JPH06345641A - Immunosuppressing agent - Google Patents

Abstract

PURPOSE: To provide a medicine which consists of 5,6-dihydro-1,8-dihydroxy-3- methylbenz[a]anthracene-7,12-quinone, etc., as effective components, is free from side effects and is used for the treatment, etc., of the rejection reaction at the time of transplantation, the autoimmune diseases, etc. CONSTITUTION: The immunosuppressive agent which has the decreased side effects and is applicable to the treatment, etc., of the rejection reaction accompanying the organ transplantation, various kinds of the autoimmune diseases, etc., is obtd. by using the 5,6-dihydro-1,8-dihydroxy-3- methylbenz[a]anthracene-7,12-quinone (salt) expressed by formula I isolated from the cultured matter of Streptomyces rimosns or the 1,8-dihydroxy-3- methylbenz[a]anthracene-7,12-quinone (salt) expressed by formula II as the effective component, using this component alone or mixing the component with an excipient or carrier and subjecting the mixture to pharmaceutical manufacturing to the form of an injection, peroral drug, suppository, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an immunosuppressant. More specifically, the present invention relates to an immunosuppressive agent containing a low-molecular compound as an active ingredient, which can be applied to the therapeutic use such as rejection associated with organ transplantation or various autoimmune diseases.

[0002]

2. Description of the Related Art Recently, an immunosuppressive substance developed as a highly selective drug has an action of specifically regulating a subgroup of certain immune cells. This type of drug, cyclosporin A (Agents and Act)
ions, Vol. 6, pp. 468-475 (197)
Since 6)) selectively inhibits the proliferation of helper T cell clones, it has achieved remarkable results in the field of organ transplantation and is clinically widely used. However, the administration of this drug has a disadvantage that it sometimes causes side effects such as acute (or chronic) renal poisoning, mild tremor, nerve lesions, gingival thickening and hirsutism. Recently discovered FK-506
(Journal of Antibiotics, V
ol. 40, 1249 (1987)) is a macrolide antibiotic (C ₄₄ H ₆₉ NO ₂₂ ), and although favorable results were obtained as an immunosuppressive substance in the experimental stage, its production process is complicated, so clinical application May be restricted. On the other hand, the compound used as an active ingredient in the present invention is Streptomyces rimosus.
Has been reported to be a new type of benz [a] anthraquinone derivative isolated from the culture of Escherichia coli and can be obtained by synthesis [Journal of Chemi.
cal Society Perkin Trans
I, pp. 997-1000 (1976) and Jour.
nal ofOrganic Chemistry, V
ol. 31, pp. 2920-2925 (196
6)]. However, no report has been made on its physiological activity.

[0003]

The object of the present invention is to provide a new immunosuppressive drug which can overcome various drawbacks of the immunosuppressive drugs hitherto known.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies for the purpose of obtaining a new immunosuppressive agent capable of solving various drawbacks of conventional immunosuppressive substances. As a result, the above-mentioned Streptomyces rimosus The benz [a] anthraquinone derivative isolated from the culture exerts a strong inhibitory effect on the function of mouse lymphocytes, which are immunocompetent cells, and therefore these compounds become next-generation immunosuppressive agents with excellent properties. The inventors have completed the present invention by finding that there is a possibility of obtaining it.

That is, the present invention provides the following formula (1)

[Chemical 3] 5,6-dihydro-1,8-dihydroxy-3-methylbenz [a] anthracene-7,12-quinone (hereinafter referred to as compound (1)) or a pharmaceutically acceptable salt thereof, or a compound represented by the following formula: 2)

[Chemical 4] 1,8-dihydroxy-3-methylbenz [a] anthracene-7,12-quinone represented by
(2)) or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound (2) is Streptomyces
It can be isolated and purified from the culture of rimosus . Compounds (1) and (2) are both Journal
ofChemical Society Perki
n Trans I, pp. 997-1000 (197
It can be chemically synthesized by the method described in 6). Compound
Both (1) and (2) may be pharmaceutically acceptable salts thereof. Examples of these salts include alkali metal salts with sodium, potassium, lithium, etc., alkaline earth metal salts with calcium, magnesium, etc. These salts can be obtained by a method known per se.

