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WO1982002386A1 - Derives d'aminothiazoles, procede de preparation et composition medicinale les contenant - Google Patents

Derives d'aminothiazoles, procede de preparation et composition medicinale les contenant Download PDF

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Publication number
WO1982002386A1
WO1982002386A1 PCT/JP1982/000011 JP8200011W WO8202386A1 WO 1982002386 A1 WO1982002386 A1 WO 1982002386A1 JP 8200011 W JP8200011 W JP 8200011W WO 8202386 A1 WO8202386 A1 WO 8202386A1
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WO
WIPO (PCT)
Prior art keywords
group
formula
low
alkoxy
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1982/000011
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English (en)
Japanese (ja)
Inventor
Toatsu Kagaku Kk Mitsui
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsui Toatsu Chemicals Inc
Original Assignee
Mitsui Toatsu Chemicals Inc
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
Priority claimed from JP273981A external-priority patent/JPS57118574A/ja
Priority claimed from JP274081A external-priority patent/JPS57118575A/ja
Application filed by Mitsui Toatsu Chemicals Inc filed Critical Mitsui Toatsu Chemicals Inc
Publication of WO1982002386A1 publication Critical patent/WO1982002386A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines

Definitions

  • the present invention relates to a novel aminothiazol having immunomodulatory ability, a method for producing the aminothiazol, a method for producing the aminothiazole, and a conductor containing the aminothiazole.
  • Zole derivatives ie, effective against immune diseases such as rheumatoid arthritis, and effective against viral diseases or anti-cancer immunotherapy;
  • the present invention also relates to a novel minothiazol derivative which has a weak toxic effect and has extremely desirable properties as a melon, a method for producing the same, and a medicinal herb containing the same.
  • the present invention also provides a novel aminothiazole derivative represented by the formula (1), a method for producing the same, and a pharmaceutical composition containing the aminothiazole derivative.
  • the present invention has an immunomodulatory effect and is therefore effective and effective against immunological diseases such as rheumatoid arthritis. It is also useful for illness or anti-cancer immunotherapy, and has only the weak toxic effect.
  • -Phenyl thiazole — 2 — yl) Caramel induction ⁇ is also useful for illness or anti-cancer immunotherapy, and has only the weak toxic effect.
  • low alkyl or low alkyl means an alkyl or alkoxy having 1 to 4 carbon atoms.
  • Examples of the aminothiazole derivative represented by the above-mentioned kill formula (1) include the following compounds.
  • BIS (,,, 2 — Tri-Cross Mouth Power, Nil) Amino 4-1 (0-Methyl Thiofeninole) Chiazol ⁇ 2 — BIS (2, 2, 2 — Tri-Cross-Etc. Power Entry, -R) AMINO 4-1 (m-methyl thiophene-Nore) thiazol ⁇ 2 One-vis (2, 2, 2 — Tri-closing mouth knuckle force; ⁇ ? Nil) Nore ⁇
  • the compound 3 ⁇ 4J shown in the killing formula (1) is the formula (2)
  • the solution may be, for example, Benzen, T. Norenkisilen-Acetone, Echinoremethinorenketone,
  • This reaction proceeds even at room temperature or lower, but the reaction can be heated to the boiling point of the solvent to accelerate the reaction.
  • This reaction is carried out by reacting with thioureas. , Tetrahydrofuran, dioxan, benzene, 1, 2 — ⁇ methoxhetane, N, N-, dimethylmethylamide 3 ⁇ 4 Mix in a solvent.
  • the reaction temperature can be freely selected from room temperature to the temperature of the above-mentioned solvent. This reaction is usually completed in 1 to 10 hours.
  • the compound represented by the above-mentioned kill formula (1) of the present invention has a descriptive activity. It is particularly surprising that the compound of the present invention, which has been found by the present inventors to have immunomodulatory activity, has a toxic property in addition to the above-mentioned theoretical activity. Since it is weak, it is useful as a medicine.
  • test Kiyoshi 1 I do Numerous experimental systems are commonly used as a method to test the immunomodulatory ability of the nervous system. Among them, the length of the most typical test, the test for enhancing the delayed-type hypersensitivity reaction, is considered. The following is an example of Test Kiyoshi 1 I do.
  • Chloride Mouse-induced delayed-type hypersensitivity caused by application of Crill (2 — Black mouth — 13, 5 — Trinithocobenzene) to the skin is an additional measure -As a pillar immune system]), Asherson. G-. L. and? Tak, ⁇ . Contact and delayed ypersensitivity in xi e two cuse I. Acti e sensitization and passive tr nsfer.Ianiuiio 1 oy, 15, 405-416 (1968)) 0
  • Test method ICR male mice weighing around 30 were used as 8 animals per group.
  • Sensitization was carried out by dissolving hydrogen chloride in a solution of oil and acetate in a ratio of 3 to 1 in a 4: 1 solution.
