WO1992004894A1 - Antirheumatic - Google Patents

Antirheumatic Download PDF

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Publication number
WO1992004894A1
WO1992004894A1 PCT/JP1991/001207 JP9101207W WO9204894A1 WO 1992004894 A1 WO1992004894 A1 WO 1992004894A1 JP 9101207 W JP9101207 W JP 9101207W WO 9204894 A1 WO9204894 A1 WO 9204894A1
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Prior art keywords
compound
sat
ethyl
pharmaceutically acceptable
benzyl
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PCT/JP1991/001207
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French (fr)
Japanese (ja)
Inventor
Katsumi Asano
Taketoshi Komori
Hiromi Hanai
Mikio Hori
Hideo Nagae
Original Assignee
Meito Sangyo Kabushiki Kaisha
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Publication of WO1992004894A1 publication Critical patent/WO1992004894A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to an antirheumatic agent
  • non-steroid anti-inflammatory drugs have been regarded as the first-line drugs for rheumatoid arthritis, but they have anti-inflammatory effects by the mechanism of action that inhibits prostaglandin biosynthesis, and are used to treat rheumatoid arthritis. Is a symptomatic treatment and does not change the course of the disease.
  • DMARDs include gold preparations, D-penicillamine, bucillamine, oral benzalit, methotrexate, etc., which are widely used in clinical practice, but these drugs have reduced efficacy over long periods of administration. Or the efficacy or side effects They were not always satisfactory.
  • JP-A-58-140655 discloses the following formula:
  • R represents a lower alkyl group and n is 1 or 2.
  • the compound in which R represents an ethyl group and n is 1 that is, the compound of the above formula (I) has an excellent antirheumatic effect, and is useful for treating rheumatic diseases. They have found that they are useful as therapeutic agents and have completed the present invention.
  • the present invention uses the formula
  • the compounds of formula (I) have at least two asymmetric carbon atoms and can exist in optically active forms (diastereomers) or in mixtures thereof.
  • the compound of formula (I) may be used in the form of a pharmaceutically acceptable salt.
  • Such salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metals such as magnesium salts and calcium salts; ammonium salts; triethanolamine Amin salts such as salts are mentioned.
  • alkali metal salts such as sodium salts and potassium salts
  • alkaline earth metals such as magnesium salts and calcium salts
  • ammonium salts such as magnesium salts and calcium salts
  • triethanolamine Amin salts such as salts are mentioned.
  • Anti-SRBC-PFC reaction test (in vivo) The test compound is suspended in physiological saline, and the pH is adjusted to 7.0 by adding IN NaOH solution. And adjusted to a test solution.
  • the experiment was performed using 5-week-old ddY mice and using 5 animals per group. During the experiment, animals were kept in a breeding room at a temperature of 23 ⁇ 2 ° C and a relative humidity of 55 ⁇ 5%, and were allowed free access to feed and water. 5'x10 8 cells were injected into the tail vein using immunized red blood cells (SRBC) as an antigen and immunized. The spleen was removed on the 4th day, and hemolytic plaque forming cells (HPFC) in splenocytes were used as SRBC antigen Cells) were counted.
  • SRBC immunized red blood cells
  • 0.25 ml of a single cell suspension of spleen was added to 1.75 ml of Eagle MEM medium, and 0.25 ml of a 35% suspension of SRBC as an antigen and 0.25 ml of guinea pig serum diluted twice with MEM as complement were added.
  • Mix well put 50/1 each in a commercially available Cunninghamchamber, seal both ends with paraffin, and heat for 45 minutes in a CO2 incubator with a temperature of 37 ° C and a CO2 concentration of 5%. After culturing, the number of hemolysis spots was counted to determine the number of HPFC.
  • test solution was intraperitoneally administered once for four days from the day of immunization.
  • the dose was set to be 2 OmgZkgZday (0.134 mmol / kg / day) for D-penicillamine (compound ⁇ ⁇ ⁇ ), which was a comparative drug, and to be equal to this molar ratio.
  • Table 1 shows the number of HPFC in the spleen.
  • N 5, *: P 0.01 0.01, average soil S. D.
  • the active ingredient compound of the present invention acts suppressively on antibody production.
  • SRBC red blood cells
  • a spleen cell suspension was prepared from BALB c mice according to a modified method of Mishell-Dutton [Mishell, RI and Dutton, Rf: Science 153, 1004 (1966)]. Splenocytes were mixed with SRBC and specimen, 37 ° C, C0 2 4 days after culture in an incubator, hemolysis plaque forming cells (HPFC) The number was measured. The results are shown in Table 2. Table 2: Number of HPFC (hemolytic plaque forming cells)
  • the test wave was orally administered once daily for 21 days from the day of adjuvant treatment.
  • the dose was 1 OmgZkgZday (0.067 mmol / kg / day) for Compound A, which was a comparative control drug, and the molar ratio was equal to this.
  • the volume of the administered solution was 1 ml per 100 g of body weight, and the concentration of the test solution was adjusted.
  • the volume of glare after non-treatment was measured on the 22nd day after adjuvant treatment, and the swelling ratio with respect to the volume immediately before adjuvant treatment was determined by the following formula.
  • the results are shown in Table 3.
  • the degree of inflammation of both forelimbs, untreated hindlimbs and tail was evaluated according to the method of Koga et al. (J. I Maraudal unol., Vol. Ill, 599-608 (1973)). The score was divided into five grades from 0 to 4 points, and a total of 16 points was scored as the highest.
  • Table 3 The results are shown in Table 3.
  • V n is the volume of the hind limb on day 22
  • N 5, * is P ⁇ 0.05, average soil S.D., As a control, only physiological saline was administered.
  • the active ingredient compound of the present invention suppressed paw edema and inflammation due to adjuvant arthritis, and had a stronger inhibitory action than Compound A.
