JPS58225014A - Preventive and remedy for disease caused by incompetence of immune function - Google Patents

Abstract

PURPOSE:The titled preventive and remedy useful as a preventive especially for infectious diseases, having actions on the normalization of the immune functions of men and animals and on the raise of infection resistance, suitable for long- term continuous administration, containing a specific polyprenyl ketone as an active ingredient. CONSTITUTION:A drug containing a polyprenyl ketone shown by the formula I (a and b are H or a-b forms a bond; n is 1-10), such as 6,10,14,18,22,26-hexamethyl-5,9,13,17,21,25-heptacosahexaen-2-one shown by the formula II, etc. as an active ingredient. The compound has extremely low toxicity, high safety, so that the use of the compound in combination with an antibiotic raises extremely remedying effect on infectious diseases. In case of men, the remedy is effective against infectious diseases such as rheumarthritis, autoimmune disease, cancer, asthma, ichorrhemia, pneumonia, cephalomeningitis, various kinds of virus infectious diseases, etc., and, in case of animals, against swine diarrhea, pneumonia, chicken pneumonia, Marek's disease, bovine diarrhea, pneumonia, mammitis, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to preventive/therapeutic agents for diseases caused by immune dysfunction, particularly to preventive agents I for infectious diseases. Let me explain in more detail.

Immunization of humans or animals using a polyprenyl ketone represented by the general formula (in the formula, a and b are hydrogen atoms or a-b form a bond; n means an integer of 1 to 10) as an active ingredient. The present invention relates to preventive/therapeutic agents for diseases caused by malfunction, particularly to preventive agents against infectious diseases in humans or animals.

In recent years, advances in immunology have been rapid, and various diseases are believed to be caused by immune dysfunction. For example, cancer, bacterial infections, asthma, rheumatoid arthritis, autoimmune diseases, and the like are listed as diseases caused by immune dysfunction.

BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND BACKGROUND OF THE INVENTION Bacterial infections are becoming a serious problem due to an increase in complex infections accompanied by various serious underlying diseases, in addition to simple infections caused solely by infiltration of pathogenic bacteria. For example, infectious diseases associated with cancer are a serious clinical problem. Systemic by bearing cancer.

This results in a localized decrease in resistance, leading to complications and subsequent infections in immunocompromised conditions. Infections associated with cancer often include respiratory tract infection, urinary tract infection, fetal canal infection, and skin infection in the early stages, and pneumonia 1 and sepsis are common in the late stages.

The primary mechanism of infection associated with this tumor is generally as follows.

In other words, as leukemia, malignant lymphoma, and cancer progress, they cause damage to normal tissues and cells, especially lymphoid cells and granulocyte cell function, which makes them susceptible to infection and is thought to cause infections. There is.

In such cases, the curative effect of antibiotic administration is poor and 1
For repeated infections, bacterial replacement, and intractable infections, it is almost impossible to expect a complete cure with drugs alone, and it is impossible to treat the disease without improving the body's defense function, so the development of drugs that enhance the body's defense function is desired. .

On the other hand, antibiotics play a central role in combating bacterial infections in animals such as livestock and poultry.

In fact, with the advent of various antibiotics, serious infections caused by pathogenic bacteria are decreasing. However, in the livestock industry, overuse of antibacterial agents has caused two social problems, including an increase in residual and resistant bacteria in livestock and marine products, and bacterial replacement. In other words, #the host's ability to defend against infection is significantly reduced and its repair function against infection is impaired, making it difficult to recover from bacterial infections (creating a condition that is susceptible to reinfection).Furthermore, spontaneous infections ( Opportunistic infections (opportunistic infections) reduce the productivity of livestock, resulting in large losses.Therefore, the immune system of the host is activated.

It is necessary to enhance the defense function of the living body.
4. .

In view of the above-mentioned circumstances, the present inventors have developed a drug that normalizes the immune function and enhances the defense function of the living body.

