WO1994028893A1 - Remedy for systemic autoimmune disease or inflammatory nervous disease - Google Patents

Abstract

A remedy for systemic autoimmune diseases or inflammatory nervous diseases, containing a mycophenolic acid derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient and being excellent in the drug activity against the above diseases and safety.

Description

 Description Remedy for systemic autoimmune disease or inflammatory neurological disease

 The present invention relates to a therapeutic agent for systemic autoimmune diseases such as rheumatism, lupus erythematosus, systemic sclerosis, Behcet's disease, and other inflammatory neurological diseases such as multiple sclerosis. Background of the Invention

 The substance itself of a mycophenolic acid derivative represented by the following formula (I) (hereinafter, abbreviated as a mycophenolic acid derivative Z or CAM) has already been disclosed in JP-A-48-237756. Are shown and are known. On the other hand, regarding the pharmaceutical use of this compound, its effect as an anticancer agent has been known. A wide range of compounds including mycophenolic acid derivative Z (CAM) are disclosed in U.S. Pat. No. 4,959,387, and these compounds are useful for anti-inflammatory, anti-tumor, anti-viral, It is described that it can be used for therapeutic agents such as anti-dryness and rheumatism. Also, US Patent No. 4,727,069 discloses a similar pharmaceutical use as a similar mycophenolenoic acid derivative. However, although the above-mentioned U.S. Patent Publication states that the compound can be used as a therapeutic drug for anti-inflammatory, anti-tumor, anti-viral, anti-dry, and rheumatic, etc., experimental data showing specific effects are not disclosed. Not disclosed. Also, these US patents do not specifically disclose mycophenolic acid derivative Z (CAM).

 On the other hand, Japanese Patent Application Laid-Open No. 57-187377 discloses a method for producing mycophenolic acid derivative Z (CAM). Although there is a description in the upper left column on page 2 of the publication that the compound has “cancer action, immunosuppressive action, central nervous action, insecticide, bactericidal or antiviral action” as a pharmaceutical use of the compound, There was no specific description that indicates that there was no disclosure, and there was no disclosure on Experiment Day.

As described above, although there is a description that mycophenolic acid derivative Z (CAM) has an immunosuppressive effect such as anti-inflammatory and anti-dryness, its effect is specifically disclosed and its efficacy is described. It has never been demonstrated that it is effective as a therapeutic agent for systemic autoimmune diseases or an inflammatory neurological disease. Considering that it has been conventionally developed as a carcinostatic agent for pharmaceutical use only and it is desirable that the immunosuppressive effect is rather low as a carcinostatic agent, the mycophenolic acid derivative Z (CAM) is a systemic autoantigen. It is by no means easy to assume that it is effective as a therapeutic agent for immune diseases.

 On the other hand, U.S. Pat. No. 4,786,637 describes that mycophenolic acid derivatives having a morpholinoethyl group at the end can be used as an inhibitor of rejection and a therapeutic agent for rheumatism. However, the mycophenolic acid derivative Z (CAM) itself is not described. Disclosure of the invention

 An object of the present invention is to provide a therapeutic agent for a systemic autoimmune disease or an inflammatory neurological disease and a method for treating these.

 The present inventors have conducted intensive studies and found that the mycophenolic acid derivative Z (CAM) represented by the following formula (I) has excellent effects and safety for the treatment of systemic autoimmune diseases and inflammatory neurological diseases. The present invention has been completed. That is, the present invention provides a therapeutic agent for a systemic autoimmune disease or an inflammatory neurological disease, comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient: provide.

〇〇H

(I)

C ₂ H ^ OOC BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 shows the daily change of the erythrocyte sedimentation rate when the mycophenolic acid derivative Z (CAM) represented by the formula (I) or the comparative compound was administered.

 FIG. 2 shows the change in body weight of a test rat when the mycophenolic acid derivative Z (CAM) represented by the formula (I) or the comparative compound was administered.

 FIG. 3 shows the daily change in the arthritis score of a sample rat when the mycophenolic acid derivative Z (CAM) represented by the formula (I) or the comparative compound was administered. BEST MODE FOR CARRYING OUT THE INVENTION

 When the mycophenolic acid derivative Z (CAM) represented by the formula (I) is used as a therapeutic agent for systemic autoimmune diseases or inflammatory neurological diseases, intravenous administration, alone or in a mixture with an appropriate pharmaceutical carrier, orally Administration, transdermal administration. Formulations include injections, tablets, granules, fine granules, powders, capsules, creams, suppositories and the like. Pharmaceutical carriers include, for example, lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium salt , Magnesium stearate, talc, acetyl cellulose, sucrose, titanium oxide, benzoic acid, paraoxybenzoic acid ester, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactant, sucrose, monosaccharide, queen Acid, distilled water, ethanol, glycerin, propylene glycol, macrogol, sodium monohydrogen phosphate, glucose, sodium chloride, Hainaut Honoré, thimerosal, Paraokishi benzoic acid ester, Ri sodium hydrogen sulfite there, depending on the form of the preparation, is used in combination with the present compounds.