  • Adjuvant arthritis test (Therapeutic effect) As an adjuvant, Mycobacterium 'Bocberg erium tuberculosis (0.6 mg / rat) was administered intradermally to the ridge of rat (SD). Oral administration of 1, 10, 100, and 30 OmgZkg of compound 1 and 1 OmgZkg of compound B for 12 days from the 17th day of adjuvant treatment (final administration: after treatment 28) to evaluate the therapeutic effect after adjuvant arthritis onset did. The results are shown in Table 4. Compound 1 significantly inhibited paw edema due to adjuvant arthritis at a dose of 1 Omg / kg. Compound 1 had a stronger inhibitory effect than compound B. Table 4: Therapeutic effect of the compound of the present invention on hind limb swelling due to adjuvant arthritis Dose Hind limb swelling rate (%)
  • Ty pen collagen (CD) is dissolved in a 0.01 M acetic acid aqueous solution, mixed with Incomplete Freund's Adjuvant, and administered to four places in the shaved back skin of rats (SD strain) ( After 7 days, the same Cn mixed solution was additionally administered intradermally to the ridge (0.2 mg / rat). 1, 2, 10, 100, and 300 mg Zkg of Compound 2 and 10 mg / kg of Compound C were orally administered for 7 consecutive days from 7 days before the first immunization to the day before the immunization. The results are shown in Tables 5 and 6.
  • Paw edema Compound 1 showed a low paw edema rate at doses of 1 to 300 mg / kg, and showed almost the same level of suppression as Compound B in the 10 and 10 OmgZkg groups.
  • Table 5 Effect of the compound of the present invention on hind limb swelling of collagen arthritis Dose Edema rate (%)
  • MRLZ1 mice spontaneously develop arthritis similar to rheumatoid arthritis, and produce rheumatoid factor (RF), production of antinuclear antibodies, glomerulonephritis due to immune complexes, and the like.
  • RF rheumatoid factor
  • 5 mg / kg of Compound 2 and Compound C were orally administered continuously from the age of 8 weeks to the age of 20 weeks in MRL / 1 mice, and the effect on disease onset was examined.
  • Table 7 shows the results.
  • Table 7 Amount N BUN urine protein (mg / kg) (mg / dl) (mg / ml)
  • the active ingredient compound of the present invention has an effect of suppressing the onset of glomerulonephritis due to the deposition of an immune complex in MRLZ1 mice.
  • the acute toxicity of the active ingredient compound of the present invention is as follows.
  • the compound of the formula (I) of the present invention can be used as a safe drug for treating or treating rheumatic diseases.
  • the administration route, dosage form, dose, and the like of the rheumatic agent of the present invention can be appropriately selected depending on the disease to be treated, the condition of the patient, and the like.
  • oral administration tablets, granules, powders, capsules, syrups, etc. can be exemplified.
  • Injections include subcutaneous, intramuscular, intra-articular injections, etc.
  • transmucosal agents include lozenges, suppositories and the like.
  • Such a dosage form can be prepared by mixing a compound of the formula (I) with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent for example, starch, sucrose, lactose, glucose, mannitol, sorbitol, cellulose, methylcellulose, hydro5
  • Examples include xypropylcellulose, polyethylene glycol, calcium phosphate, calcium carbonate, talc, gelatin, sodium lauryl sulfate, polysorbate, water, cocoa butter, white petrolatum, and the like. If necessary, stabilize sodium benzoate, methyl paraben, sodium citrate, sodium sulfite, etc.
  • Agents can also be added.
  • the pharmaceutical composition of the present invention thus prepared depends on the dosage form and the like, but generally contains 1 to 95% by weight, particularly 5 to 90% by weight of the compound of the formula (I). Can be.
  • the dosage of the active ingredient compound of the formula (I) is generally in the range of 0.1 mg to 20 mg, preferably 2 mg to 10 m, as a daily dose per kg of body weight. .
  • compositions of the formulation examples are described below.
  • Example 2 (capsule)
  • Macrogol 400 000 mg The above ingredients were prepared into suppositories according to a conventional method.

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  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
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  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An antirheumatic containing as the active ingredient N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine sulfone represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

明 細 書  Specification
抗リウマチ剤  Anti-rheumatic drug
技術分野  Technical field
本発明は抗リウマチ剤に関し、 さらに詳しくは式  The present invention relates to an antirheumatic agent,
HSCH 2 CHCONHCHCH 2 SO 2 C 2 H 5 ( I ) HSCH 2 CHCONHCHCH 2 SO 2 C 2 H 5 (I)
C00H  C00H
で示される N— ( 2—ベンジル一 3—メルカプトプロパノィル） 一 S— ェチルー L _システィンスルホン又はその製薬学的に許容しうる塩の抗 リウマチ剤としての用途及びそれを用いるリゥマチの処置法に関する。 背景技術  N- (2-Benzyl-1-mercaptopropanoyl) -1-S-ethyl-L-cysteine sulfone or a pharmaceutically acceptable salt thereof as an anti-rheumatic agent and a method for treating rheumatism using the same About. Background art
慢性関節リゥマチの成因は未だ完全に解明されていないが、 一般には、 免疫系の異常、 特に自己を攻撃する抗体ゃリンパ球の多量産生による免 疫能の亢進に基づくという概念が定着してきた。 したがって、 免疫異常 の是正こそが慢性関節リウマチのより根本的な治療法と考えられ、 病気 の流れを良い方向にかえるものとして疾患修飾性抗リゥマチ薬 （DMARD) が抗リウマチ剤の主流になってきた。 一方、 非ステロイ ド性抗炎症剤は 従来より慢性関節リゥマチの第一選択薬とされてきたが、 プロスタグラ ンジン生合成を抑制する作用機序による抗炎症作用を有し、 慢性関節リ ゥマチの治療に対しては対症療法であり、 病状の流れを変えるものでは ない。  Although the etiology of rheumatoid arthritis has not yet been fully elucidated, the concept has generally been established that it is based on abnormalities in the immune system, in particular, increased immune capacity through the production of large numbers of self-attacking antibodies and lymphocytes. . Therefore, correction of immune abnormalities is considered to be a more fundamental treatment for rheumatoid arthritis, and disease-modifying antirheumatic drugs (DMARDs) have become the mainstream of antirheumatic drugs as a way to change the course of the disease in a better direction. Was. On the other hand, non-steroid anti-inflammatory drugs have been regarded as the first-line drugs for rheumatoid arthritis, but they have anti-inflammatory effects by the mechanism of action that inhibits prostaglandin biosynthesis, and are used to treat rheumatoid arthritis. Is a symptomatic treatment and does not change the course of the disease.
D M A R Dには金製剤、 D—ぺニシラミン、 ブシラミン、 口べンザリ ット、 メ ト トレキサ一トなどが含まれ、 臨床に広く用いられているが、 これらの薬剤は長期間の投与で効力が減じたり、 有効性や副作用などの 点で必ずしも満足できるものではなかった。 DMARDs include gold preparations, D-penicillamine, bucillamine, oral benzalit, methotrexate, etc., which are widely used in clinical practice, but these drugs have reduced efficacy over long periods of administration. Or the efficacy or side effects They were not always satisfactory.
