WO1992004894A1 - Antirhumatismal - Google Patents

Antirhumatismal 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
Authority
WO
WIPO (PCT)
Prior art keywords
compound
sat
ethyl
pharmaceutically acceptable
benzyl
Prior art date
Application number
PCT/JP1991/001207
Other languages
English (en)
Japanese (ja)
Inventor
Katsumi Asano
Taketoshi Komori
Hiromi Hanai
Mikio Hori
Hideo Nagae
Original Assignee
Meito Sangyo Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Meito Sangyo Kabushiki Kaisha filed Critical Meito Sangyo Kabushiki Kaisha
Publication of WO1992004894A1 publication Critical patent/WO1992004894A1/fr

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Classifications

    • 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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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un antirhumatismal qui contient comme ingrédient actif de la sulfone de N-(-2-benzyl-3-mercaptopropanoyl)-S-éthyl-L-systéine, représentée par la formule (I), ou un sel pharmaceutiquement acceptable de ce composé.
PCT/JP1991/001207 1990-09-13 1991-09-12 Antirhumatismal WO1992004894A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/242313 1990-09-13
JP2242313A JPH04124131A (ja) 1990-09-13 1990-09-13 抗リウマチ剤

Publications (1)

Publication Number Publication Date
WO1992004894A1 true WO1992004894A1 (fr) 1992-04-02

Family

ID=17087359

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/001207 WO1992004894A1 (fr) 1990-09-13 1991-09-12 Antirhumatismal

Country Status (2)

Country Link
JP (1) JPH04124131A (fr)
WO (1) WO1992004894A1 (fr)

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 (ja) * 1982-02-10 1983-08-19 Meito Sangyo Kk メルカプトベンジル脂肪酸誘導体類及びその製法
JPS61165362A (ja) * 1985-01-18 1986-07-26 Meito Sangyo Kk メルカプト脂肪酸類誘導体およびその利用

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 (ja) * 1982-02-10 1983-08-19 Meito Sangyo Kk メルカプトベンジル脂肪酸誘導体類及びその製法
JPS61165362A (ja) * 1985-01-18 1986-07-26 Meito Sangyo Kk メルカプト脂肪酸類誘導体およびその利用

Also Published As

Publication number Publication date
JPH04124131A (ja) 1992-04-24

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