  • the compound of the present invention was dissolved in 0.2-carboxymethylcellulose physiological saline, and the solution was turbid. Oral administration was performed. For control details, 0.2% carboxymethylcellulose physiological saline was similarly administered.
  • the compound of the present invention has an action of regulating the mouse immune response (immunomodulation ability).
  • rat adjuvant a-node inflammation caused by injection of Mycobacterium tuberculosis adjuvant is frequently used as an experimental model for human light-bodied rheumatoid arthritis. ing.
  • the compounds of the present invention have a potent activity as an immunomodulator.] Therefore, it is known that abnormalities in immune ragging ability are trapped. It is effective in treating autoimmune diseases such as rheumatoid arthritis.
  • Test Example 3 shows a toxicity test of the compound of the above formula (1) relating to Hon-ki.
  • Example 3 Acute toxicity test by oral administration ⁇
  • Test method ddY male mice, 5 animals per group, were used to administer animals dissolved or obscured in physiological saline. Observing the elapsed administration contact 7 days was determined estimated LD 50 value.
  • the estimated LD5a value of the compound of the present invention was 1,000 or more. This value is much rather the size compared to the estimated LD 50 200 ⁇ 300 ⁇ Zk? Les Bas Mi Orres salt ⁇ , toxicity of of compounds of this ⁇ is considered to be weak.
  • the compound of the present invention when used as a pharmaceutical, it can be used as a raw material for a drug substance without using a labile base, but as a salt of a pharmaceutically acceptable type. Thus, it can be used as a raw material for a drug.
  • the medicament of the present invention can be used in the same dosage form and administration method as ordinary immunomodulators or anticancer agents.
  • oral preparations capsules, granules, pills, fine granules, tablets, syrups and the like can be used.
  • Suppositories are suitable for rectal administration; subcutaneous, intramuscular, or intravenous injections are used for injections.
  • Examples of the immunomodulator of the present invention include: "! ⁇ Diseases are diseases that are known to be accompanied by impaired dysfunction, eg, rheumatoid arthritis, polycystic inflammation. 3 ⁇ 4 There are various autoimmune diseases, infectious diseases of each miso, and various thoughts, and the harm of the diseases and normalization of the immune function of the person can be expected.
  • the administration method and dosage form of the medicament of the present invention be appropriately selected according to the nod of the disease, the condition of the patient, and the like.
  • the daily dose per body weight is
  • chemotherapeutic agents for cancer such as alkylating agents and antimetabolites, have side effects that reduce the patient's immune function.
  • Example 3 The compounds of Examples 3 to 10 below were produced according to the operations of Examples 1 and 2 described above.
  • Example 3 The compounds of Examples 3 to 10 below were produced according to the operations of Examples 1 and 2 described above.
  • the sample was taken out into ⁇ film and washed with dilute salt drum and dilute aqueous sodium hydrogen carbonate solution.
  • the bath solution is applied to the boiler solution and the remaining oily material is applied to a gel gel chromatograph. : 1), and eluted with 2,2,2-trichloroethyl H _ (5-methylthio-4- (4-phenylazole) -2-yl) car Ha * mate 1.6 was obtained.
  • Example 6 The thiazole 1.8 of Example 6 was replaced with tetrahydrofuran.
  • the crystal is recrystallized with the combined volume of
  • Bonyl) aminotiazol- 5 -a ⁇ 3 ⁇ 4 0.9 was obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composes representes par la formule generale: (FORMULE) (ou R1 represente H, un halogene, un alkyle inferieur, un alkoxy inferieur, un alkylthio inferieur, un alkylsulfinyle inferieur, alkylsulfonyle inferieur, un nitro ou un cyano, R2 represente un alkoxycarbonyle inferieur ou un halogeno-alkoxycarbonyle inferieur, R3 represente H, un alkyle inferieur, un alkoxycarbonyle inferieur ou un halogeno-alkoxycarbonyle inferieur, R4 represente H, un halogene, un alkyle inferieur, un alkoxy inferieur, un alkylthio inferieur, un phenyle, un phenyle substitue par un alkyle inferieur ou un alkoxy inferieur, un carboxyalkyle ou un aralkyloxycarbonylalkyle), procede de preparation, et composition medicinale les contenant possedant une action de controle de l'immunite efficace contre les rhumatismes articulaire chroniques, les maladies virales, le cancer, etc.
PCT/JP1982/000011 1981-01-13 1982-01-13 Derives d'aminothiazoles, procede de preparation et composition medicinale les contenant Ceased WO1982002386A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP273981A JPS57118574A (en) 1981-01-13 1981-01-13 N-(4-phenylthiazol-2-yl)carbamate derivative, its preparation and medicinal composition containing the same
JP81/2740810113 1981-01-13
JP81/2739 1981-01-13
JP274081A JPS57118575A (en) 1981-01-13 1981-01-13 Disubstituted aminothiazole derivative, its preparation and medicinal composition