The pharmaceutically acceptable salts of the mycophenolenic acid derivative Z (CAM) used in the present invention include sodium salt, potassium salt, calcium salt, magnesium salt, ruminium salt, iron salt, phosphate, sulfonate, Hydrochloride, lysine salt, ordinine salt and the like are preferably used. An example of the production of the mycophenolate derivative Z (CAM) will be described. First, mycophenolate ethyl ester and p- ^ r socyanato-benzoyl chloride are prepared in the presence of an organic amine having no active hydrogen in the molecule. After the reaction, the hydroxyl group of the mycophenolate ester was converted to a 0 (0) CNHPhCOCl group (where Ph is a phenyl group) to form a compound, which was then converted to a hydroxyl group such as water or alcohol. It can be produced by treating with a contained compound.

 Mycophenolic acid derivative Z (CAM) is used for systemic autoimmune diseases such as rheumatism, lupus erythematosus, Behcet's disease and lupus nephritis, especially rheumatoid arthritis, patients with systemic lupus erythematosus and beetet's disease, and inflammatory neurological diseases, especially It can be administered orally, intravenously, transdermally, etc. to patients with sclerosis in an amount of 0.1 to 10 OmgZKg. Of these, oral administration is preferred. Next, the present invention will be described with reference to examples.

Example 1

 The therapeutic effect of mycophenolic acid derivative Z (CAM) on rheumatoid arthritis is disclosed in U.S. Pat. No. 4,786,637 and its use is being developed. X was compared with the following method.

Eight-week-old male Lewis rats (Nippon Charlriva Co., Ltd.) were bred in a pathogen free (SPF) environment and subjected to experiments at 9-10 weeks. Liquid paraffin (Me rck, Ra hwa y) containing 6 mg / ml of Mycobac teri umbutyr ic um was produced as a cause of adjuvant arthritis. 0.1 ml of adjuvant band (CFA) was inoculated into the left foot and foot of the rat. Each sample was suspended in 0.5% cmc and orally administered continuously from the day of inoculation with Ajunon (day; day 0) until day 21. The dose for each sample was 1.10 mg / kg of mycopentanoleic acid derivative Z (CAM) used in the present invention. Cophenolic acid compound X was 10 mg / kg and indomethacin 1 mgZkg. Fig. 1 shows the daily changes in erythrocyte sedimentation rate, Fig. 3 shows the results of daily arthritis scores, and Fig. 2 shows the changes in body weight.

 Erythrocyte sedimentation rate (ESR): Blood is collected from the fundus vein on both days 17 and 27, placed in a capillary tube (VC—C110P, manufactured by Terumo Corporation) together with an anticoagulant, and ESR (2-hour value) ) Was measured.

 Arthritis score: On the day (0 day), 3 days, 6 days, 10 days, 14 days, 17 days, 21 days, and 27 days after vaccination, extremities and tail excluding limbs inoculated with rat adjuvant On the basis of ear redness and swelling, a score of 0 to 5 was given for one location, and the total score was used as an arthritis score.

 The mycophenolic acid derivative Z (CAM) used in the present invention shows that the arthritic score in oral administration is lower than that of the mycophenolic acid compound X represented by the formula (Π) which is already known and the control group. As shown in Fig. 3, the value was generally less than half the value, indicating a very good therapeutic effect. This is as effective as the drug indomethacin.

 Figures 1 and 2 show the changes in erythrocyte sedimentation rate and weight gain in rats during the drug administration period. The erythrocyte sedimentation rate is slower than that of the normal rat, but almost the same as that of indomethacin. Yes, indicating a strong therapeutic effect. On the other hand, body weight was increasing steadily over the days, which was comparable to normal rats. Moreover, the rats in the control group and the rats to which the mycophenolic acid compound X represented by the formula (Π) and indomethacin were administered did not gain weight, which was a good control result. From these results, it can be said that the mycophenolic acid derivative Z (CAM) used in the present invention is safe with minimal adverse effects on individuals due to the drug.

Example 2

 The effect of CAM on multiple scleroderma was compared with the effect of compound X using an experimental allergic encephalo-meningitis (EAE) model.

