JP2714731B2 - Cachexia treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic agent for improving cachexia.

[0002]

2. Description of the Related Art Cachexia refers to a state of severe malnutrition or weakness due to a chronic disease. For example, cancer cachexia, infectious cachexia, thyroid cachexia and the like are generally well known. I have.

Among the cachexia, cancer cachexia has been reported to be one of the major causes of death of cancer patients along with respiratory failure, circulatory failure, gastrointestinal diseases, bleeding, systemic infection, etc. [ Cocchi U.,
Strahlentherapie, 69 , 503-520, (1941): Kunisuke Utsumi et al., Clinical Cancer, 7, 271-283 (1961), etc.]. In addition, the above-mentioned cancer cachexia is known to reduce the durability to chemotherapy and radiation therapy for cancer, and thus greatly hinder cancer treatment [Johanna T. Dwyer, Cancer, 43 , 2077-2086.
(1979): Sarah S. Donaldson et al., Cancer, 43 , 20
36-2052 (1979) etc.]. Therefore, attempts have been made to provide a high-fat diet or a high-carbohydrate diet, or to administer a high-calorie infusion to patients with terminal cancer in the past. However, it is not possible to obtain a sufficient effect, and there is no known effective means for improving cachexia.

[0004]

An object of the present invention is to provide a therapeutic agent for improving cachexia which cannot be solved by the prior art, in particular, a new agent capable of improving and treating cachexia of cancer.

[0005]

Means for Solving the Problems As a result of diligent studies, the present inventors have found that a specific carboxylic acid amide derivative represented by the following general formula (1) is suitable for cachexia, particularly for cancer, which meets the above-mentioned object. It has been found that a therapeutic effect of improving liquid quality can be obtained, and the present invention has been completed here.

That is, the present invention provides a compound represented by the general formula

[0007]

Embedded image [Wherein, R ¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group or a group

[0008]

Embedded image (Wherein 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, A represents a lower alkylene group). R ² is a group

[0009]

Embedded image (Wherein R ⁵ , R ⁶ and R ⁷ are as defined above). R ³ represents a hydrogen atom, an alkyl group or a phenyl lower alkyl group. R ⁴ represents a lower alkyl group. X represents an oxygen atom or a sulfur atom. ] The present invention relates to a therapeutic agent for improving cachexia, comprising a carboxylic acid amide derivative represented by the formula

Specific examples of the groups represented by the general formula (1) include the following groups.

Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
Undecyl and dodecyl groups can be exemplified.

Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The halogen atom includes a fluorine atom, a chlorine atom,
Bromine and iodine atoms are included.

The lower alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert
-Butoxy group and the like.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

As the lower alkyl group, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,
Examples include pentyl and hexyl groups.

Examples of the halogen-substituted lower alkyl group include trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl and the like.

Examples of the lower alkylene group include methylene, ethylene, methylmethylene, 1-methylethylene, trimethylene, 2-methylpropylene, and tetramethylene.

In the compound represented by the general formula (1),
Preferred examples of the active ingredient for treating and improving cachexia of the present invention include those in which both R ¹ and R ³ are hydrogen atoms. Among them, a compound having a halogen atom and a cyano group as substituents (R ⁵ , R ⁶ and R ⁷ ) in the substituted phenyl group represented by R ² is particularly preferable as the active ingredient compound.

The carboxylic acid amide derivative represented by the general formula (1) is a known compound previously developed by the present applicant [JP-A-61-151199;
No. 9393, JP-A-3-68592].

The therapeutic agent for improving cachexia of the present invention is required to contain at least one compound included in the above general formula (1) as an active ingredient. Utilizing the nontoxic pharmaceutical carrier to be used, it is prepared into various pharmaceutical forms depending on the administration method, applied to patients as a target therapeutic agent, and used as a preventive agent for such diseases. Here, the pharmaceutical carrier includes various diluents or solvents, fillers, extenders, binders, suspending agents, disintegrants, surfactants, lubricants, excipients, which are generally used depending on the form of the pharmaceutical preparation to be prepared. Excipients and wetting agents can be exemplified. In addition, the above-mentioned preparations may optionally contain, if necessary, commonly used solubilizers, buffers, preservatives, coloring agents, flavors, flavors and the like.

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 such as injections (subcutaneous, intravenous, intramuscular, intraperitoneal injections, etc.) and suppositories can be employed.
Of these, orally administered drugs are particularly preferred.

The above 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. Suppositories are prepared in a usual manner using, for example, polyethylene glycol, lanolin, coconut oil and the like.

The dose of the therapeutic agent for improving cachexia of the present invention can be arbitrarily determined according to the formulation, administration route, age, weight, sensitivity, degree of disease, etc., and is not particularly limited. However, the amount of the active ingredient usually contained in each of the preparation forms is suitably about 0.05 to 80 mg, preferably about 0.1 to 50 mg per kg of body weight per day. is there. Of course, a dose outside the above range can be employed as needed.

[0025]

EXAMPLES In order to explain the present invention in more detail, preparation examples (formulation examples) and pharmacological test examples of the therapeutic agent for improving cachexia of the present invention will be given below.