特開昭 5 8— 1 4 0 0 6 5号公報には、 下記式 JP-A-58-140655 discloses the following formula:
Figure imgf000004_0001
Figure imgf000004_0001
HSCH 2CHC0NHCH (CH 2 ) nSO 2R ( Π ) HSCH 2 CHC0NHCH (CH 2 ) nSO 2 R (Π)
C00H  C00H
式中、 Rは低級アルキル基を表わし、 nは 1又は 2である、 で示される化合物が開示されている。  Wherein R represents a lower alkyl group and n is 1 or 2.
今回、 上記式 （Π ) の化合物中、 Rがェチル基を表わし且つ nが 1で ある化合物、 すなわち前記式 （I ) の化合物が優れた抗リウマチ作用を 有しており、 リゥマチ疾患の治療ないし処置薬として有用であることを 見いだし本発明を完成するに至った。  This time, among the compounds of the above formula (Π), the compound in which R represents an ethyl group and n is 1, that is, the compound of the above formula (I) has an excellent antirheumatic effect, and is useful for treating rheumatic diseases. They have found that they are useful as therapeutic agents and have completed the present invention.
発明の開示 Disclosure of the invention
本発明は式 The present invention uses the formula
Figure imgf000004_0002
Figure imgf000004_0002
HSCH2CHC0NHCHCH2S02C2H5 ( I ) HSCH 2 CHC0NHCHCH 2 S0 2 C 2 H 5 (I)
C00H  C00H
で示される N— ( 2—ベンジルー 3—メルカプトプロパノィル） 一 S— ェチル一 L -システィンスルホン又はその製薬学的に許容しうる塩を有 効成分として含有することを特徴とする抗リウマチ剤を提供するもので める。 N- (2-Benzyl-3-mercaptopropanoyl) -1-S-ethyl-1L-cysteine sulfone or a pharmaceutically acceptable salt thereof represented by the following formula: It is something that provides.
式 （I ) の化合物は少なくとも 2個の不斉炭素原子を有しており、 光 学活性体 （ジァステレオマー） 又はそれらの混合物の状態で存在するこ とができる。  The compounds of formula (I) have at least two asymmetric carbon atoms and can exist in optically active forms (diastereomers) or in mixtures thereof.
また、 式 （I ) の化合物は薬学的に許容しうる塩の形で使用すること も可能であり、 そのような塩としては、 例えば、 ナトリウム塩、 力リウ ム塩などのアル力リ金属塩；マグネシウム塩、 カルシウム塩などのアル 力リ土類金属；アンモニゥム塩； トリエタノールァミン塩などのァミン 塩が挙げられる。 上記式 （I) の化合物の抗リウマチ剤としての有効性は、 以下に示す 動物実験により実証される。 なお、 以下の動物実験においては次の化合物を用いた。 The compound of formula (I) may be used in the form of a pharmaceutically acceptable salt. Such salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metals such as magnesium salts and calcium salts; ammonium salts; triethanolamine Amin salts such as salts are mentioned. The effectiveness of the compound of the above formula (I) as an antirheumatic agent is demonstrated by the following animal experiments. The following compounds were used in the following animal experiments.
化合物 1 ： N— (2—ベンジルー 3—メルカプトプロパノィル） 一 S— ェチルー L一システィンスルホン ィ匕合物 A： D-ぺニシラミン （D- penicillamine)  Compound 1: N- (2-benzyl-3-mercaptopropanol) -S-ethyl-L-cysteine sulfone conjugate A: D-penicillamine
(対照） （現在抗リウマチ剤として臨床的に実用化されている化合物） 化合物 B ： ブシラミン （bucillamine)  (Control) (A compound currently clinically used as an antirheumatic drug) Compound B: bucillamine
(対照） （現在抗リゥマチ剤として臨床的に実用化されている化合物） 抗 SRBC— PFC反応試験 (in vivo) 供試化合物を生理食塩水に懸濁し IN N a OH液を加えて pHを 7.0 に調整して溶解し、 被検液とした。  (Control) (A compound currently clinically used as an anti-rheumatic drug) Anti-SRBC-PFC reaction test (in vivo) The test compound is suspended in physiological saline, and the pH is adjusted to 7.0 by adding IN NaOH solution. And adjusted to a test solution.
5週令の d dY系マウスを使用し、 各群動物数を 5匹として実験を行 なった。 また、 実験期間中動物は温度 23±2°C、 相対湿度 55 ±5% の飼育室で飼育し、 飼料及び水は自由に摂取させた。 抗原としてヒッジ赤血球 （SRBC) を用い 5'x 108個を尾静脈に投与 して免疫し 4日目に脾臓を摘出し、 SRBC抗原として脾細胞中の hemolytic plaque forming cell (HPFC：溶血班形成細胞） の数を測定 した。 即ち、 脾臓の単細胞浮遊液 0.25 mlを Eagle MEM培地 1.7 5 ml に加え、 ついで抗原である S RB Cの 35%浮遊液0.25 ml 及 び補体として MEMで 2倍に希釈したモルモット血清 0.25 ml を加え てよく混合し、 市販のカニンガムチャンバ一 （Cunninghamchamber) 中 に 50 /1 ずつ入れて、 パラフィンで両端を封じ、 温度 37°C、 炭酸ガ ス濃度 5%の炭酸ガスィンキュベータ一中で 45分間培養したのち、 溶 血班数を数えて HP F C数とした。 The experiment was performed using 5-week-old ddY mice and using 5 animals per group. During the experiment, animals were kept in a breeding room at a temperature of 23 ± 2 ° C and a relative humidity of 55 ± 5%, and were allowed free access to feed and water. 5'x10 8 cells were injected into the tail vein using immunized red blood cells (SRBC) as an antigen and immunized. The spleen was removed on the 4th day, and hemolytic plaque forming cells (HPFC) in splenocytes were used as SRBC antigen Cells) were counted. That is, 0.25 ml of a single cell suspension of spleen was added to 1.75 ml of Eagle MEM medium, and 0.25 ml of a 35% suspension of SRBC as an antigen and 0.25 ml of guinea pig serum diluted twice with MEM as complement were added. In addition Mix well, put 50/1 each in a commercially available Cunninghamchamber, seal both ends with paraffin, and heat for 45 minutes in a CO2 incubator with a temperature of 37 ° C and a CO2 concentration of 5%. After culturing, the number of hemolysis spots was counted to determine the number of HPFC.
