JPH01168616A - Antiviral agent containing sugar lactam - Google Patents

Abstract

PURPOSE:To obtain an antiviral agent containing D-glucaro-delta-lactam or salt thereof as an active ingredient, having action significantly preventing virus infection, especially breakage and destruction of human T-lymphocytic cell infected by human immunodeficiency virus as well as low toxicity. CONSTITUTION:D-glucaro-delta-lactam expressed by the formula (R is H or 1-8C alkyl) or salt thereof (e.g., ammonium salt or alkali metal salt) or D-glucaro-delta- lactamalkyl ester is contained as active ingredient. Acquired immune deficiency syndrome(AIDS) is a disease which infects immune cell, especially helper T- lymphocyte by human immunodeficiency virus to cause immunodeficiency containing mainly cell immune and as a result, leads to death by opportunistic infection, malignant tumor, etc. A compound expressed by the formula is a sugar lactam derivative which is a chemically converted substance derived from natural substance and can be safely used in remedy for AIDS continuing to administer through life and can be also used together with other anti-AIDS remedy in addition to be used as a single agent.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention provides an antiviral agent containing sugar lactam derivatives Ri-glucaro-δ-lactam and D-glucaro-δ-lactam furkyl ester as active ingredients, particularly for use in the treatment of AIDS virus. The present invention relates to a prophylactic and therapeutic agent for retrovirus infections, including:

[Conventional technology and its problems]

Acquired immunodeficiency syndrome (AIDS) is a completely new disease for humankind, and in recent years, its epidemic has continued to expand on a global scale and has become a major social problem. According to a WHO report issued in March of this year, there were approximately 100,000 patients worldwide, and it is estimated that there are 5 to 10 million people infected with the virus (carriers).

AIDS is a human immunodeficiency virus belonging to a retrovirus7.
(human in++nunodeficiency
It is a fatal disease characterized by severe weakening of immune function caused by infection with Kaboji's sarcoma.

Opportunistic infections are Pneumocystis carinii, Protosia, and fungi.

A wide range of pathogenic microorganisms such as viruses and bacteria are responsible for the disease, and Kaposi's sarcoma, non-Hodgkin's lymphoma, and primary lymphoma are known to be associated with malignant tumors.

The AIDS virus (HIV) is highly mutable, and its infected target cells are protected against viral infection 8! T-lymphocytes (helper T-lymphocytes) are at the heart of the virus, and since they belong to retroviruses, their genes are integrated into the host cell genes. ``These diverse characteristics of the AIDS virus are deeply related to the difficulty of its treatment.

Research on the treatment of AIDS is being actively conducted all over the world.2 For example, the antiviral drug azidothymidine (^
ZT) has been clinically proven to have a life-prolonging effect on AIDS patients. However, serious side effects such as bone marrow disorders, anemia, and neurological symptoms such as headaches and convulsions are considered problematic in its use. Other attempts have been made to use immunostimulants, vaccine therapy, and treatments for concurrent opportunistic infections and malignant tumors, but none of these have led to a fundamental treatment for AIDS.

The compound of the present invention is different from conventional compound groups and is a glycolactam derivative which is a chemically converted product derived from a natural product, and has a significant effect on the destruction and killing of T-+7 lymphocytes of humans infected with the AIDS virus (Hm). It has the effect of inhibiting

One of the characteristics of the compound of the present invention is its low toxicity, and no particular side effects were observed in acute toxicity, sub-2, sexual toxicity, and chronic toxicity tests using mice and rats.

TECHNICAL FIELD The present invention relates to a therapeutic agent for acquired immunodeficiency syndrome (AIDS) containing as active ingredients a sugar lactam derivative, di-glucaro-delta-lactam or a salt thereof, and an ester derivative, and specifically provides these compounds. It is.

[Means for solving problems]

The present invention is expressed by formula (1) [In the formula, R is a hydrogen atom or a C1 to C8 linear or branched chain.

The present invention relates to an antiviral agent containing a D-glucaro-δ-lactam alkyl ester as an active ingredient, or a pharmacologically acceptable salt thereof.

The compound is known and is known as a β-glucuronidase inhibitor (Japanese Patent Publication No. 45-28375. Japanese Patent Publication No. 56-34590, J. Biochem, 72.207-21).
1.1972) and its evaluation as an anti-inflammatory agent (filed by the present inventors as Japanese Patent Application No. 1972-90899), but this time, this compound has been newly shown to be effective against viral infections.

Especially retroviral infections, especially human immunodeficiency virus (human immunodeficiency virus)
virus:IIIV) was found to be effective against infection.

