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WO1982002385A1 - Derives de n-(2-thiazolyl) carbamate, procede de preparation et composition medicinale les contenant - Google Patents

Derives de n-(2-thiazolyl) carbamate, procede de preparation et composition medicinale les contenant Download PDF

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Publication number
WO1982002385A1
WO1982002385A1 PCT/JP1982/000009 JP8200009W WO8202385A1 WO 1982002385 A1 WO1982002385 A1 WO 1982002385A1 JP 8200009 W JP8200009 W JP 8200009W WO 8202385 A1 WO8202385 A1 WO 8202385A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
thiazolyl
general formula
derivative
lower 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/JP1982/000009
Other languages
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 JP213481A external-priority patent/JPS57118573A/ja
Application filed by Mitsui Toatsu Chemicals Inc filed Critical Mitsui Toatsu Chemicals Inc
Publication of WO1982002385A1 publication Critical patent/WO1982002385A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical

Definitions

  • the present invention relates to a novel chemical substance, an N- (2-thiazolyl) caprate derivative, a method for producing the same, and a pharmaceutical composition containing the same.
  • the present invention has immunomodulatory ability, and thus effectively acts against immune diseases such as rheumatoid arthritis rheumatism, and is effective for viral species.
  • the present invention relates to a carbonate derivative, a method for producing the same, and a pharmaceutical composition containing the same.
  • Conventionally, steroidal and non-steroidal anti-inflammatory drugs have been used clinically in many autoimmune diseases such as rheumatism. However, many of these drugs are still not satisfactory in terms of side effects, toxicity, etc., including the effects of Hexi-1.
  • INDUSTRIAL APPLICABILITY The novel compound according to the present invention exerts a specific effect on cells related to an immune response, and has an effect of improving the immunity of a host.
  • the present invention exerts a specific effect on cells related to an immune response, and has an
  • the present invention provides a novel chemical substance, an N- (2-thiazolyl) carbamate derivative, a process for producing the same, and a pharmaceutical composition containing the novel substance.
  • a novel chemical substance according to the present invention is a compound represented by the following general formula W.
  • R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a carboxyl group, a furyl group, or a viridyl group.
  • the lower alkyl group represented by R in the above formula means an alkyl group having 1 to 4 carbon atoms.
  • the starting material represented by the general formula (2) (which may be present in the form of an appropriate acid addition salt) is dissolved or suspended in a solvent.
  • 2,2-Trik mouth Mouth ester can be added and dropped.
  • the solvent used in this case include benzene, tonolene, xylene, acetate, ethylenol methyl ketone, 'quoxan, 1, 2 — ⁇ Metixethane, Tetrahydrofuran, ⁇ , ⁇ — ⁇ methylformamide, etc. are suitable.
  • an organic base such as pyridin triethylamine or charcoal sodium is used for the purpose of removing hydrogen chloride generated by the reaction.
  • Inorganic bases such as potassium carbonate and sodium bicarbonate can be used.
  • This reaction proceeds at a temperature lower than room temperature, but the reaction can be heated to the boiling point of the solvent to accelerate the reaction.
  • 2-aminothiazoles represented by the formula (2) is a known compound, and is, for example, Jacques V. Metzger, ed. The Chemistry of Heterocyclic Com— pounds, Vol. 34: Thiazole And Its Derivatives, Part Two, John Wiley & Sons, (1979)).
  • the compound represented by the general formula (3) is a known compound, and is, for example, Jacques V. Metzger, ed. The Chemistry of Heterocyclic Com— pounds, Vol. 34: Thiazole And Its Derivatives, Part Two, John Wiley & Sons, (1979)).
  • the compound represented by the general formula (3) is another method for producing the compound represented by the general formula (1).
  • This reaction usually involves the conversion of these two compounds into alcohol, tetrahydrofuran, dixan, benzene, 1,2— —methoxine. Shetan, N, N — 'Mix in a solvent such as dimethylformamide.
  • the reaction temperature can be freely selected usually from room temperature to the boiling point of the solvent. This reaction is usually completed in 1 to L0 hours.
  • the compound represented by Formula (1) of the present invention has useful and practical activities.
  • Compounds of the invention are immunomodulatory ⁇ It has the special property of low toxicity and is extremely useful as a medicament. '
  • Test Example 1 An example is given below.
  • Test method ICR male mice weighing around 30 ⁇ were used as 8 animals per group.
  • Sensitization is a solution of olive oil and acetate in a 4: 1 ratio
  • the compound of the present invention was added for 0.2 ° h
  • mice were orally administered at a mouse body weight of 11 ⁇ ⁇ j ⁇ 50 ⁇ .
  • the control group was similarly administered with 0.2 ° h carboxymethylcellular saline.
  • Delayed type hypersensitivity was induced 7 days after sensitization by applying a salt in which 1 saline solution had been dissolved and a felt impregnated with dissolved olive oil.
  • the ears of the mouse were applied with a mouse.
  • the thickness of the mouse ears was measured before and after the challenge, and the rate of increase in the thickness (average value of the eight ears of the eight mice) is shown in Table 1. '
  • F. t test is performed on the test results, and the significance level is P ⁇ 0.05 compared to the control group.
  • the activity of the compound of the present invention was equal to or higher than that of levamisole used for comparison.
  • the compound of the present invention is considered to have an action of regulating the mouse immune response (immunomodulation action).
  • Rats with rheumatoid arthritis that develop U by injection of Mycobacterium tuberculosis adjuvant are frequently used as experimental models for rheumatoid arthritis.
  • Test method Using an 8-week-old SD male rat, 0.4 dry dead bacterial cells of Mycobacterium um tuberculosis were flowed. It was suspended in raffin and injected into the cucumber of the right hind limb. The compound of the present invention was administered subcutaneously nine times before and after the injection of the compound. Compounds were dissolved or suspended in 0.2 calcium methyl ⁇ -salt saline and administered at a rate of 5 ⁇ per body weight.
  • the activity of the compound of the present invention was equal to or higher than that of repamisol used for comparison. That is, the compound of the present invention has immunomodulatory activity and anti-arthritic effects.
  • the compounds of the present invention have potent activity as immunomodulators as shown in Test Examples 1 and 2]), and are therefore known to be associated with decreased or abnormal immune function. It is effective for treating autoimmune diseases, for example, rheumatoid arthritis.
  • Test Example 3 shows the toxicity test of the compound of the present invention.
  • Test example 3 Oral acute toxicity test
  • Test method ddY male mice were orally administered with a compound dissolved or suspended in physiological saline using 5 mice per group. After administration
  • the compound of the present invention had an estimated LD 50 value of 1 000 w or more. This value is the estimated LD 50 for repamisol. Hydrochloride.
  • the compound of the present invention when used as a medicament, it can be used as a raw material for a drug as a free-radical base, but as a salt of a kind acceptable as a medicament. Thus, it can be used as a raw material for a drug.
  • oral preparations include capsules, granules, pills, fine granules, tablets, syrups
  • Suppositories are suitable for rectal administration]
  • subcutaneous, intramuscular, or intravenous administration can be used for injection.
  • the diseases to which the immunomodulator of the present invention is applied include diseases known to be accompanied by abnormal immune function, such as autoimmune diseases such as rheumatoid arthritis and polymyositis, and various types of diseases. Infectious diseases and various cancers can be expected to normalize the immune function of patients with such diseases.
  • the dose is 0.5 ⁇ or 100 W / day for oral administration, and is preferably 0.5 ⁇ or 100 W, or less preferably j9, or 100 for intrarectal administration.
  • the appropriate dose is 10 for intravenous administration and 1 ⁇ or 30 ⁇ for subcutaneous or intramuscular administration, but the type of disease, patient condition, etc. It is desirable to select a more appropriate amount according to the situation. Also, depending on the type of the disease and the condition of the patient, use other drugs as necessary! ), It is also possible to increase the therapeutic effect of the compounds of the present invention.
  • chemotherapeutic drugs for cancer such as alkylating agents and antimetabolites, which have side effects that reduce the patient's immunity, should be administered.
  • the effective component of the present invention is used together! )
  • it can be expected to prevent the side effects of these drugs from appearing and enhance the therapeutic effect synergistically.
  • cm- 1 3420, 1760, 1740, 1570, 1300, 1230,