被検液は、 免疫の日から 1曰 1回 4日間腹腔内に投与した。 投与量は、 比較対照薬とした D—ぺニシラミン （化合物 Α) を 2 OmgZkgZday (0.134m mol/kg/day) とし、 これとモル比で等しくなるように した。  The test solution was intraperitoneally administered once for four days from the day of immunization. The dose was set to be 2 OmgZkgZday (0.134 mmol / kg / day) for D-penicillamine (compound と し た), which was a comparative drug, and to be equal to this molar ratio.
脾臓中の H P F C数を表 1に示す。  Table 1 shows the number of HPFC in the spleen.
表 1 : HPFC (溶血班形成細胞） 数 （X 103個） 検 体 Table 1: HPFC (hemolysis plaque forming cells) Number (X 10 3 cells) test body
対 照 291.2 ± 56.2  Reference 291.2 ± 56.2
化合物 1 158.2 ± 31.0 *  Compound 1 158.2 ± 31.0 *
化合物 A 349.4 i 52.4  Compound A 349.4 i 52.4
N=5、 * : Pく 0.01、 平均土 S. D.  N = 5, *: P 0.01 0.01, average soil S. D.
以上の結果より、 本発明の有効成分化合物は、 抗体産生に抑制的に作 用することが認められる。  From the above results, it is recognized that the active ingredient compound of the present invention acts suppressively on antibody production.
抗 SRBC— PFC反応試験 (in vitro) Anti-SRBC-PFC reaction test (in vitro)
ヒッジ赤血球 （SRBC) による抗体産生に及ぼす供試化合物の効果を濃 度を変化させて in vitro で検討した。  The effect of the test compound on antibody production by shedding red blood cells (SRBC) was examined in vitro at different concentrations.
Mishell- Dutton の変法 [Mishell, R. I. and Dutton, R. f. ： Science 153， 1004 (1966) ] に従い、 B A L B cマウスから脾細 胞浮遊液を調製した。 脾細胞、 SRBC及び検体を混和し、 37°C、 C02インキュベーター内にて 4日間培養後、 溶血班形成細胞 （HPFC) 数を測定した。 その結果を表 2に示す。 表 2 ： HPFC (溶血班形成細胞） 数 A spleen cell suspension was prepared from BALB c mice according to a modified method of Mishell-Dutton [Mishell, RI and Dutton, Rf: Science 153, 1004 (1966)]. Splenocytes were mixed with SRBC and specimen, 37 ° C, C0 2 4 days after culture in an incubator, hemolysis plaque forming cells (HPFC) The number was measured. The results are shown in Table 2. Table 2: Number of HPFC (hemolytic plaque forming cells)
HPFC数 Z106脾細胞 HPFC number Z10 6 splenocytes
濃度 (M)  Concentration (M)
106SRBC/ml 107SRBC/ml 化合物 1 0 97 土 61 90 土 17 10 6 SRBC / ml 10 7 SRBC / ml Compound 1 0 97 Sat 61 90 Sat 17
10-6 75 ± 5 115 ± 19 10"5 78 ± 10 93 ± 55 10-4 46 + 15 27 土 19 * If)-3 230 + 33 * 122 ± 4 # 化合物 B 0 57 土 13 90 + 40 10- 6 75 ± 5 115 ± 19 10 " 5 78 ± 10 93 ± 55 10- 4 46 + 15 27 Sat 19 * If) -3 230 + 33 * 122 ± 4 # Compound B 057 Sat 13 90 + 40
10— 6 145 ± 138 197 i 51 * 10- 6 145 ± 138 197 i 51 *
10—5 175 + 57 * 212 ± 110 10—4 111 ± 32 * 59 土 30 If)-3 2 ± 3 0 ± 0 10- 5 175 + 57 * 212 ± 110 10- 4 111 ± 32 * 59 Sat 30 If) - 3 2 ± 3 0 ± 0
*： P< 0.05 Mean土 S. D. *: P <0.05 Mean soil S. D.
B A L B cマウスでは化合物 2は 10— 4 Mで抗体産生を抑制、 10—3Mで増強を示したのに反して、 化合物 Bは 10— 6〜10— 4Mで増 強作用を示した。 以上の結果より、 本発明の有効成分化合物は免疫調節剤としての特徴 を有することが認められる。 アジュバンド関節炎試験 (予防効果） 供試化合物を生理食塩水に懸濁し、 I N N a OH液を加えて rfiを 7.0に調整して溶解し、 被検液とした。 BALB c Compound 2 in mice is suppressed antibody production by 10- 4 M, contrary to that shown enhanced at 10- 3 M, compound B showed increasing strength acts 10- 6 ~10- 4 M. From the above results, it is confirmed that the active ingredient compound of the present invention has characteristics as an immunomodulator. Adjuvant arthritis test (preventive effect) The test compound was suspended in physiological saline, adjusted to rfi 7.0 by adding INNaOH solution, and dissolved to give a test solution.
8週令の L e w i s系雄性ラットを使用し、 各群動物数を 5匹として 実験を行った。 また、 実験期間中動物は温度 23±2°C、 相対湿度 55 ±5%の飼育室で飼育し、 飼料及び水は自由に摂取させた。 Using 8-week-old male Lewis rats, the number of animals in each group was 5, An experiment was performed. During the experiment, animals were kept in a breeding room with a temperature of 23 ± 2 ° C and a relative humidity of 55 ± 5%, and had free access to feed and water.
マイコノヾクテリウム -フチリクム (Mycobacterium butyricum) (Difco社） 6mg を流動パラフィン 0.5 ml に懸濁しエーテル麻酔下 にその 0.05ml を右側後肢足しよ皮下に注射した。 また、 被検波はァ ジュバンド処置当日から毎日 1回 21日間経口投与した。 投与量は比較 対照薬とした化合物 Aを 1 OmgZkgZday (0.067m mol/kg/day) とし、 これとモル比で等しくなるようにした。 投与液量は体重 100 g 当たり lml とし、 被検液濃度を調整した。  6 mg of Mycobacterium butyricum (Difco) was suspended in 0.5 ml of liquid paraffin, and 0.05 ml of the suspension was injected subcutaneously into the right hind limb under ether anesthesia. The test wave was orally administered once daily for 21 days from the day of adjuvant treatment. The dose was 1 OmgZkgZday (0.067 mmol / kg / day) for Compound A, which was a comparative control drug, and the molar ratio was equal to this. The volume of the administered solution was 1 ml per 100 g of body weight, and the concentration of the test solution was adjusted.
