltoligosaccharide derivatives having a specific molecular structure and their uses. More particularly, it relates to an &agr;-amylase inhibitor and the pharmaceuticals useful for the prophylaxis and treatment of hyperglycemia, for example, diabetes and their complications, which contain said derivatives as an active ingredient.
BACKGROUND ART
Carbohydrates ingested by mammals are digested (hydrolyzed) to some extent by salivary &agr;-amylase in the oral cavity and stomach, and then digested thoroughly by pancreatic &agr;-amylase in the duodenum and jejunum to become oligosaccharides or disaccharides. Then they are further hydrolyzed by a glucoside-hydrolaze such as glucoamylase and maltase to finally become a monosaccharide such as glucose which is absorbed from the fimbriae on the intestinal membranes. After ingestion of carbohydrates, there takes place a primary increase in blood glucose level, or so-called hyperglycemic symptom, due to the absorption of glucose, but this abnormal phenomenon is usually remedied in due course as the blood glucose level is brought back to a normal range and controlled to stay therein by the homeostasis maintaining system in the living body.
However, if a person suffers an alimentary hyperglycemic symptom for a long time or has abnormality in carbohydrate metabolism, such as an abnormal rise of blood glucose level, he or she is liable to a disease called hyperglycemia, which leads to obesity or diabetes. Obesity is caused as the hyperglycemic condition resulting from overeating incites much secretion of insulin to promote fat synthesis and to decrease lipolysis, inducing accumulation of fat in the body. On the other hand, diabetes is caused as the promoted secretion of insulin by the hyperglycemic condition resulting from overeating invites a reduction of sensitivity of the insulin receptors or fatigue of the &bgr; cells of the pancreatic Langerhans islet. It is known that obesity and diabetes tend to provoke many serious complications such as hyperlipidemia, hypertension, arteriosclerosis, autonomic imbalance, and cataract.
As a potent therapeutic agent for such hyperglycemia, certain digestive enzyme inhibitors, for example, “Basen” containing Voglibose (produced by Takeda Chemical Industries Co., Ltd.) and “Glucobay” containing Acarbose (produced by Bayer Chemical Corp.), are clinically used. Both of these compounds, however, have the disadvantage of inciting such side effects as causing abdominal distention, meteorism, increase of flatus, loose passage, diarrhea, abdominal pain, etc., because of their strong inhibitory action against glucosidase. Also, the maltoligosaccharide derivatives which the present inventors had previously proposed (JP-A-9-278789) are not necessarily satisfactory in certain respects, such as strength of their amylase inhibitory activity.
DISCLOSURE OF THE INVENTION
The present invention is intended to provide a chemical substance which is free of said defects of the conventional therapeutic and prophylactic agents for hyperglycemia and capable of strongly inhibiting human &agr;-amylase to work effectively for the prophylaxis and treatment of hyperglycemia, for example diabetes and the diseases induced thereby, and an &agr;-amylase inhibitor and prophylactic and therapeutic agents for hyperglycemia containing said substance as an active ingredient.
The inventors extensively studied for attaining the above object, and found that the maltoligosaccharide derivatives produced by converting the reduced terminal glucose of oligosaccharides into hexahydro-1H-azepine-3R, 4R, 5R, 6S-tetrol and also converting the 6-position of the 3rd glucose residue (as counted from the hexahydro-1H-azepine-3R, 4R, 5R, 6S-tetrol) into a hydrophobic group, and their hydrates or their physiologically acceptable salts strongly inhibit &agr;-amylase derived from human pancreatic juice (hereinafter referred to as HPA) and &agr;-amylase derived from human salivary gland (hereinafter referred to as HSA) and also act to suppress or retard digestion and absorption of glucose, and that it is possible to overcome the said defects of the prior art by using these compounds as an active ingredient of the therapeutic and prophylactic agents for hyperglycemia. The present invention has been attained on the basis of the above finding.
According to the present invention, there are provided the maltoligosaccharide derivatives represented by the following general formula (1):
(wherein n is an integer of 0 to 3, and X is a hydrogen atom or a hydrophobic group) or their hydrates or physiologically acceptable salts; an &agr;-amylase inhibitor containing one of said maltoligosaccharide derivatives of the formula (1) or their hydrates or physiologically acceptable salts as an active ingredient; and a prophylactic or therapeutic agent for hyperglycemia containing one of said maltoligosaccharide derivatives of the formula (1) or their hydrates or physiologically acceptable salts as an active ingredient. The present invention is explained in detail.
BEST MODE FOR CARRYING OUT THE INVENTION
The maltoligosaccharide derivatives according to the present invention (hereinafter referred to as the present derivatives) are those which are represented by the general formula (1) as mentioned above wherein n is an integer of 0 to 3 and X is a hydrogen atom or a hydrophoblic group. The present derivatives include their hydrates and physiologically acceptable salts. The hydrophobic group represented by X can be, for instance, a halogen atom such as fluorine, chlorine, b romine and iodine atom, a substituted or non-substituted alkyloxy group, a substituted or non-substituted alkylthio group, a substituted or non-substituted alkylsulfonyl group, a substituted or non-substituted alkylcarbamoyl, or azido group.
In use of the present derivatives for producing an &agr;-amylase inhibitor or a prophylactic or therapeutic agent for hyperglycemia, it is desirable, for the reasons stated below, that in the formula (1) n is 0 to 3, especially 0 or 1, and X is a hydrogen atom or a halogen atom, especially a hydrogen atom.
The present derivatives can be synthesized efficiently from, for instance, 6
3
-modified maltoligosaccharides represented by the general formula (2):
(wherein n is an integer of 0 to 3, and X is a hydrogen atom or a hydrophobic group). In the formula (2), n is an integer of 0 to 3, and X is a hydrogen atom or a hydrophobic group. The hydrophobic group can be, for instance, a halogen atom such as fluorine, chlorine, bromine and iodine atom, a substituted or non-substituted alkyloxy group, a substituted or non-substituted alkylthio group, a substituted or non-substituted alkylsulfonyl group, a substituted or non-substituted alkylcarbamoyl, or azido group. Said 6
3
-modified maltoligosaccharides can be synthesized, for instance, by a method described in Carbohydrate Research, Vol. 307, pp. 69-76, 1998.
A 6
3
-modified maltologosaccharide synthesized by the above method is reacted with, for instance, p-toluenesulfonyl chloride in pyridine, and if necessary 6
1
-tosyl-6
3
-modified maltoligosaccharide are separated by a conventional method and reacted with sodium azide in N,N-dimethylformamide (DMF) to give 6
1
-azido-6
3
-modified maltoligosaccharides. These 6
1
-azido-6
3
-modified maltoligosaccharides are separated from each other by a known method, and the latter is reduced by introducing hydrogen gas in the presence of palladium carbon to produce the present derivative represented by the formula (1).
The thus obtained present derivative can be purified by a conventional method, for example, precipitation using a pertinent organic solvent or column chromatography using an ion exchange resin, aminopropyl silica gel, silica gel, active
Iwai Yukihiko
Nasu Ayako
Someya Takao
Tobe Koichiro
Uchida Riichiro
Banner & Witcoff , Ltd.
Barts Samuel
Henry Michael C.
Kikkoman Corporation
LandOfFree
Malto-oligosaccharide derivatives and uses thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Malto-oligosaccharide derivatives and uses thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Malto-oligosaccharide derivatives and uses thereof will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3022729