After many years of intensive research, it was unexpectedly possible to find a polyester represented by the following general formula (where a and b are hydrogen atoms or a-b form a bond; n means an integer from 1 to 10). The present invention has been completed based on the discovery that prenylketone compounds are effective as prophylactic and therapeutic agents for diseases caused by immune dysfunction 4R in humans and animals, particularly as preventive agents against infectious diseases in humans and animals.

In other words, the compound of the present invention has the effect of normalizing the immune function of humans and animals and increasing resistance to infection, and is therefore useful as a prophylactic/therapeutic agent for diseases caused by immune dysfunction in humans and animals, and as a preventive agent against various infectious diseases. It is.

A specific example in humans is rheumatoid arthritis.

autoimmune diseases, cancer, asthma, and sepsis for example.

It is effective against various infectious diseases such as pneumonia, 1iliitis, and various viral infections.

In addition, to give a specific example in the case of animals, for example, pig diarrhea,
uitis (SELF, AkL, Haemophilus, Bath')
y ) + T G b + chicken pneumonia (microplasma.

Haemophilus), Marek's disease, bovine diarrhea, pneumonia.

It is effective for mastitis, etc.

Furthermore, when the compounds of the present invention are administered to treat infectious diseases in humans and animals, their therapeutic effects are significantly enhanced when used in combination with antibiotics. This is of great significance because it also solves the aforementioned problem of overuse of antibiotics in the livestock industry.

Furthermore, in the case of animals such as livestock and poultry, it increases the organism's resistance to infection, so it is useful as a pace drug at the time of birth, and it is useful for alleviating stress caused by raising multiple birds and transporting them. To be.

and useful for enhancing vaccine efficacy.

Therefore, one object of the present invention is to provide a novel prophylactic/therapeutic agent for immune dysfunction in humans and animals.

A further object of the present invention is to provide a novel preventive agent against infectious diseases in humans and animals.

Typical polyprenyl ketone compounds in the present invention are listed below, but it goes without saying that the present invention is not limited to these.

0 6,10.14-)dimethyl-5,9,13-pentadecatrien-2-one0 6,10.14.18-tetramethyl-5,9,1
3゜17-nonazocatetraen-2-one 0 6, 10.14.18.22-pentamethyl-5,
9゜13, 17.21-) Licosapentaen-2-one 0 6, 10.14.18.26-hexamethyl-5
,9113,17,21,25-heptacosahexaen-2-one0 6,10.14.18.22.26.30-hebutamethyl-5,9,13,17,21,25,29-hentria Contahebutaen-2-one o 6.10.14.18.22.26.30.34
-octamethyl-5,9,13,17,21,25,2
9,33-pentatriacontaoctaen-2-one 0 6, 10. 14. 18.22.26.30.
34.38-nonamethyl-5,9,13,17,21,
25,29,33,37°-nonatriacontanonaen-2-one o 6.10.14.18.22.26.
30.34.38.42-decamethyl-5,9,13,
1? , 21.25.29.33゜37,41-) Litetracontadecaen-2-one 0.6.10-Dimethyl-5,9-undecadien-2-one 06-Methyl-5-hebutaene-2 -On o 6.1
0.14.18.22.26.30.34.38.42
-decamethyl tritetracontan-2-one 0 6, 1
0.14.18.22.26.30.34.38-/
-J-Methylnonatriacontan-2-one o 6.10.14.18.22.26.30.34
-octamethylpentatriacontan-2-one o 6.10.14.18.22.26.30-heptamethyl-hentriacontan-2-one 06, 10.14.18.22.26-hexamethylhebutacontan -2-one ('') 6.10.14.18.22-Pentamethyltricosapentan-2-one 0 6,10.14.18-Tetramethylnonadecane-
2-one 0 6,10.14-)rifthylpentadecane-2-one 06.10-dimethylundecane-2-one o 6-methylhebutan-2-one The compounds of the present invention can be synthesized by two different methods. but.

One of the common methods will be described below.