アジュバンド処置後 22曰目に非処置後眩の容積を測定し、 アジュバ ンド処置直前の容積に対する腫脹率を次式により求めた。 その結果を表 3に示す。 また、 22日目には Ko g a等の方法 （J. I匪 unol., Vol. I l l, 599-608 (1973) ) に準拠して両前肢、 非処置後肢 及び尾の炎症強度をその程度により 0〜4点の 5段階に分け、 合計 16 点を最高として採点した。 その結果を表 3に示す。  The volume of glare after non-treatment was measured on the 22nd day after adjuvant treatment, and the swelling ratio with respect to the volume immediately before adjuvant treatment was determined by the following formula. The results are shown in Table 3. On the 22nd day, the degree of inflammation of both forelimbs, untreated hindlimbs and tail was evaluated according to the method of Koga et al. (J. I Maraudal unol., Vol. Ill, 599-608 (1973)). The score was divided into five grades from 0 to 4 points, and a total of 16 points was scored as the highest. The results are shown in Table 3.
腫脹率 （％) = (V„ ZV。— 1) x 100  Swelling rate (%) = (V „ZV. — 1) x 100
但し、 Vn は 22日目の後肢の容積 Where V n is the volume of the hind limb on day 22
V。 はアジュバンド処置前の後肢容積 表 3 ： アジュバンド注射後 22日目の非処置足腫脹率及び炎症強度 検 体 腫脹率（％) 炎症強度 対 照 138.4 ± 24.9 13.4 ± 1.5 化合物 1 95.8 ± 26.1 9.8 ± 2.2 * 化合物 A 105.7 ± 34.2 11.0 ± 0.7 V. Is the hind limb volume before adjuvant treatment Table 3: Untreated paw swelling rate and inflammation intensity on day 22 after injection of adjuvant Specimen swelling rate (%) Inflammation intensity Control 138.4 ± 24.9 13.4 ± 1.5 Compound 1 95.8 ± 26.1 9.8 ± 2.2 * Compound A 105.7 ± 34.2 11.0 ± 0.7
N=5、 * は P<0.05、 平均土 S .D. 、 対照は生理的食塩水のみ投与 本発明の有効成分化合物はアジュバンド関節炎による足浮腫及び炎症 を抑制し、 化合物 Aより抑制作用は強かった。 N = 5, * is P <0.05, average soil S.D., As a control, only physiological saline was administered. The active ingredient compound of the present invention suppressed paw edema and inflammation due to adjuvant arthritis, and had a stronger inhibitory action than Compound A.
アジュバン ド関節炎試験 (治療効果） アジュバントとしてマイコバクテリゥム 'ッベルク口シス （Mycobact erium tuberculosis) (0.6 mg/rat) をラッ ト （SD系） の尾根部皮 内に投与した。 化合物 1の 1、 10、 100、 30 OmgZkg、 化合物 B の 1 OmgZkg をアジュバント処理 17日目から 12日間経口投与 （最 終投与曰 ：処理 28曰後） し、 アジュバント関節炎発症後の治療効果を 検討した。 その結果を表 4に示す。 化合物 1は 1 Omg/kg の用量で有意にアジュバン卜関節炎による足 浮腫を抑制した。 化合物 1の抑制作用は化合物 Bより強かった。 表 4 ： アジュバント関節炎による後肢腫脹に対する本発明化合物の 治療効果 投与量 後肢腫脹率 （％)  Adjuvant arthritis test (Therapeutic effect) As an adjuvant, Mycobacterium 'Bocberg erium tuberculosis (0.6 mg / rat) was administered intradermally to the ridge of rat (SD). Oral administration of 1, 10, 100, and 30 OmgZkg of compound 1 and 1 OmgZkg of compound B for 12 days from the 17th day of adjuvant treatment (final administration: after treatment 28) to evaluate the therapeutic effect after adjuvant arthritis onset did. The results are shown in Table 4. Compound 1 significantly inhibited paw edema due to adjuvant arthritis at a dose of 1 Omg / kg. Compound 1 had a stronger inhibitory effect than compound B. Table 4: Therapeutic effect of the compound of the present invention on hind limb swelling due to adjuvant arthritis Dose Hind limb swelling rate (%)
27曰後 3 1曰後  After 27 After 3
3ン 卜ロール 50.7 土 89.9 50.6 ± 16.69 化合物 1 1 41.7 土 9· 08 37.3 ± 7.37  3 Control 50.7 Sat 89.9 50.6 ± 16.69 Compound 1 1 41.7 Sat 9 08 37.3 ± 7.37
10 28.9 ± 3.13 * 27.5 土 5.03 10 28.9 ± 3.13 * 27.5 Sat 5.03
100 41.3 土 10.64 43.6 土 13.10 100 41.3 Sat 10.64 43.6 Sat 13.10
300 32.6 + 5.59 29.7 土 4.77 化合物 B 10 47.5 ± 11.92 43.9 士 12.74 300 32.6 + 5.59 29.7 Sat 4.77 Compound B 10 47.5 ± 11.92 43.9 J 12.74
N = 9、 *： P < 0 .05、 平均土 S. E. 以上の結果より、 本発明の有効成分化合物はアジュバント関節炎の抑 制作用を有していることが認められる。 コラーゲン関節炎 （予防効果） N = 9, *: P <0.05, average soil SE From the results above, it is confirmed that the active ingredient compound of the present invention has an effect of producing adjuvant arthritis. Collagen arthritis (preventive effect)
Ty p e nコラーゲン （CD) は 0.01 M酢酸水溶液に溶解した後 不完全フロイントァジュバント （Incomplete Freund' s Adjuvant) と混 合し、 ラット （SD系） の刈毛した背部皮内 4箇所に投与 （lmgZrat) し、 さらに 7日後に同 Cn混合液を尾根部皮内に追加投与 （0.2mg/ rat) した。 化合物 2の 1、 10、 100、 300 mgZkg、 化合物 Cの 10 mg/kg は初回免疫前 7曰から免疫前日までの 7日間連続経口投与 した。 その結果を表 5及び表 6に示す。 ① 足浮腫 化合物 1は 1〜 300 mg/kg の投与量で足浮腫率に低値を示し、 特 に 10、 10 OmgZkg 群では化合物 Bとほぼ同程度の抑制を示した。 表 5 ： コラーゲン関節炎の後肢腫脹に対する本発明化合物の効果 投与量 浮腫率 （％)  Ty pen collagen (CD) is dissolved in a 0.01 M acetic acid aqueous solution, mixed with Incomplete Freund's Adjuvant, and administered to four places in the shaved back skin of rats (SD strain) ( After 7 days, the same Cn mixed solution was additionally administered intradermally to the ridge (0.2 mg / rat). 1, 2, 10, 100, and 300 mg Zkg of Compound 2 and 10 mg / kg of Compound C were orally administered for 7 consecutive days from 7 days before the first immunization to the day before the immunization. The results are shown in Tables 5 and 6. (1) Paw edema Compound 1 showed a low paw edema rate at doses of 1 to 300 mg / kg, and showed almost the same level of suppression as Compound B in the 10 and 10 OmgZkg groups. Table 5: Effect of the compound of the present invention on hind limb swelling of collagen arthritis Dose Edema rate (%)