D-glucaro-δ-lactam (formula Ia below)! ! Regarding the treatment method, the present inventors investigated the fermentation metabolite of actinomycetes, nojirimycin (5-7 minnow 5-deoxy D f ).
Hif / -X + Formula II) t(Tetrahe
drone.

23, 2] 25.1968) by chemical and enzymatic oxidation.

(ff) (Ia) That is, the chemical oxidation product of 7-jirimycin (II) was treated with glucose oxyglucose to obtain an oxidized product of the 1-position hydroxyl group (D-glutu δ-lactam), which was then subjected to a catalytic air oxidation reaction. It is synthesized by (Meiji Confectionery Research Annual Report, 13
．． 80-84. (Special Publication No. 45-28375).

D-glucaro-δ-lactam alkyl ester (Ib)
is m/-ol to D-glucaro-δ-lactam (Ia),
Obtained by reacting a halogenated furkyl or diazoalkane in tetrahydrofuran, dioxane, N,N-dimethylformamide, etc. or a mixed solvent thereof (Japanese Patent Publication No. 56-34589.56-34590)
Publication No.).

(Ia) (■b) (R' represents a C0 to C, linear or branched alkyl group) Examples of pharmacologically acceptable salts of the compound of the present invention include ammonium salts, alkali salts such as sodium, potassium, etc. Metal salts, alkaline earth metal salts such as magnesium and calcium, salts with organic bases such as triethylamine, triethanolamine, diethylaminoethylamine, piperidine,
piperazine.

Examples include salts with heterocyclic amines such as Morihorn, and salts with amino acids such as lysine.

This compound exhibits anti-inflammatory effects (e.g., carrageenan paw edema inhibition test) and strong β-glucuronidase 3
Because it has inhibitory activity, it is expected that it will be useful in the treatment of various diseases in which β-glucuronidase activity increases, such as bladder cancer, rheumatism, and diabetes. The present invention, which is effective against infection, was made based on an unexpected discovery for the inventor.

Acquired immunodeficiency syndrome (AIDS) is a disease in which the human immunodeficiency virus (HIV) infects immune cells, especially the helper's 928 bulb, causing immunodeficiency centered on cell-mediated immunity, resulting in opportunistic infections and malignant tumors. .

- It is a tragic disease in which almost 100% of patients die once the disease develops.

Azidothymidine (8ZT), which is currently used clinically, is ineffective against cells in which the old provirus has been integrated once infection has been established.

Therefore, the side effects of AZT on the bone marrow system, etc., have become an even more important issue because the administration of medication to HIV-infected individuals cannot be stopped in a short period of time and must be kept alive.

The compound D-glucan-δ-lactam of the present invention has low toxicity compared to its medicinal efficacy, and is a drug with an extremely high safe therapeutic index.Although it can be used as a single agent, it is also used in other drugs, including AZT, where side effects are a problem. Anti-AIDS drugs 1 e.g. 2,3
-Dideoxycytidine.

2.3-dideoxy7denine, interferon.

Combination use with interleukin-2 (■L-2) etc. is also effective.

The therapeutic and prophylactic routes of administration of the compounds of the present invention include oral administration, intravenous, subcutaneous, intradermal, intramuscular, and other injections, and parenteral administration using suppositories. In particular, ester derivatives are suitable for use in oral administration.

The dosage is 100-300011g per day for adults.
Administer once a day or in divided doses. However, the exact dosage will depend on the age and weight of the patient, symptoms, route of administration, and frequency of administration. The dosage form of the drug is a capsule or one tablet for oral administration.

Examples include granules, fine granules, and powders. These preparations contain starch, lactose, mannitol, ethyl cellulose, sodium carboxymethyl cellulose, etc. as excipients, and magnesium stearate or calcium stearate is added as a lubricant. As the binder, gelatin, gum arabic, cellulose ester, polyvinylpyrrolidone, etc. are used. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions or emulsions. Examples of the base for non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, glycerin, olive oil, corn oil, and ethyl oleate. Cocoa butter, macrogol, etc. can be used as a base for suppositories.

The compounds of the present invention have low toxicity, with an acute toxicity test of -1 LD in mice. D-glucaro-δ-lactam sodium salt has a toxicity of 3 g or more when administered intravenously and 58 or more when administered orally, and D-glucaro-δ-lactam methyl ester has a toxicity of 5 g or more when administered intravenously and 10 g or more when administered orally. Low data will be changed.

