JPS6092216A - Antirheumatic agent - Google Patents

Abstract

PURPOSE:An antirheumatic agent containing a dithiol derivative. CONSTITUTION:An antirheumatic agent, containing a compound expressed by the formula (R<1> and R<2> are 1-5C alkyl) and an adrenocortical steroidal agent together, and administrable orally or parenterally to mammals including humans. The dosage form thereof is powder, granule, tablet, embrocation, sugar-coated tablet, pill, capsule, suppository, suspension, solution, emulsion, ampule, injection, aerosol and inhalant, etc. The compound expressed by the formula which is an active constituent is contained in an amount of 0.01-100wt% in the composition. The dose thereof is 0.1-500mg/kg/day, preferably 1-200mg/kg/day for oral administration and 0.01-250mg/kg/day, preferably 0.1-100mg/kg/day for parenteral use. In the case of a high dose, administration in several portions is preferred.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention contains a dithiol derivative represented by the general formula (■); The present invention relates to anti-rheumatic drugs.

The compound represented by the general formula (1) is
No. 506 and Japanese Patent Publication No. 56-18579, some of these compounds are already known as active ingredients in agricultural fungicides and liver disease therapeutics, but there is no knowledge that these compounds have antirheumatic effects. It has not been done.

Generally speaking, rheumatism is a disease that causes chronic pain in movement organs such as joints and muscles, and one representative example is rheumatoid arthritis, which is accompanied by swelling and pain in the joints and gradually becomes difficult to move.

As the disease progresses and gets old, it becomes unresponsive to various treatments and steroid therapy such as cortiscin is required, but while corticosteroids have a dramatic anti-inflammatory effect, It is known that the risks of typical side effects are also large (References, 1
) Sasaki et al., “Rheumatoid Pain” published by Ishiyaku Publishing ■, 2)
Sentama, “Rheumatology Story” published by Dobunshoin, 3) Okuda,
“Practical steroid therapy”).

Therefore, it would be very useful to reduce the amount of steroids and reduce the side effects caused by steroids by administering them in combination with non-steroidal drugs.

As a result of intensive research, the present inventors have found that the compound represented by the above general formula (1) has an excellent antirheumatic effect;
It was also discovered that the combination of the above-mentioned corticosteroid and the compound represented by the general formula (I) has an excellent anti-rheumatic effect, thereby completing the present invention.

Representative examples of the compound represented by the above general formula (I) are as follows.

Hereinafter, the numbers assigned to compounds in this specification correspond to the numbers assigned to the above-mentioned exemplified compounds.

The compound represented by the above general formula (1) has extremely low toxicity to warm-blooded animals, and as shown in the table below, the acute oral toxicity LDso value for mice (male) is generally 1D00 to 6,000.
omgr/Kg range or lower toxicity level.

Compound A LDso (rR9/ni9) 1 〉6000 2 4900 3 ) 6000 4 3120 5 ) 6000 6 4700 7 2700 8 5800 The compound represented by the general formula (I) has an antirheumatic effect and can be administered orally or parenterally. It is useful as a therapeutic and prophylactic agent for horses.

The antirheumatic agent of the present invention has the general formula (
Although the compound represented by 1) itself can be administered to mammals including humans as it is, it is generally administered in the form of various pharmaceutically acceptable formulations.

Examples of the dosage form of the pharmaceutical composition include powders, granules, tablets, liniments, sugar-coated tablets, pills, capsules, suppositories, suspensions,
Examples include liquids, emulsions, ampoules, injections, aerosols, and inhalants.

Those used in pharmaceutically acceptable pharmaceutical compositions include, for example, excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, and flavoring agents. agent,
Examples include flavoring agents, dyes, fragrances, preservatives, solubilizing agents, solvents, coating agents, sugar coating agents, etc., and these are appropriately selected depending on the type of formulation.

The antirheumatic agent of the present invention can be used as a sole therapeutic agent or mixed or used in combination with other antirheumatic agents or preparations containing other pharmacologically active substances, and these are within the scope of the present invention. .