(mg/kg 14曰後 21曰後 28曰後 対 照 49.8 ± 5.30 51.9 土 7.88 51.0 ± 7.26 化合物 1 1 39.3 ± 6.95 48.8 + 8.50 49.0 ± 7.17  (mg / kg 14 words 21 words 28 words Reference 49.8 ± 5.30 51.9 Sat 7.88 51.0 ± 7.26 Compound 1 1 39.3 ± 6.95 48.8 + 8.50 49.0 ± 7.17
10 32.8 ± 6.03 * 40.3 ± 6.56 38.4 ± 6.86 10 32.8 ± 6.03 * 40.3 ± 6.56 38.4 ± 6.86
100 34.0 ± 6.77 33.8 + 5.98 35.3 ± 6.56 100 34.0 ± 6.77 33.8 + 5.98 35.3 ± 6.56
300 45.3 ± 7.76 43.2 士 7.74 45.7 土 7.76 化合物 B 10 28.1 ± 5.17 38, 1 士 8.05 41.8 ί 9.29 300 45.3 ± 7.76 43.2 J 7.74 45.7 Sat 7.76 Compound B 10 28.1 ± 5.17 38, J 8.05 41.8 ί 9.29
0. * : P< 0.05. ** ： P< 0. 01、 平均土 S. E. 0. *: P <0.05. **: P <0.01, average soil S. E.
② 遅延型皮膚反応 免疫 14、 21曰後に耳殻皮内に Cn液を注射し、 24時間後の耳殻 の浮腫率を検討した。 化合物 1の 10、 10 Omg/kg投与群において耳殻の浮腫率に低値 が認められたが、 化合物 Bは作用を及ぼさなかった。 表 6 ： コラーゲン関節炎の遅延型皮膚反応に対する本発明の有効成 分化合物の効果 投与量 (%) ② Delayed skin reaction Immunization After 14 and 21 days, Cn solution was injected into the crust of the ear shell, and the edema rate of the ear crust 24 hours later was examined. In the 10 and 10 Omg / kg dose groups of Compound 1, a low value was observed in the ear edema rate, but Compound B had no effect. Table 6: Effect of the active ingredient compounds of the present invention on delayed skin reaction in collagen arthritis Dose (%)
(rag/kg) 4曰後 21曰後 対 照 196.6 ± 16.20 197.5 + 7.40 化合物 1 1 160.1 土 13.90 179.5 ± 10.87  (rag / kg) 4 after 21 after comparison 196.6 ± 16.20 197.5 + 7.40 Compound 1 1 160.1 Sat 13.90 179.5 ± 10.87
10 129.6 ί 14.01 ** 122.2 ± 11.75 ** 100 118.1 + 13.08 ** 129.4 ± 21.67 * l o 300 164.7 土 14.99 173.8 ί 12.13 化合物 B 10 179.1 ± 16.97 179.0 土 14.84  10 129.6 ί 14.01 ** 122.2 ± 11.75 ** 100 118.1 + 13.08 ** 129.4 ± 21.67 * l o 300 164.7 Sat 14.99 173.8 ί 12.13 Compound B 10 179.1 ± 16.97 179.0 Sat 14.84
Ν=10、 *： Ρく 0.05、 **： Ρく 0.01、 平均土 S.E. 以上の結果より、 本発明の有効成分化合物はコラーゲン関節炎の抑制 作用を有していることが認められる。 Ν = 10, *: open 0.05, **: open 0.01, average soil S.E. From the above results, it is confirmed that the active ingredient compound of the present invention has an inhibitory effect on collagen arthritis.
5 MRL 1マウスに対する作用  5 Effects on MRL 1 mice
MRLZ 1マウスは慢性関節リウマチに類似した関節炎を自然発症 し、 リウマチ因子 （RF) 、 抗核抗体の産生、 免疫複合体による糸球体 腎炎などが観察される。 化合物 2及び化合物 Cの 5、 20 mg/kg を M RL/1マウス 8週令から 20週令まで連続経口投与し、 疾患発症に対 0 する作用を検討した。 その結果を表 7に示す。 表 7 用 量 N BUN 尿タンパク (mg/kg) (mg/dl) (mg/ml) MRLZ1 mice spontaneously develop arthritis similar to rheumatoid arthritis, and produce rheumatoid factor (RF), production of antinuclear antibodies, glomerulonephritis due to immune complexes, and the like. 5, 20 mg / kg of Compound 2 and Compound C were orally administered continuously from the age of 8 weeks to the age of 20 weeks in MRL / 1 mice, and the effect on disease onset was examined. Table 7 shows the results. Table 7 Amount N BUN urine protein (mg / kg) (mg / dl) (mg / ml)
8wks 処置刖 31 16.6 土 0.59 2.3 + 0.17 20wks コン ト口一ノレ 7 64.4 ί 7.31 3.7 土 0.18 化合物 1 5 7 61.2 土 15.20 2.4土 0.37 **8wks treatment 刖 31 16.6 Sat 0.59 2.3 + 0.17 20wks Control opening 7 64.4 ί 7.31 3.7 Sat 0.18 Compound 1 5 7 61.2 Sat 15.20 2.4 Sat 0.37 **
〃 20 7 41.6 士 5.49 * 3.1 ± 0.21 * 〃 20 7 41.6 k 5.49 * 3.1 ± 0.21 *
8wks 処置前 - 20 17.2 土 1.32 1.8 土 0.06 20wks コン トロール 一 5 32.2 土 3.73 3.5 + 0.32 化合物 B 5 3 25.8 + 0.77 3.0 士 0.208wks Before treatment-20 17.2 Sat 1.32 1.8 Sat 0.06 20wks Control 1 5 32.2 Sat 3.73 3.5 + 0.32 Compound B 5 3 25.8 + 0.77 3.0 J 0.20
〃 20 4 32.6 4.83 3.0 士 0.39〃 20 4 32.6 4.83 3.0 3.00 0.39
* : Ρ< 0.05、 ** : Ρ<0.01 (対コン トロール） 、平均土 S. Ε. 化合物 1は BUN (血中尿素態窒素 Blood Urea Nitrogen) の上昇及び 尿タンパクの增加を有意に抑制した。 一方、 化合物 Bは MRLZ1マウ スに影響しなかった。 *: Ρ <0.05, **: Ρ <0.01 (vs. control), mean soil S. Ε. Compound 1 significantly increased BUN (Blood Urea Nitrogen) and increased urinary protein . Compound B, on the other hand, did not affect MRLZ1 mice.