When the compounds (1) and (2) are used as an immunosuppressive agent, they are administered alone or in admixture with an excipient or carrier as an injection, an oral preparation, a suppository or the like. As the excipient and the carrier, pharmaceutically acceptable and commonly used ones are selected, and their type and composition depend on the administration route and administration method. Compound in drug product (1)
The content of (2) and (2) varies depending on the type of preparation, but is usually 0.1 to 100% by weight, preferably 1 to 98%. For example, in the case of an injection, it is preferable that the active ingredient is usually contained in an amount of 0.1 to 30% by weight, preferably 1 to 10% by weight. For oral administration, tablets, capsules, along with a commonly used solid carrier or liquid carrier,
It is used in the form of powders, granules, liquids, dry syrups, etc. Generally, capsules, tablets, granules, powders, etc.
˜100% by weight, preferably 25-98% by weight, of the active ingredient. The dose of the compounds (1) and (2) is determined depending on the age, weight, symptoms, therapeutic purpose, etc. of the patient, but the therapeutically effective amount is generally 1 to 1 by parenteral administration.
100 mg / kg / day, 5 to 500 mg / k by oral administration
g · day. It is also possible to use the compounds (1) and (2) in combination, and when they are used in combination, the combined content and dose are the same as above. Compounds (1) and (2) are both relatively low in toxicity, and both compounds are characterized by low toxicity accumulation after continuous administration.

[0008]

[Function] Compounds (1) and (2) exert a strong inhibitory effect on the function of mouse lymphocytes, which are immunocompetent cells. That is, the method by Umezawa et al. (Umezawa e
tal. , "Supression of Tissue
e Graft Rejection by Sper
gualin ”, The Journal of Ant
ibiotics, Vol. 38, pp. 283-28
4,1985), the effects on the lymphocyte blastogenesis reaction were examined. Compounds (1) and (2) markedly suppressed the blast transformation reaction of T lymphocytes stimulated by ConA (concanavalin A). . The above results show that the compounds (1) and (2)
Significantly suppresses the function of T lymphocytes. Since this suppressive action means suppression of humoral immunity and cellular immunity, the compound (1) and
(2) is extremely useful. Compounds (1) and (2) are also extremely useful for the treatment of autoimmune diseases thought to be mainly caused by various autoimmunity, for example, lupus nephritis.

[0009]

EXAMPLES Next, the pharmacological actions of the compounds (1) and (2) of the present invention will be specifically described with reference to test examples. Further, the formulation of the present invention will be specifically described with reference to Examples. Test example T lymphocyte blastogenesis by concanavalin A (ConA)
Reaction suppression test C57BL16 mouse splenocytes were plated on a microplate.
Dispense into 10 ⁵ cells / 0.2 ml / well,
Each concentration of test compound was added to each well other than the control group,
Further, ConA was added to all the wells at 5 μg / ml, and this cell suspension was cultured at 37 ° C. in a 5% carbon dioxide incubator for 72 hours. For the lymphocyte blastogenic reaction, ³ H-thymidine was added at 1 μCi /
Wells were added, and the amount of incorporation into cultured cells was measured by a liquid scintillation counter. The uptake count when only ConA was added was Adpm, the count when ConA and the test compound were added was Bdpm, and (1-
The numerical value of (Bdpm / Adpm) × 100 was defined as the inhibition rate of each test compound against blastogenesis. The results are shown in Table 1.

[0010]

[Table 1] Inhibition of T lymphocyte blastogenesis by ConA Example Tablet Production Compound (1) or (2) 30 parts by weight, crystalline lactose 120 parts by weight, crystalline cellulose 147 parts by weight and magnesium stearate 3 parts by weight were tabletted using a V-type mixer to give 1 tablet 300 m.
g tablets were obtained.

[0011]

As is clear from the results shown in Table 1,
Compound (1) showed an inhibition rate of 45.7% against the lymphocyte blastogenic reaction at a concentration of 1 μg / ml. Compound (2) showed an inhibition rate of 87.6% at a concentration of 1 μg / ml.
Therefore, since the compounds (1) and (2) significantly suppress the function of T lymphocytes, they are extremely useful for suppressing rejection in organ transplantation and for treating autoimmune diseases.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Seiichi Saito 4-7-2-407 Matsuba-cho, Kashiwa-shi, Chiba Prefecture (72) Inventor Wang Nankin No. 1 Nishizato, Tendan, Beijing Xuanwu District, People's Republic of China

Claims (1)

[Claims] 1. The following formula (1): 5,6-dihydro-1,8-dihydroxy-3-methylbenz [a] anthracene-7,12-quinone or a pharmaceutically acceptable salt thereof, or the following formula:
(2) [Chemical 2] An immunosuppressant containing 1,8-dihydroxy-3-methylbenz [a] anthracene-7,12-quinone or a pharmaceutically acceptable salt thereof as an active ingredient.