JPH05170653A - Treating agent for diabetes mellitus - Google Patents

Abstract

PURPOSE:To obtain a medicine containing a specific carboxylic acid amide derivative as an active ingredient, having excellent blood sugar lowering action, high in safety and useful in treatment for diabetes mellitus and diabetic complication. CONSTITUTION:The objective treatment contains a compound of formula I [R<1> and R<2> are H, alkyl, cycloalkyl, diphenyl-lower alkyl, formula II [R<2> to R<7> are H, halogen, nitro, etc.; A is lower alkylene; (1) is 0 or 1], etc.; R<3> is H, alkyl or phenyl-lower alkyl; R<4> is lower alkyl or phenyl; X is O or S], e.g. 4-diethoxyphosphinoylmethyl-N-benzyl-N-(4-chlorophenyl) benzamide as an active ingredient, The treatment exhibits excellent effect, especially on insulin- independent II type diabetes mellitus without side effects.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic agent for diabetes, more specifically to a therapeutic agent for diabetes which comprises a specific carboxylic acid amide derivative as an active ingredient.

[0002]

2. Description of the Related Art In recent years, it has been recognized that the number of patients with diabetes and diabetic complications is increasing and becoming younger as the standard of living changes to Western habits due to the improvement of living standards or the tendency of lack of exercise increases.

Generally, insulin-dependent (I
Type) and non-insulin-dependent (type II), and 90% or more of diabetic patients are the latter. Insulin injections are used for the treatment of type I diabetes, and oral agents other than insulin are mainly used for the treatment of type II diabetes together with exercise therapy and diet therapy. Oral agents used for the treatment of type II diabetes include insulin secretagogues such as SU agents and anaerobic glycolytic accelerators such as biguanides.

[0004]

[Problems to be Solved by the Invention]

1) The biggest goal of diabetes treatment is to prevent the onset of diabetic complications. According to clinical reports on the prognosis of long-term treatment with insulin secretagogues and anaerobic glycolysis promoters, the preventive effect of onset of diabetic complications due to administration of these drugs is not always satisfactory.

2) Various insulin secretagogues may cause severe and persistent hypoglycemia, and their long-term administration may cause the pathological condition to shift to type I diabetes or become chronic as the burden on the pancreas increases. There is also a report that the excessive insulin secretion promotes the onset of complications. In addition, anaerobic glycolysis promoters have been reported to have serious side effects such as severe lactic acidosis and hypoglycemia [Clinical adult disease, 6 (6),
859-865 (1976), etc.].

The object of the present invention is to solve all of the above-mentioned drawbacks found in conventionally known antidiabetic drugs and to provide an excellent pharmacological action.
In particular, it is to provide a novel antidiabetic agent having a hypoglycemic action and high safety.

[0007]

[Means for Solving the Problems] In view of the above situation, the inventors of the present invention have conducted extensive studies and as a result, as a result, a specific carboxylic acid amide derivative represented by the following general formula (1), particularly general formula (2), has been obtained. However, they have found that they are effective for the treatment of diabetes, and have thus provided a novel therapeutic agent for diabetes of the present invention.

That is, the present invention has the general formula

[0009]

[Chemical 4]

[Wherein R ¹ and R ² are each a hydrogen atom,
Alkyl group, cycloalkyl group, diphenyl lower alkyl group or group

[0011]

[Chemical 5]

Is shown. In said group R ⁵ , R ⁶ and R ⁷
Is a hydrogen atom, a halogen atom, a nitro group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group, a halogen-substituted lower alkyl group, a cyano group, a carboxyl group or a hydroxyl group, A is a lower alkylene group, and 1 is 0 or 1 is shown. R ¹ and R ² together with the nitrogen atom to which they are bonded may be bonded to each other with or without a nitrogen atom or oxygen atom to form a heterocyclic group, and the heterocyclic group is a lower alkyl group. It may be substituted with a phenyl lower alkyl group or a phenyl group which may have a lower alkyl group, a lower alkoxy group, a halogen atom or a halogen-substituted lower alkyl group as a substituent. R ³ represents a hydrogen atom, an alkyl group or a phenyl lower alkyl group. R ⁴ represents a lower alkyl group or a phenyl group. X represents an oxygen atom or a sulfur atom. ] It is related with the diabetes therapeutic agent characterized by containing the carboxylic acid amide derivative represented by these as an active ingredient.

Among the compounds of the above-mentioned general formula (1) used as an active ingredient in the therapeutic agent for diabetes of the present invention, preferred compounds are represented by the following general formula (2), and among them, 4-diethoxyphosphinoylmethyl-N -Benzyl-N- (4-chlorophenyl) benzamide and 4-diethoxyphosphinoylmethyl-N- (4-bromophenyl) benzamide are optimal.