以上の結果より、 本発明の有効成分化合物は MRLZ1マウスに対し ては、 免疫複合体の沈着による糸球体腎炎の発症を抑制する作用を有し ていることが認められる。  From the above results, it is confirmed that the active ingredient compound of the present invention has an effect of suppressing the onset of glomerulonephritis due to the deposition of an immune complex in MRLZ1 mice.
急性毒性試験 Acute toxicity test
本発明の有効成分化合物の急性毒性は次のとおりである。  The acute toxicity of the active ingredient compound of the present invention is as follows.
表 8 ： 静脈内投与における急性毒性試験  Table 8: Acute toxicity studies for intravenous administration
動物種 LD50値 (mg/kg) Species LD 50 value (mg / kg)
化合物 1 マウス 1968  Compound 1 mouse 1968
以上の実験結果から、 本発明の前記式 （I) の有効成分化合物は、 ヒ ッジ赤血球 （SBBC) による抗体産生に及ぼす影響をプラーク形成法 （PF C法） で検討すると、 免疫能に対して抑制的に作用し、 ヒ卜の慢性関節 リゥマチの病態モデルとして周知のラットのアジュバント関節炎試験に おいて予防的及び治療的投与ともに足浮腫を抑制し、 慢性関節リウマチ の関節病変に近い病変を示す動物モデルとして近年よく用いられている コラーゲン関節炎に対して足浮腫を抑制し、 しかも毒性が低いことがわ 力、る。 From the above experimental results, the effect of the active ingredient compound of the formula (I) of the present invention on antibody production by shed red blood cells (SBBC) was examined by the plaque formation method (PFC method). In a rat adjuvant arthritis test well-known as a pathological model for rheumatoid arthritis in humans, both prophylactic and therapeutic administration suppressed paw edema, It has been shown that it suppresses foot edema and has low toxicity for collagen arthritis, which is often used recently as an animal model showing a lesion similar to that of the joint.
本発明の式 （ I ) の化合物は安全なリウマチ疾患治療ないし処置薬と The compound of the formula (I) of the present invention can be used as a safe drug for treating or treating rheumatic diseases.
, して有用である。 , And useful.
本発明のリウマチ剤は、 処置すべき疾患や患者の状態等に応じて、 投 与経路、 剤型、 投与量等を適宜選択することができる。 例えば、 経口投 与の場合は錠剤、 顆粒剤、 散剤、 カプセル剤、 シロップ剤などを例示す ることができ、 注射剤としては皮下、 筋肉内、 関節腔内投与剤などが挙 げられ、 また経粘膜投与剤としては、 トローチ剤、 坐剤等を例示するこ The administration route, dosage form, dose, and the like of the rheumatic agent of the present invention can be appropriately selected depending on the disease to be treated, the condition of the patient, and the like. For example, in the case of oral administration, tablets, granules, powders, capsules, syrups, etc. can be exemplified. Injections include subcutaneous, intramuscular, intra-articular injections, etc. Examples of transmucosal agents include lozenges, suppositories and the like.
■ 0 ■ 0
とができる。  Can be.
このような剤型の製剤は、 式 （I ) の化合物に製薬学的に許容しうる 担体又は希釈剤を配合することにより調製することができ、 その際に使 用しうる担体又は希釈剤としては、 例えば、 澱粉、 白糖、 乳糖、 ブドウ 糖、 マンニット、 ソルビット、 セルロース、 メチルセルロース、 ヒ ドロ 5  Such a dosage form can be prepared by mixing a compound of the formula (I) with a pharmaceutically acceptable carrier or diluent. For example, starch, sucrose, lactose, glucose, mannitol, sorbitol, cellulose, methylcellulose, hydro5
キシプロピルセルロース、 ポリエチレングリコール、 リン酸カルシウム、 炭酸カルシウム、 タルク、 ゼラチン、 ラウリル硫酸ナトリウム、 ポリソ ルベート、 水、 カカオ脂、 白色ワセリンなどを例示することができ、 こ れらを適宜選択して所望の剤型とし、 必要に応じて安息香酸ナトリウム、 メチルパラベン、 クェン酸ナトリウム、 亜硫酸ナトリウムなどの安定化0  Examples include xypropylcellulose, polyethylene glycol, calcium phosphate, calcium carbonate, talc, gelatin, sodium lauryl sulfate, polysorbate, water, cocoa butter, white petrolatum, and the like. If necessary, stabilize sodium benzoate, methyl paraben, sodium citrate, sodium sulfite, etc.
剤を添加することもできる。  Agents can also be added.
かく して調製される本発明の製薬学的組成物は、 その剤型等によって 異なるが、 式 （I ) の化合物を一般に 1〜9 5重量％、 特に 5〜9 0重 量％含有することができる。 式 （I ) の有効成分化合物の投与量としては一般には体重 l kg 当た りの一日量として 0 . l mg ないし 2 0 mg、 好ましくは 2 mg ないし 1 0 m の範囲内が適当である。 The pharmaceutical composition of the present invention thus prepared depends on the dosage form and the like, but generally contains 1 to 95% by weight, particularly 5 to 90% by weight of the compound of the formula (I). Can be. The dosage of the active ingredient compound of the formula (I) is generally in the range of 0.1 mg to 20 mg, preferably 2 mg to 10 m, as a daily dose per kg of body weight. .