In the present invention, since the compound represented by the above general formula can itself be an anti-rheumatic agent, the active ingredient is contained in the composition in an amount of 0.01-100% (by weight).

The antirheumatic agent of the present invention can be applied for the treatment of rheumatoid arthritis by conventional methods in this field. It is administered orally or parenterally. Oral administration includes sublingual administration. Parenteral administration includes administration by injection (including, for example, subcutaneous, intramuscular, intravenous, and infusion).

The dosage of the antirheumatic agent of the present invention is determined based on sensitivity differences, age, sex, body weight, administration method, administration timing, interval, medical condition, physical condition,
Although it varies depending on various factors such as the nature of the pharmaceutical preparation, the type of preparation, and the type of active ingredient, in the case of oral administration, the dosage per body weight per day is 0.1 to 500, preferably 1 to 200.
m9, if administered parenterally, body weight IKf 0.0 per day
Optimum doses are often selected within the range 1-250 mg, preferably 0.1-100 m9.

However, in some cases it may be sufficient to use less than the minimum dosages indicated above, and in some cases it may be necessary to administer doses in excess of the upper drug limits indicated above. In addition, in the case of large-dose administration, it is preferable to divide the administration into several times a day.

Next, it will be explained by test examples that the compound represented by the general formula (1) of the present invention has excellent pharmacological effects.

Experimental Examples Among experimental arthritis, adjuvant arthritis has a relatively chronic course and is recognized to involve late-onset allergies in its developmental mechanism.

Although there is no evidence that allergy is involved in the onset of rheumatoid arthritis, adjuvant arthritis is similar to human rheumatoid arthritis compared to other experimental inflammations in terms of the mechanism of onset, the affected area, and the course of inflammation. However, it is known to be an important model for studying the pathogenesis of rheumatoid arthritis (References, 1), Tsuda et al., "Evaluation of drug efficacy (1),"
Published by Chijinshokan, 2) Fukuda et al. "Preclinical evaluation method of drug activity", published by Yakuji Nipposha).

Aziband arthritis is a symptom that occurs after about 10 days when Freund's Complete Asband (killed tubercle bacterium) is injected into the hind limb vault of rats, accompanied by repeated floating moon chewing. It is also well known that

1. Test materials 1) Test animals Five-week-old and 10-week-old Wistar female rats (purchased from the Shizuoka Laboratory Animal Agricultural Cooperative Association) were acclimatized and then subjected to testing at 17-week and 12-week old, respectively. . In addition,
When withdrawing animals, the body weight for 17 weeks of age was adjusted to the literature value (180
The age of 12 weeks was determined based on the judgment that the animal had reached sufficient maturity and could be used for testing.

2) Test compound The compound of the present invention was added to an aqueous solution of 2-thia arabic gum at 5% (W/V).
) and tested.

As prednisolone, water-soluble Bredonin manufactured by Shionogi & Co., Ltd. was used. In addition, Freund's complete azyband (killed bacteria of Mycobacterium tuberculosis, hereinafter referred to as FCA) is DIFCOLABORATORIES.

A product manufactured by Detroit Michigan USA was used.

2 Test method 1) Test example 1. Single administration of test drug before readministration of FCAC.

FCA 0.05+++4 using 17 week withdrawal rats
/ Inject into the hind paw of a T4 rat.

The compound of the present invention and prednisolone were each administered daily at a rate of 6 days a week for 7 days after FCA administration and for 2 days after re-administration of FCAC, and on the 16th day, month, 8th day, and 22nd day after FCA administration. A constant volume (in terms of mercury weight) was measured by the mercury gravimetry method, and the edema rate was calculated according to the formula shown below.

The compound of the present invention is added to a 2% gum arabic aqueous solution at a concentration of 5% (W).
/V), 1.0ml/200 f
(25 amp/Kp as the active ingredient of the compound of the present invention)
) was administered orally.

Prednisolone: 0.04 m7 of 1% (W/V) aqueous solution
/201 (2FV/Kf as prednisolone) was administered intramuscularly.