[0014]

[Chemical 6]

[Wherein R ^{1 '} is a halogen-substituted phenyl group,
R ^{2 ′} represents a hydrogen atom or a benzyl group, and R ^{4 ′} represents a lower alkyl group. The carboxylic acid amide derivatives represented by the above general formulas (1) and (2) have been developed by the present inventors as compounds effective for pharmacological use such as anti-inflammatory agents (see JP-A-61-15199). ), And subsequently as an active ingredient of a therapeutic agent for hyperlipidemia (see JP-A-63-264421), it is a known compound that has been developed and can be obtained by the method described in U.S. However, in each of the above publications, there is no description that the carboxylic acid amide derivative is effective in the treatment of diabetes, and there is no report regarding that the carboxylic acid amide derivative other than the above publication has some pharmacological use. Of course, there is no example suggesting its hypoglycemic effect.

Therefore, the present invention has been completed by finding that the respective derivatives represented by the above-mentioned general formulas (1) and (2) have a therapeutic effect on diabetes which is completely unrelated to the conventionally known pharmacological use. It is a thing. Each of the above-mentioned derivatives has an excellent effect in treating type II diabetes and prevention of diabetic complications, in particular, and has extremely excellent characteristics that there are no serious side effects seen in conventional drugs of this kind. ing.

The antidiabetic agent of the present invention generally contains at least one compound included in the above general formulas (1) and (2) as an active ingredient, and generally, the compound is At the same time, a generally used non-toxic pharmaceutical carrier is prepared into various pharmaceutical forms according to the administration method. Here, as the pharmaceutical carrier, various diluents or solvents usually used depending on the formulation form to be prepared,
Examples include fillers, extenders, binders, suspension agents, disintegrating agents, surface active agents, lubricants, excipients, wetting agents and the like. Further, the above-mentioned preparation, if necessary, a solubilizing agent which is usually used,
A buffering agent, a preservative, a coloring agent, a flavoring agent, a flavoring agent and the like can be added as appropriate.

The above-mentioned formulation form of the therapeutic agent of the present invention is not particularly limited and can be appropriately determined. For example, oral administration agents such as tablets, capsules, granules, pills, syrups, solutions, emulsions and suspensions, Various forms of parenteral administration agents such as injections (subcutaneous, intravenous, intramuscular, intraperitoneal injections, etc.) can be adopted.

The above-mentioned various forms of the drug of the present invention are prepared by a conventional method. For example, tablets, capsules, granules,
Orally administered agents such as pills include excipients such as sucrose, lactose, glucose, starch, mannitol; syrup, gum arabic,
Binders such as sorbit, tragacanth, methylcellulose, polyvinylpyrrolidone; starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose,
A disintegrating agent such as polyethylene glycol; a lubricant such as talc, magnesium stearate, calcium stearate, and silica; a wetting agent such as sodium laurate, glycerol, etc., and the like are prepared according to a conventional method. Also injections,
Liquids, emulsions, suspensions, syrups and the like include solvents for dissolving active ingredients such as ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, sesame oil; sorbitan fatty acid ester, poly Surfactants such as oxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, hydrogenated castor oil polyoxyethylene ether, and lecithin; cellulose derivatives such as sodium carboxymethyl cellulose and methyl cellulose; and natural rubbers such as tragacanth and arabic gum. Suspending agent: prepared according to a conventional method by appropriately using a preservative such as ester of paraoxybenzoic acid, benzalkonium chloride, sorbitanate and the like. The dose of the therapeutic agent for diabetes of the present invention is
It can be arbitrarily determined according to the dosage form, administration route, age, weight, susceptibility of the patient, degree of disease and the like, and is not particularly limited, but usually an oral administration agent contains the active ingredient contained in each dosage form. Is about 0.0 per kg of body weight per day
It is suitable that the amount is in the range of about 5 to 80 mg, preferably about 0.1 to 50 mg, which can of course be increased or decreased as necessary.

[0020]

EXAMPLES In order to explain the present invention in more detail, formulation examples of the antidiabetic agent of the present invention will be given below as prescription examples.

[0021]

[Formulation Example 1] Preparation of tablets 4-diethoxyphosphinoylmethyl- as an active ingredient
Tablets (1000 tablets) each containing 250 mg of N-benzyl-N- (4-chlorophenyl) benzamide (referred to as "Compound A") were prepared by the following formulation.