(I) (In the formula, a, b and n have the above-mentioned meanings, and X represents a halogen atom.) That is, prenylnolide represented by the general formula (III) and acetoacetic acid ethyl ester (lLI) are combined with a metal Condensation is carried out in the presence of a condensing agent such as sodium, metallic potassium, sodium ethylate, sodium biterade, etc., if necessary using a solvent of ethanol, t-butanol, dioxane, or bene/butane, and the resulting condensation product is In general, the target substance can be obtained without isolating it by treating it with an alkaline reagent such as a dilute caustic soda aqueous solution or a dilute caustic potassium aqueous solution to cause ester cleavage and decarboxylation.

Next, the effects of the compounds of the present invention will be explained in detail using experimental examples.

Experimental example (1) Experimental method slc: ICC male and female mice 6-7 weeks old 1 body weight 22-3
0y), the test compound described below was intramuscularly administered in the amount shown in the following table (Table 1), and 24 hours later, clinically derived E. coli (
Escherichia Co11) 2.8
10"/mouse was subcutaneously inoculated, and the survival rate was determined from the number of survivors 7 days after infection.

(2) Test compound 6, 10.14.18.22.26-hexamethyl-5
゜9, 13.17.21.25-Heptacosahexaen-2-one Compound B: 6, 10.14.18.22.26.30-Hebutamethylcontaheptaen-2-one Compound C: 6. 10-dimethyl-5,9-undecadien-2-one compound D: 6, 10.14.18.22.26.30.34.3
8.42-decamethyl-5,9,13,17,21,2
5,29°33,37.41-) Liptracontadecaen-2-one Compound E: 6.10-dimethylundecane-2-one
′□.

Compound F: 6, 10.14-trimethylpentadecane-2-one Compound G: 6, 10.14.18.22.26.30.34.3
8.42-Decamethyltritetracontan-2-one control compound: M1) P (Ac Mur -L -
Ala-1) -Qlu) (3) Experimental results The results are shown in Table 1.

Table 1 (1) Experimental method and results slc: ICR male mice (8 weeks old, 1 body weight 22
~:3Of), add 1007'l of the test compound described above.
The drug was administered intramuscularly to R/R/, and 24 hours later, a carbon clearance test was performed to measure the phagocytic ability of macrophages. Naori - Bon Clearance Test Ha, G.

BIOZZI, B, 13ENAclRAIi' AN
D B, N.

1-fALPERN, Brlt, J, exp,
It was carried out according to the method described in Path, 34.441-457.

The results are shown in Table 2.

In Table 2, the numerical values for changes in poor eating ability (96) are as follows.

The half-life time of the control is set as 100, and the percentage change is shown.

・1 In Table 2, if the ability to eat poorly is increasing.

Although the half-life time decreases, when it is 2096 or more, that is, the number is less than 80, it indicates strong promotion of poor eating ability. Therefore, it is clear that compounds A and B, which are representative compounds of the compounds of the present invention, have a very strong effect of promoting poor eating ability.

The above experimental examples revealed that the two compounds of the present invention normalize immune function and increase resistance to infection.

The compound of the present invention has extremely low toxicity.

The safety is very high, and therefore long-term continuous administration is possible, and in this sense, the value of the present invention is also high.

That is, SO rats (weight: 200 g) were given 5 doses of the aforementioned compounds (compounds A-G), which are representative compounds of the present invention.
00mf//kewo oral administration, death case.

No side effects were observed.

The compounds of the present invention can be used to prevent and treat diseases caused by immune dysfunction in humans.
The dosage when administered to patients as a therapeutic agent or preventive agent against human infectious diseases depends on the type of disease, severity of symptoms,
Although it varies greatly depending on the type of compound and is not particularly limited, approximately 1101u to 4,000μ, preferably 50q to 500"li' per day for adults is administered orally or parenterally.Administered as a preventive agent against infectious diseases. In such cases, it is of course permissible to use it in combination with antibiotics.The dosage forms include powders, fine granules, granules, one tablet, and capsules.

Examples include injections. When preparing a formulation, it is produced by a conventional method using a conventional pharmaceutical carrier.

That is, when preparing oral solid preparations, excipients are added to the crude drug, and if necessary, binders and disintegrants are added.