A Lewis rat (female, 8-9 weeks old) is inoculated with guinea pig spinal cord homogenate together with complete Freund's adjuvant, and given CAM, Compound X or CMC (control) daily for 21 days from the day of inoculation. Oral administration. EAE onset can be used to monitor animal behavior More confirmed. Table 1 shows the number of affected individuals up to 20 days after the antigen inoculation.

 table 1

 Number of individuals affected by EAE by day 20 (n = 5)

CAM 10 mg / kg 3/5

 3 0 mgZkg 1/5

 50 mg / kg 0/5 Compound X 50 mg / kg 2/5

CMC (control) 5/5 Example 3

 The effects of CAM on Beutt's disease were compared to Compound X using an experimental autoimmune uveitis retinitis (EAU) model.

 Lewis rats were inoculated in the foot with complete Freund's adjuvant extracted with the photoreceptor-binding protein extracted from the retina of the mouse and CAM, Compound X, or CMC (control) was orally administered daily for 14 days from the day of inoculation. Was administered. EAU development was confirmed by anterior eye findings in the animals. Table 2 shows the number of affected individuals up to 12 days after inoculation.

 Table 2

 1 2 Number of individuals affected by EAU up to the point (n = 5)

CAM 30 mg / kg 1/5

 50 mg / k 0/5 Compound X 50 mg / kg 2/5

CMC (control) 5/5 Example 4

 The effects of CAM on systemic lupus erythematosus and Rubus nephritis were compared to Compound X using MRL Z1 mice. MRLZ1 mice spontaneously develop systemic lupus erythematosus and lupus nephritis due to them from about 8 weeks of age.

 MRL / 1 mice were orally administered daily with CAM, Compound X or CMC (control) from the age of 5 weeks, and the preventive effects on the development of nephritis were examined. The onset of nephritis was confirmed by measuring the amount of protein in urine. Table 3 shows the urinary protein levels of mice at the age of 10 weeks.

 Table 3

 Urinary protein content of 10-week-old mice (n = 8)

 MRLZ1 mouse

CAM 50 mg / kg 34 Omg / dl Compound X 50 mg / kg 4 7 9 mg / dl

CMC (control) 5 9 2mg / dl

Claims

The scope of the claims 1. An agent for treating a systemic autoimmune disease, comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The therapeutic agent for systemic autoimmune disease according to claim 1, which comprises a pharmaceutically acceptable carrier.  3. The pharmaceutically acceptable salt is a sodium, potassium, calcium, magnesium, aluminum, iron, besylate, sulfonate, hydrochloride, lysine, or orutin salt. 2. The therapeutic agent for a systemic autoimmune disease according to claim 1.  4. The therapeutic agent for systemic autoimmune disease according to claim 1, which is in an oral administration form.  5. The therapeutic agent for systemic autoimmune disease according to claim 1, wherein the systemic autoimmune disease is rheumatism. 6. A therapeutic agent for systemic autoimmune disease containing a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is administered to a patient with systemic autoimmune disease. A method for treating a systemic autoimmune disease comprising administering.

C ₂ H _K OOC (I) CH ₃₀ 7. The therapeutic method according to claim 6, wherein the therapeutic agent for systemic autoimmune disease is orally administered.  8. The pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, an aluminum salt, an iron salt, a potassium salt, a sulfonate, a hydrochloride, a lysine salt or an ornithine salt. 6. The treatment method according to 6.  9. The treatment method according to claim 6, wherein the systemic autoimmune disease is rheumatism.  10. Use of a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for systemic autoimmune disease.

11. The use according to claim 10, wherein the therapeutic agent for systemic autoimmune disease is in an oral administration form.  12. The pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, iron salt, phosphate, sulfonate, hydrochloride, lysine salt or ornithine salt. Use as described in 0.  13. A therapeutic agent for inflammatory neurological diseases, comprising as an active ingredient a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. 〇〇H (I) C ₂ HcOOC CH3O 14. The therapeutic agent for an inflammatory neurological disease according to claim 13, which comprises a pharmaceutically acceptable carrier.  15. Pharmaceutically acceptable salt, sodium, potassium, calcium, magnesium, aluminum, iron, phosphate, sulfonate, hydrochloride, lysine, or orutin salt 14. The therapeutic agent for an inflammatory neurological disease according to claim 13.  16. The therapeutic agent for inflammatory neurological disease according to claim 13, which is in an oral administration form.  17. Administering a therapeutic agent for inflammatory neurological disease containing a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier to a patient with inflammatory neurological disease: A method for treating an inflammatory neurological disease. (I)

 18. The method according to claim 17, wherein the therapeutic agent for inflammatory neurological disease is orally administered.  19. Pharmaceutically acceptable salt strength: sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, iron salt, phosphate, sulfonate, hydrochloride, lysine salt or ornithine salt. 17. The treatment method according to 17.