Component (g) Compound A 250 Lactose (Japanese Pharmacopoeia) 33.3 Corn Starch (Japanese Pharmacopoeia) 16.4 Carboxymethylcellulose Calcium (Japanese Pharmacopoeia) 12.8 Methylcellulose (Japanese Pharmacopoeia) ) 6.0 Magnesium stearate (Japanese Pharmacopoeia) 1.5 Total amount 320 According to the above formulation, compound A, lactose, corn starch and carboxymethyl cellulose calcium are thoroughly mixed,
Granulated with an aqueous solution of methylcellulose, passed through a 24 mesh screen, mixed with magnesium stearate and pressed into tablets.

[0023]

[Formulation Example 2] Preparation of capsule 4-diethoxyphosphinoylmethyl- as an active ingredient
Hard gelatin capsules (1000 capsules) containing 250 mg of N- (4-bromophenyl) benzamide (referred to as "Compound B") per capsule were prepared by the following formulation.

Component (g) Compound B 250 Crystalline cellulose (Japanese Pharmacopoeia) 30 Corn starch (Japanese Pharmacopoeia) 17 Talc (Japanese Pharmacopoeia) 2 Magnesium stearate (Japanese Pharmacopoeia) 1 Total quantity 300 Following the above formulation, each component was finely divided into powders, thoroughly mixed so as to form a uniform mixture, and then filled into a gelatin capsule for oral administration having a desired size to obtain a target capsule.

[0025]

Formulation Example 3 Preparation of Granules Granules (1000 g) containing 500 mg of Compound A as an active ingredient were prepared according to the following formulation.

Component (g) Compound A 500 Corn starch (Japanese Pharmacopoeia) 250 Lactose (Japanese Pharmacopoeia) 100 Crystalline cellulose (Japanese Pharmacopoeia) 100 Carboxymethylcellulose calcium (Japanese Pharmacopoeia) 40 Hydroxypropylcellulose (Japanese Pharmacopoeia product) 10 Total 1000 Compound A, corn starch, lactose, crystalline cellulose and carboxymethyl cellulose calcium are mixed according to the above formulation, and then a hydroxypropyl cellulose aqueous solution is added to the mixture and kneaded, and granulated by an extrusion granulator. And 50 ℃
And dried for 2 hours to obtain the target granule.

The following are examples of pharmacological tests conducted on the active ingredients of the drug of the present invention.

[0028]

[Pharmacological test example] Non-insulin-dependent diabetic mouse "KK"
-A ^y mouse "(male, 16-20 weeks old, 1 group = 6 mice)
Are fed ad libitum, and the test compound is further added at 100 mg / kg /
Oral administration was carried out daily for 7 days. Blood was collected from the tail vein on the first and seventh days of administration, and the glucose concentration in plasma was measured using Glucose C-II Test Wako (enzyme method, Wako Pure Chemical Industries, Ltd.). In addition, the group of only free feeding was used as a control group.

Table 1 shows the results obtained using Compound A and Compound B as test compounds. In addition, Table 1 also shows the results of testing the significant difference from the control group by Student's t-test.

[0030]

[Table 1]

From Table 1, the group to which each of the above compounds (carboxylic acid amide derivative) was administered had a significantly lower glucose concentration in plasma than the non-administered control group. It is found that the agent has an excellent effect on the treatment of diabetes.

Claims (2)

[Claims] 1. A general formula: [Wherein R ¹ and R ² are each a hydrogen atom, an alkyl group,
Cycloalkyl group, diphenyl lower alkyl group or group Indicates. In the group, R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom, a halogen atom, a nitro group, a lower alkoxy group,
A lower alkoxycarbonyl group, a lower alkyl group, a halogen-substituted lower alkyl group, a cyano group, a carboxyl group or a hydroxyl group, A is a lower alkylene group, and 1 is 0 or 1. R ¹ and R ² together with the nitrogen atom to which they are bonded may be bonded to each other with or without a nitrogen atom or oxygen atom to form a heterocyclic group, and the heterocyclic group is a lower alkyl group. It may be substituted with a phenyl lower alkyl group or a phenyl group which may have a lower alkyl group, a lower alkoxy group, a halogen atom or a halogen-substituted lower alkyl group as a substituent. R ³ represents a hydrogen atom, an alkyl group or a phenyl lower alkyl group.
R ⁴ represents a lower alkyl group or a phenyl group. X represents an oxygen atom or a sulfur atom. ] A therapeutic agent for diabetes comprising a carboxylic acid amide derivative represented by the following as an active ingredient. 2. The active ingredient is represented by the general formula: [In the formula, R ^{1 ′} represents a halogen-substituted phenyl group, R ^{2 ′} represents a hydrogen atom or a benzyl group, and R ^{4 ′} represents a lower alkyl group. ] The diabetes therapeutic agent of Claim 1 selected from the carboxylic acid amide derivative represented by these.