After adding a lubricant, a coloring agent, a flavoring agent, etc., the mixture is prepared into tablets, coated tablets, granules, powders, capsules, etc. by a conventional method.

Examples of excipients include 1, lactose, and 1 cornstarch.

White sugar, glucose, sorbitol, crystalline cellulose, etc.
Examples of binders include polyvinyl alcohol, polyvinyl ether, and ethyl cellulose.

Methylcellulose, gum arabic, tragacanth.

Gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc., and disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, etc. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. Coloring agents that are permitted to be added to pharmaceuticals include flavoring agents.

Cocoa powder, peppermint, aromatic acid, peppermint oil, cybernetic acid.

Cinnamon powder etc. are used. It goes without saying that these tablets and 1li1 granules may be coated with sugar coating, gelatin coating, or other coatings as appropriate.

When preparing injections, add pH adjusters, buffers, stabilizers, preservatives, solubilizers, etc. to the main drug as necessary, and prepare subcutaneous, intramuscular, or intravenous injections using conventional methods. .

When administering to animals such as livestock and poultry, the drug is administered orally or parenterally. Oral administration is usually done by adding it to feed. As an example of parenteral administration, an injection is prepared by a conventional method and administered subcutaneously, intramuscularly, intravenously, etc.

Next, 6,10゜14, which is a representative compound of the compounds of the present invention.
, 18.22.26-hexamethyl-5,9,13,1
An example of a formulation containing 7゜21.25-hebutacosahexaen-2-one (hereinafter referred to as the active ingredient) as an active ingredient is shown below.

Formulation example 1 (capsule) Main drug 5f!
Microcrystalline cellulose 809 corn starch 20 lactose sugar
22p total amount
130 f The above ingredients were granulated by a conventional method and then filled into 1,000 hard gelatin capsules. One capsule contains 5 parts of the main drug.

Formulation example 2 (powder) Main drug 50f
! Microcrystalline cellulose 400 f total
Amount 1.00Of! The main drug was added to acetone, and the mixture was adsorbed onto fine octopus cellulose, followed by drying. This is 1
1 and corn starch to prepare a crude drug Kabe-san as a powder using a conventional method.

Formulation example 3 (tablet) Crude drug 5
corn starch lof milk
Sugar 20 f carboxymethyl cellulose calcium
1 (HF microcrystalline cellulose 4 (1
Polyvinylpyrrolidone 5g
Ruri
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The main ingredient 1009 was dissolved in acetone and then adsorbed onto microcrystalline cellulose, followed by drying. Corn starch, lactose, and carboxymethyl cellulose calcium were mixed with this mixture, and in a second step, an aqueous solution of polyhinylpyrrolidone was added as a binder, and the mixture was granulated by a conventional method. After adding talc as a lubricant and mixing it, 1
The mixture was compressed into 100 square tablets. One tablet contains 5Tnf of the main calyx.
Contains.

Formulation example 4 (injection) Main drug 1 Oy
Nikkol HCO-60 (product name of B Hikari Chemical Co., Ltd.) 37 seeds oil
2f sodium chloride
9g propylene glycol 40y
Distilled water Total: it 1,0009 main ingredient, N1k
Mix kol HCO-60, sesame oil, and Hansha's propylene glycol, heat and dissolve at about 80°C, and add distilled water in which phosphate buffer, sodium chloride, and propylene glycol have been dissolved in advance and heat to about 80°C. and added to make an aqueous solution with a total amount of 1,000. 2nrl of this aqueous solution
After dispensing it into ampoules and sealing them, they were sterilized by heat.

Features 20 main drugs in 1 tube patent applicant Ko-zai Co., Ltd.

Claims (2)

[Claims] (1) A human or polyprenyl ketone represented by the general formula (wherein a and b are hydrogen atoms or a-b form a bond; n means an integer of 1 to 10) as an active ingredient. A preventive/therapeutic agent for diseases caused by immune dysfunction in animals. (2) A human or polyprenyl ketone represented by the general formula (wherein a and b are hydrogen atoms or a-b form a bond; n means an integer of 1 to 10) as an active ingredient. Preventive agent against infectious diseases in animals.