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Derives de N-(2-thiazolyl) carbamate representes par la formule generale (1): (FORMULE) (ou R represente un atome d'hydrogene, un groupe alkyle inferieur, un groupe cycloalkyle, un groupe thienyle, un groupe furfuryle ou un groupe pyridyle), procede de preparation, et composition medicinale de controle de l'umminite les contenant, efficace contre le rhumatisme articulaire chronique, les maladies virales, le cancer, etc.
PCT/JP1982/000009 1981-01-12 1982-01-12 Derives de n-(2-thiazolyl) carbamate, procede de preparation et composition medicinale les contenant Ceased WO1982002385A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP56003000A JPS57116067A (en) 1981-01-12 1981-01-12 Novel 8-quinolinesulfonyl derivative, its synthesis and use
JP81/2134810112 1981-01-12
JP213481A JPS57118573A (en) 1981-01-12 1981-01-12 N-(2-thiazolyl)carbamate derivative, its preparation, and drug composition comprising it

Publications (1)

Publication Number Publication Date
WO1982002385A1 true WO1982002385A1 (fr) 1982-07-22

Family

ID=26335456

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1982/000009 Ceased WO1982002385A1 (fr) 1981-01-12 1982-01-12 Derives de n-(2-thiazolyl) carbamate, procede de preparation et composition medicinale les contenant

Country Status (3)

Country Link
JP (1) JPS57116067A (fr)
GB (1) GB2096596A (fr)
WO (1) WO1982002385A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9663529B2 (en) 2013-07-02 2017-05-30 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US9914740B2 (en) 2013-07-02 2018-03-13 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors

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

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9663529B2 (en) 2013-07-02 2017-05-30 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US9914740B2 (en) 2013-07-02 2018-03-13 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors

Also Published As

Publication number Publication date
GB2096596A (en) 1982-10-20
JPS57116067A (en) 1982-07-19

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