〔Effect of the invention〕

The antiviral (URV) therapeutic agent of the present invention is D-glucaro-
It contains δ-lactam and its ester as an active ingredient. Acquired immunodeficiency syndrome (AIDS) of the present invention
The in vitro anti-HIV activity values of the invented compounds are shown to demonstrate their usefulness as therapeutic agents for HIV. That is, human T-lymphocyte cells (hua+an T-1ym-photo) were placed on a microplate.
pic virus-old-2cell 1ine) was planted as a host, and cultured for 7 days with or without addition of HIV virus and with each graded concentration of the test compound. Thereafter, the number of remaining viable cells is determined using a chromogenic method (colorimetric method), and the number of viable cells is determined as 1. Table 1 shows the results measured using D-glucaro-δ-lactam calcium salt.

Table 1 IC5, Kimoto >2,5X102/jg/m
l tree: drug concentration that reduces the cell-killing effect by HIV virus by 50%.

Plants: drug concentration that inhibits the growth of normal non-infected cells by 50%.

〔Example〕

Reference examples and examples are shown below to further specifically explain the present invention.

Reference Example 1 9 g of nojirimycin (5-amino-5-deoxy-D-glucobylase) was dissolved in 3001 L1 of water.

Barium benzoate 30. After adding bromine 3*(1
drip. After reacting at room temperature for 30 hours, the precipitate formed after neutralization with 5N sulfuric acid was filtered off. After washing the filtrate with chloroform, silver carbonate 22. Add and stir.

The formed precipitate is filtered and the filtrate is transferred to Amberlite IR-1.
20 (H type 100zn) column. The filtered liquid and the washing liquid were combined and concentrated, and then crystallized from water-methanol to obtain D-
6.5 g of gluco-δ-lactam was obtained.

Reference Example 2 Dissolve 9 g of D-gluco and -lactam in 400 z1 of distilled water, add 3 g of hydrogenated platinum oxide, and stir at 60 to 65°C while maintaining the pH at 8 to 9 with 2N caustic sorg. React for 3.5 hours under oxygen bath.

The reaction solution was filtered to remove the catalyst, decolorized with charcoal powder, concentrated to dryness,
9.2 g of sodium salt of D-glucaro-δ-lactam was obtained.

Reference Example 3 1.89 D-glucaro-δ-lactam was added to a solution of 2011 N,N-methylformamide and 2COs2.5FI
Then, 3 g of ethyl iodide was added thereto, and the mixture was reacted at 50° C. with stirring for 10 hours. After the reaction, the insoluble portion was filtered off and concentrated, and the residue was extracted with 5011 warm ethanol, concentrated to about LOzl, and precipitated with ethyl ether to obtain 1.4 g of D-glucaro-δ-lactam ethyl ester.

Silica sol thin layer chromatography (chloroform-methanol 4:1): Rfo, 17 Example 1 Tablets were prepared consisting of the following li composition:

D-glucaro-δ-lactam potassium salt 100zy lactose
100 potato starch
75〃Polyvinylpyrrolidone
10〃Magnesium stearate 2.5〃D-
Glucaro-δ-lactam potassium salt, lactose and potato starch are mixed and this is mixed with polyvinylpyrrolidone.
It was evenly moistened with a 0% ethanol solution, passed through a 1 mm mesh sieve, dried at 45° C., and passed through a 1 mm mesh sieve. The granules thus obtained were mixed with magnesium stearate and compressed into one tablet.

Example 2 100 g of D-glucaro-δ-lactam sodium salt was dissolved in sterile, pyrogen-free 150 mM phosphate buffer, pH 7, and 5 mg of sodium pyrosulfite was added, and the solution was passed through a sterile microporous filter (0.22μ). .

The mixture was filtered into a sterile glass vial, replaced with nitrogen, and then sealed aseptically to prepare an injection (total volume: 20Rn).

Example 3 The following IflIij was filled into hard gelatin capsules to produce capsules.

D-glucaro-δ-lactam ethyl ester 200zy lactose
50〃CMC-Calcium
100 Magnesium stearate 3 Patent applicant Meiji Seika Co., Ltd.

Claims (4)

[Claims] (1) D-glucaro-δ-lactam or its pharmacological An antiviral agent containing D-glucaro-δ-lactam alkyl ester as an active ingredient. (2) The antiviral agent according to claim 1, wherein the virus is a human retrovirus infection. (3) Viral infection is human immunodeficiency virus (HIV)
The antiviral agent according to claim 1, which is an antiviral agent for infection. (4) The antiviral agent according to claim 1 for the treatment or prevention of acquired immunodeficiency syndrome (AIDS).