Publications (1)

Publication Number Publication Date
WO1982002386A1 true WO1982002386A1 (fr) 1982-07-22

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PCT/JP1982/000011 Ceased WO1982002386A1 (fr) 1981-01-13 1982-01-13 Derives d'aminothiazoles, procede de preparation et composition medicinale les contenant

Country Status (1)

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WO (1) WO1982002386A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087138A1 (fr) * 2003-03-31 2004-10-14 Sucampo Ag Procede de traitement de maladie vasculaire hyperpermeable

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS52125164A (en) * 1976-04-14 1977-10-20 Stauffer Chemical Co Cyclopropanecarboxamidehalothiazoles and their use as antiinflammatory agent
JPS5461172A (en) * 1977-10-19 1979-05-17 Fabre Sa Pierre Novel 44phenyll22aminothiazole derivative* its manufacture and immunity stimulant containing it
JPS54154764A (en) * 1978-04-24 1979-12-06 Pfizer Novel nn*22thiazolyl*amides
JPS54160369A (en) * 1978-06-02 1979-12-19 Pfizer Novel aminothiazoles

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS52125164A (en) * 1976-04-14 1977-10-20 Stauffer Chemical Co Cyclopropanecarboxamidehalothiazoles and their use as antiinflammatory agent
JPS5461172A (en) * 1977-10-19 1979-05-17 Fabre Sa Pierre Novel 44phenyll22aminothiazole derivative* its manufacture and immunity stimulant containing it
JPS54154764A (en) * 1978-04-24 1979-12-06 Pfizer Novel nn*22thiazolyl*amides
JPS54160369A (en) * 1978-06-02 1979-12-19 Pfizer Novel aminothiazoles

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Arzneimittel Forshung, Vol. 24, No. 6, (1974-6), H. LIEBIG et al., "Experimentelle Ergebnisse mit gezielt synthetisierten Substanzen zur antiviralen Chemotherapie", p. 887. *
CHEMICAL ABSTRACTS 60, 1727e (1964). *
CHEMICAL ABSTRACTS 78, 58365Z (1973). *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087138A1 (fr) * 2003-03-31 2004-10-14 Sucampo Ag Procede de traitement de maladie vasculaire hyperpermeable

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