2) Test example 2. After FCA administration, the compound of the present invention and prednisolone are administered together.

Using 12-week-old rats, the compound of the present invention (2509/Kr as the active ingredient, oral administration) and prednisolone (prednisolone, 2/7 days, intramuscular injection) were administered in combination with the FCA injection port on days 15 to 21. A constant volume was measured on day one. The method for adjusting the compound of the present invention and prednisolone and calculating the edema rate is the same as in 1) above.

Test results 1) Results of test example t (effect of the compound of the present invention on edema on days 16, 18, and 22 after administration of FCA).

Umbrella P (0,05, ** P<0.001 VS: 7 ml group 2) Test example 2 (After re-administration of FCAC, 17,
Compound of the present invention and prednisolone against edema on day 19.2j
Discussion The above results showed that the compound of the present invention is effective for adjuvant arthritis.

Since adjuvant arthritis is an important model for human rheumatoid arthritis compared to other experimental inflammations, compounds of the present invention that are effective against adjuvant arthritis are useful as therapeutic agents for human rheumatoid arthritis, particularly rheumatoid arthritis.

Furthermore, the above results indicate that the combined use of prednisolone, a corticosteroid, and the compound of the present invention has an excellent therapeutic effect on adjuvant arthritis.

Therefore, by co-administering the compound of the present invention, the amount of certain steroids can be reduced, and the side effects caused by steroids can be alleviated.

The compositions of formulation examples are illustrated below.

Powder formulation A Formulation B Compound A2 10 orn9911Q Prednisolone 0-9m9 Light anhydrous silicic acid 2orn92oIn9 Precipitated calcium carbonate 101n9107719 Lactose 300■3oo
m9 total 500 soom9 Tablet formulation A formulation B Compound 44 1007Q 90a7 Prednisolone 0 da 10 ■ Crystalline cellulose 50 rv 5 o da Lactose 5 o ■ 50 ■ Hydroxypropyl cellulose 18ri18rn9 Magnesium stearate 2 mp 2 mg total 220 da
The 220 dab tablets may be coated with a conventional film or sugar coated.

Capsule compound A5 200 ■ Light silicic anhydride 25 da Lactose 100 ~ Starch 50 Instant talc 25 m9 Total 400 ■ Granule compound 72001 n9 Lactose 500 Fn9 Cornstarch 190 m9 Carboxymethyl cellulose sodium salt 10 Fn
9 hydroxypropyl cellulose 1oo+y total 1,
000■ Suppository compound 7 100m9 Macrogol 400 250rn9 y 1540 250rv #4000 400■ Total 1,000m9 Syrup compound 1 100~ Light silicic anhydride 10■ Avicel RC-59189■ Bruronic F-681m9 Total 200m9 Injectable compound 5 10 ■ Nitsukor HC06080η Propylene glycol 60m9 Egg yolk lecithin 3m9 Sorbitan triolate 51 Tadextrose 50m9 Patent applicant Nippon Nohyaku Co., Ltd. Agent Yumi Kali (and one other person) Procedural amendment” Dec. 29, 1980 Commissioner of the Japan Patent Office → ← Scream Nagadono 9 (1. Indication of the incident 1982 Patent Application No. 199529 2)
, Title of the invention: Anti-rheumatic drug 3. Relationship with the person making the amendment: Patent applicant (and 1 other person) 5. Date of amendment order 2. “Voluntary” 6. Subject of the amendment 7. Contents of the amendment (1) Full text of the specification amended as shown in the attached document (the specification has been typewritten, there is no change in the content).

(2) Submit a power of attorney.

Claims (2)

[Claims] (1) An antirheumatic agent containing a dithiol derivative represented by the general formula (I); 1 1 (wherein R1 and V are the same or different alkyl groups having 1 to 5 carbon atoms). (2) Contains a dithiol derivative represented by the general formula (I); 1 1 (wherein R1 and R2 are the same or different alkyl groups having 1 to 5 carbon atoms) and a corticosteroid compound An anti-rheumatic drug.