以下に製剤例についてその組成を例示する。  The compositions of the formulation examples are described below.
実施例 1 (錠剤） Example 1 (tablet)
錠あたり  Per tablet
化合物 1 0 0 mg Compound 100 mg
乳糖 5 0 mg Lactose 50 0 mg
結晶セルロース 5 0 mg Microcrystalline cellulose 50 mg
ヒ ドロキシプロピルセルロース 1 8 mg Hydroxypropyl cellulose 18 mg
ステアリン酸マグネシウム 2 mg Magnesium stearate 2 mg
上記の成分を常法に従って打錠して錠剤を得た。 本錠には通常行われ るフィルムコーティングを行ってもよく、 更に糖衣を施してもよい。 実施例 2 (カプセル剤）  The above components were tableted according to a conventional method to obtain tablets. The tablet may be subjected to usual film coating or sugar coating. Example 2 (capsule)
1カプセル当たり  Per capsule
化合物 2 0 0 mg Compound 200 mg
乳糖 9 5 mg Lactose 95 mg
ステアリン酸マグネシウム 5 mg Magnesium stearate 5 mg
とうもろこしでんぶん 6 0 mg Corn starch 60 mg
結晶セルロース 4 0 mg Microcrystalline cellulose 40 mg
上記成分を充分混合し硬カプセルに充填し、 カプセル剤とする, 実施例 3 (注射剤）  Mix well the above ingredients and fill in hard capsules to make capsules, Example 3 (injection)
化合物 3 (ナトリウム塩） 1 0 0 mg Compound 3 (sodium salt) 100 mg
塩化ナトリウム 9 0 mg 上記成分を注射用蒸留水 1 0 ml に溶解し注射剤とする。 実施例 4 (坐剤） Sodium chloride 90 mg The above components are dissolved in 10 ml of distilled water for injection to prepare an injection. Example 4 (suppository)
1剤当たり  Per drug
化合物 2 1 0 0 mg マクロゴール 4 0 0 2 5 0 mg Compound 2 1 0 0 mg Macrogol 4 0 0 2 5 0 mg
マクロゴール 1 5 0 0 2 5 0 mg Macrogol 1 5 0 0 2 5 0 mg
マクロゴール 4 0 0 0 4 0 0 mg 上記の成分を常法に従って坐剤に調製した。 Macrogol 400 000 mg The above ingredients were prepared into suppositories according to a conventional method.

Claims

請求の範囲 The scope of the claims
1 . 式
Figure imgf000016_0001
1 set
Figure imgf000016_0001
HSCH2CHC0冊 CHCH2S02C2H5 COOH で示される N— ( 2—ベンジルー 3—メルカプトプロパノィル） 一 S— ェチルー L—システィンスルホン又はその製薬学的に許容しうる塩を有 効成分として含有する抗リウマチ剤。 HSCH 2 CHC0 Book CHCH 2 S0 2 C 2 H 5 COOH N- (2-benzyl-3-mercaptopropanoyl) -S-ethyl-L-cysteine sulfone or a pharmaceutically acceptable salt thereof is effective An antirheumatic agent contained as a component.
2 . 式
Figure imgf000016_0002
2. Expression
Figure imgf000016_0002
HSCH2CHC0題 CHCH2S02C2H5 COOH で示される N— ( 2—べンジルー 3—メルカプトプロパノィル） 一 S— ェチル一L—システィンスルホン又はその製薬学的に許容しうる塩の有 効量と製薬学的に許容しうる担体又は希釈剤から成る抗リゥマチ作用を 有する製薬学的組成物。 HSCH 2 CHC0 title CHCH 2 S0 2 C 2 H 5 COOH N— (2-benzyl 3-mercaptopropanoyl) -S-ethyl-L-cysteine sulfone or a pharmaceutically acceptable salt thereof A pharmaceutical composition having an anti-rheumatic effect comprising an effective amount and a pharmaceutically acceptable carrier or diluent.
3 . 式
Figure imgf000016_0003
3 expression
Figure imgf000016_0003
HSCH2CHC0NHCHCH2S02C2H5 HSCH 2 CHC0NHCHCH 2 S0 2 C 2 H 5
I I
COOH で示される N— （2—ベンジルー 3—メルカプトプロパノィル） 一 S _ ェチル一L一システィンスルホン又はその製薬学的に許容しうる塩の有 効量を患者に投与することからなるリゥマチの処置方法。 A rheumatism comprising administering to a patient an effective amount of N- (2-benzyl-3-mercaptopropanol) -S-ethyl-L-cysteine sulfone or a pharmaceutically acceptable salt thereof represented by COOH. Treatment method.
4 . N— （2—ベンジルー 3—メルカプトプロパノィル） 一 S—ェチル 894 4. N— (2-benzyl-3-mercaptopropanoyl) -S-ethyl 894
15  Fifteen
一 L一システィンスルホンをリゥマチの処置における使用。 Use of L- cysteine sulfone in the treatment of rheumatism.
PCT/JP1991/001207 1990-09-13 1991-09-12 Antirheumatic WO1992004894A1 (en)

Applications Claiming Priority (2)

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JP2242313A JPH04124131A (en) 1990-09-13 1990-09-13 Antirheumatic agent
JP2/242313 1990-09-13

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5481219A (en) * 1977-10-25 1979-06-28 Merck & Co Inc Substituted mercapto acid amide and its use
JPS58140065A (en) * 1982-02-10 1983-08-19 Meito Sangyo Kk Mercaptobenzyl fatty acid derivative and its preparation
JPS61165362A (en) * 1985-01-18 1986-07-26 Meito Sangyo Kk Mercapto fatty acid derivative and use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5481219A (en) * 1977-10-25 1979-06-28 Merck & Co Inc Substituted mercapto acid amide and its use
JPS58140065A (en) * 1982-02-10 1983-08-19 Meito Sangyo Kk Mercaptobenzyl fatty acid derivative and its preparation
JPS61165362A (en) * 1985-01-18 1986-07-26 Meito Sangyo Kk Mercapto fatty acid derivative and use thereof

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