JP2835547B2 - Diabetes treatment - Google Patents

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, and more particularly to a therapeutic agent for diabetes characterized by containing 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 diabetic and diabetic complication patients has increased and their age has been increased due to a change to a Western-style diet due to an improvement in living standards or an increase in the tendency to lack exercise.

[0003] In general, diabetes is dependent on insulin (I
Type) and insulin-independent (type II), and more than 90% of the 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 along with exercise therapy and diet therapy. Oral preparations used for the treatment of type II diabetes include insulin secretion stimulants such as SU preparations and anaerobic glycolysis accelerators such as biguanides.

[0004]

[Problems to be solved by the invention]

1) The primary goal of diabetes treatment is to prevent the development of diabetic complications. According to clinical reports on the prognosis of long-term treatment with insulin secretion stimulants and anaerobic glycolysis accelerators, the effects of these drugs on preventing the onset of diabetic complications are not always satisfactory.

[0005] 2) Various insulin secretion stimulants may cause severe and prolonged hypoglycemia, and long-term administration thereof may cause the pathology to shift to type I diabetes with an increase in the burden on the pancreas, It has been reported that excessive insulin secretion may promote the onset of complications. In addition, serious side effects such as severe lactic acidosis and hypoglycemia have been reported for anaerobic glycolysis accelerators [Clinical Adult Disease, 6 (6),
859-865 (1976) etc.].

[0006] An object of the present invention is to solve all of the above-mentioned drawbacks found in conventionally known drugs for treating diabetes, and to provide an excellent pharmacological action.
In particular, it is an object of the present invention to provide a new antidiabetic agent which has a blood sugar lowering effect and is highly safe.

[0007]

Means for Solving the Problems In view of the above-mentioned situation, the present inventors have made intensive studies and as a result, have found that a specific carboxylic acid amide derivative represented by the following general formula (1), particularly, general formula (2) Have found that they are effective for the treatment of diabetes, and have now provided a novel therapeutic agent for diabetes of the present invention.

That is, the present invention relates to the general formula

[0009]

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

[0011]

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FIG. In the group, R ⁵ , R ⁶ and R ⁷
Each represents 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 represents a lower alkylene group, l represents 0 or 1 is shown. R ¹ and R ² may form a heterocyclic group together with or without a nitrogen atom to which they are bonded via a nitrogen atom or an oxygen atom, and the heterocyclic group may be a lower alkyl group. Or 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. ] As an active ingredient.

Among the compounds of the above general formula (1) used as an active ingredient in the therapeutic agent for diabetes of the present invention, preferred ones 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]

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[Wherein 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 carboxylic acid amide derivatives represented by the general formulas (1) and (2) have already been developed by the present inventors as compounds effective for pharmacological uses such as anti-inflammatory agents (see JP-A-61-15199). ), And thereafter, a known compound that has been developed as an active ingredient of a therapeutic agent for hyperlipidemia (see JP-A-63-264421) and can be obtained by the method described in the publication. However, there is no report in the above publications that the carboxylic acid amide derivative is effective for treating diabetes, and there is no report that the carboxylic acid amide derivative has any pharmacological use other than the above publications. Of course, there is no example suggesting its hypoglycemic effect.

Thus, the present invention has been completed by finding that each of the derivatives represented by the general formulas (1) and (2) has a therapeutic effect on diabetes which is completely unrelated to conventionally known pharmacological uses. Things. Each of the above-mentioned derivatives has an excellent effect particularly in treating type II diabetes and preventing diabetic complications, and also has a very excellent characteristic that there is no serious side effect seen in conventional drugs of this type. ing.

The antidiabetic agent of the present invention is required to contain at least one compound included in the above general formulas (1) and (2) as an active ingredient. At the same time, it is prepared into various pharmaceutical forms depending on the administration method using a commonly used nontoxic pharmaceutical carrier. Here, as the pharmaceutical carrier, various diluents or solvents commonly used depending on the pharmaceutical form to be prepared,
Examples include fillers, extenders, binders, suspending agents, disintegrants, surfactants, lubricants, excipients, wetting agents and the like. The above-mentioned preparations may contain, if necessary, a solubilizer usually used,
Buffers, preservatives, coloring agents, fragrances, flavors and the like can be added as appropriate.