[0026]

Formulation Example 1 Preparation of tablet 4-diethoxyphosphinoylmethyl- as an active ingredient
Tablets (1000 tablets) containing 250 mg of N- (4-bromo-2-cyanophenyl) benzamide (hereinafter referred to as "Compound A") per tablet were prepared according to the following formulation. Compound A 250 g Lactose (Japanese Pharmacopoeia) 33.3 g Corn starch (Japanese Pharmacopoeia) 16.4 g Carboxymethylcellulose calcium (Japan Pharmacopoeia) 12.8 g Methylcellulose (Japanese Pharmacopoeia) 6.0 g Magnesium stearate (Japan) That is, the compound A, lactose, corn starch, and carboxymethylcellulose are sufficiently mixed according to the above-mentioned formulation, granulated using a methylcellulose aqueous solution, passed through a 24-mesh sieve, and treated with magnesium stearate. And pressed into tablets.

[0027]

[Formulation Example 2] Preparation of capsules 4-diethoxyphosphinoylmethyl- as an active ingredient
N- (2-chloro-4-cyanophenyl) benzamide (hereinafter, referred to as "compound B") is added at a rate of 250 per capsule.
Hard gelatin capsules containing 1000 mg (1000) were prepared according to the following formulation. Compound B 250 g Microcrystalline cellulose (Japanese Pharmacopoeia product) 30 g Corn starch (Japanese Pharmacopoeia product) 17 g Talc (Japanese Pharmacopoeia product) 2 g Magnesium stearate (Japan Pharmacopoeia product) 1 g Total amount 300 g That is, each component is finely powdered according to the above prescription. Then, the mixture was sufficiently mixed so as to form a uniform mixture, and filled in a gelatin capsule for oral administration having a desired size to obtain a desired capsule.

[0028]

[Formulation Example 3] Preparation of granule 4-diethoxyphosphinoylmethyl- as an active ingredient
A granule (1000 g) containing 500 mg / g of N- (2-bromo-4-cyanophenyl) benzamide (hereinafter referred to as "compound C") was prepared according to the following formulation. Compound C 500 g Corn starch (Japanese Pharmacopoeia) 250 g Lactose (Japanese Pharmacopoeia) 100 g Microcrystalline cellulose (Japanese Pharmacopoeia) 100 g Carboxymethylcellulose calcium (Japanese Pharmacopoeia) 40 g Hydroxypropylcellulose (Japanese Pharmacopoeia) 10 g Total 1000 g That is, after mixing the compound C, corn starch, lactose, crystalline cellulose and potassium carboxymethylcellulose according to the above formulation, an aqueous solution of hydroxypropylcellulose is added to the mixture, kneaded, and granulated by an extrusion granulator,
After drying at 50 ° C. for 2 hours, the target granules were obtained.

[0029]

[Pharmacological Test Example 1] 1 × 10 ⁶ cancer cells (Yoshida sarcoma) were intraperitoneally transplanted into 5 male 7-week-old male Dongryu rats per group, and at the same time, the active ingredient compound (Compound 100 mg / kg of A) was orally administered once a day (Compound A)
Administration group). In addition, as a control group, a group in which cancer cells were transplanted in the same manner as described above, but no compound A was administered (5 animals).
Was provided.

With respect to the rats in both groups, the body weight, the amount of food, the symptoms, etc. were observed over time, and the life-prolonging effect of Compound A administration was examined.

As a result, no difference was observed in the body weight and the amount of food between the control group and the compound A-administered group.
His condition, such as diarrhea, was clearly worse, and he died on the 9th day.
On the other hand, in the compound A administration group, the condition of hair color, behavior, etc. was good, and 4 animals survived on the 9th day and 3 animals survived on the 10th day. Table 1 shows the results of examining the above life extension effect.

[0032]

[Table 1]

Claims (4)

(57) [Claims] 1. A compound of the general formula Wherein R ¹ is a hydrogen atom, an alkyl group, a cycloalkyl group or a group (Wherein 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 or a carboxyl group; A represents a lower alkylene group). R ² is a group (Wherein R ⁵ , R ⁶ and R ⁷ are as defined above). R ³ represents a hydrogen atom, an alkyl group or a phenyl lower alkyl group. R ⁴ represents a lower alkyl group. X represents an oxygen atom or a sulfur atom. ] The cachexia improvement therapeutic agent which contains the carboxylic acid amide derivative represented by these as an active ingredient. 2. A compound of the general formula [Wherein, Y represents a halogen atom, and R ⁴ represents a lower alkyl group. The therapeutic agent for cachexia improvement according to claim 1, comprising a carboxylic acid amide derivative represented by the formula: as an active ingredient. 3. A compound of the general formula [Wherein, Y and R ⁴ are the same as described above. The therapeutic agent for cachexia improvement according to claim 2, comprising a carboxylic acid amide derivative represented by the following formula: as an active ingredient. 4. A compound of the general formula [Wherein, Y and R ⁴ are the same as described above. The therapeutic agent for cachexia improvement according to claim 2, comprising a carboxylic acid amide derivative represented by the following formula: as an active ingredient.