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

The various forms of the drug of the present invention are prepared by a usual method. For example, tablets, capsules, granules,
Oral preparations such as pills include excipients such as sucrose, lactose, glucose, starch, mannitol; syrup, gum arabic,
Binders such as sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone; starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose,
It is prepared according to a conventional method using a disintegrant such as polyethylene glycol; a lubricant such as talc, magnesium stearate, calcium stearate and silica; a wetting agent such as sodium laurate and glycerol. Injections,
Solutions, emulsions, suspensions, syrups and the like include, for example, solvents for dissolving active ingredients such as ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, sesame oil, etc .; Surfactants such as oxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil and lecithin; cellulose derivatives such as sodium carboxymethylcellulose and methylcellulose; and natural rubbers such as tragacanth and gum arabic. A suspending agent is prepared according to a conventional method using a preservative such as an ester of paraoxybenzoic acid, benzalkonium chloride, and sorbitan salt as appropriate. The dose of the therapeutic agent for diabetes of the present invention,
Formulation, administration route, patient's age, body weight, sensitivity, the degree of disease, etc. can be arbitrarily determined, and is not particularly limited, but in the case of an oral agent, the active ingredient usually contained in each formulation Is about 0.0 per kg of body weight per day
It is appropriate to use an amount of about 5 to 80 mg, preferably about 0.1 to 50 mg, which can of course be increased or decreased as needed.

[0020]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, preparation examples of the therapeutic agent for diabetes of the present invention are given as prescription examples.

[0021]

Formulation Example 1 Preparation of Tablets 4-Diethoxyphosphinoylmethyl- as an active ingredient
Tablets (1000 tablets) containing 250 mg of N-benzyl-N- (4-chlorophenyl) benzamide (referred to as “Compound A”) per tablet were prepared according to the following formulation.

Component A (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 product) 1.5 Total amount 320 Compound A, lactose, corn starch and carboxymethylcellulose calcium were thoroughly mixed in accordance with the above formula,
Granulated using an aqueous methylcellulose solution, passed through a 24-mesh sieve, mixed with magnesium stearate, and pressed into tablets.

[0023]

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

Ingredient (g) Compound B 250 Microcrystalline cellulose (Japanese Pharmacopoeia) 30 Corn starch (Japanese Pharmacopoeia) 17 Talc (Japanese Pharmacopoeia) 2 Magnesium stearate (Japanese Pharmacopoeia) 1 Total amount 300 Each component was finely powdered according to the above-mentioned formula, thoroughly mixed so as to form a uniform mixture, and filled into a gelatin capsule for oral administration having a desired size to obtain a desired capsule.

[0025]

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

Component A (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 amount 1000 After compound A, corn starch, lactose, crystalline cellulose and calcium carboxymethylcellulose are mixed according to the above recipe, an aqueous solution of hydroxypropylcellulose is added to the mixture, kneaded, and granulated by an extrusion granulator. And 50 ℃
For 2 hours to obtain the desired granules.

Examples of pharmacological tests performed on the active ingredient of the drug of the present invention are described below.

[0028]

[Pharmacological test example] Non-insulin-dependent diabetic mouse "KK
-A ^y mouse "(male, 16-20 weeks old, 1 group = 6 animals)
, And the test compound was further fed at 100 mg / kg /
Orally for 7 days. Blood was collected from the tail vein on the 1st and 7th days after administration, and the glucose concentration in plasma was measured using Glucose C-II Test Wako (enzymatic method, Wako Pure Chemical Industries, Ltd.). In addition, the group of only free-feeding was set as the control group.

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

[0030]

[Table 1]

From Table 1, it can be seen that the group to which each of the above compounds (carboxylic acid amide derivative) was administered had a significantly lower plasma glucose concentration than the non-administered control group. It turns out that the agent has an excellent effect in treating diabetes.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-63-264421 (JP, A) JP-A-2-142732 (JP, A) JP-A-62-1776 (JP, A) JP-A-62-776 238286 (JP, A) JP-A-1-156965 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31/66 ADP C07F 9/40 CA (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula [Wherein R ¹ and R ² each represent a hydrogen atom, an alkyl group,
Cycloalkyl group, diphenyl lower alkyl group or group Is shown. In the group, R ⁵ , R ⁶ and R ⁷ each represent 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 represents a lower alkylene group, and l represents 0 or 1. R ¹ and R ² may form a heterocyclic group together with or without a nitrogen atom to which they are bonded via a nitrogen atom or an oxygen atom, and the heterocyclic group may be a lower alkyl group. Or 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 formula [1] as an active ingredient. 2. An active ingredient represented by the general formula: [Wherein 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 therapeutic agent for diabetes according to claim 1, which is selected from carboxylic acid amide derivatives represented by the following formula: