• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Novel triaryl thiazole compounds are useful as analgesic agents. These compounds are prepared by the reaction of a substituted thiobenzamide with a dimethoxy substituted benzoin.
    公开号:SU957765A3
    申请号:SU813264742
    申请日:1981-03-31
    公开日:1982-09-07
    发明作者:Мацумото Кен；Пек Кох Хо Питер
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for the preparation of new substituted triarylthazoles of the general formula where X is a hydrogen, bromine, chlorine atom. or fluorine, which exhibit pharmacological activity as prostaglandin synthetase inhibitors, analgesic agents, anti-inflammatory agents, antiarthritic agents, antipyretics and antithrombotic agents, and can be used in medicine. A known method for producing a derivative of thiazole of the formula, which consists in the fact that a compound of the formula Y5CO-U C- - (V) - and o is reacted with dimethoxy-substituted benzoin of the formula in an alcohol medium at the boiling point of the reaction mixture p. . The compound of formula (IV) has anti-inflammatory activity. The aim of the invention is to obtain new triaryl thiazoles, expanding the arsenal of means of action on a living organism. The goal is achieved by the fact that according to the method of obtaining compounds of general formula (I), thiobenzene of the general formula where X has the indicated values, is reacted with dimets substituted with benzoin of the general formula where R is hydroxyl or chlorine atom, in an organic solvent at 20-150 ° C, provided that when R is hydroxyl, the process is carried out in the presence of an acid catalyst. In addition, dioxane or toluene is preferably used as the organic solvent. Reception in the case when R is a chlorine atom, the process is carried out, preferably, at 100 ° G. At the same time, the process is carried out for a period of 2–3 hours. In addition, in the case when R is n-shroxil, the process is preferably carried out at 60–150 ° C. The process is carried out for 3 days. Preparation of 4,4-dimethoxydesyl chloride 100 g (0.37 mol) of anisoin and 45 (0.55 mol) of pyridine are heated until anisoin is completely dissolved. After cooling the beaker in a ice bath, a solid forms. The solid is pulverized and 36 ml (0.5 mol) of thionyl chloride are added. The mixture is then re-soldered to obtain a liquid mixture. 4epje3 1 h. 250 ml of water are added and the organic matter is extracted with ether, washed with water, dried over sodium sulfate and evaporated to give a mild residue. Most of the oil is extracted with ether and the residue is filtered off. Cooling results in a tan solid, which is filtered and recrystallized from the result to give 37.9 g (3%) of solid (this substance. The melting temperature is SO-Sl C. Elemental analysis: Calculated: C 66.10; H 5.20; C1 12.19. C. HjyClOj Found: C: 66.33; H 5.49; C1 12.22. Preparation of 4-fortiobenzamide. 100 g (0.826 mol) 4-fluorobenzonitrile is dissolved in 500 ml of pyridine and 116 ml of triethylamine. A stream of hydrogen sulphide is bubbled through the solution at room temperature for 3.5 hours, then the mixture is poured into ice-water. A yellow solid is obtained, which is filtered off and then dried at 65 ° C under vacuum. The resulting product has a melting point of 145-147 s and is 107.5 g (84% yield). Elemental analysis: Calculated,% C 54 , 18; H 3.90; N 9.03. Found,%: C 53.95; H 4.10; N 9.22. Preparation of thiobenzamide Following the procedure of example 2, thiobenzamide is prepared using 103 g (1, 0 mol) benzonitrile as starting material. The product has a melting point of 114.5117 ° C and is 74.4 g (54% yield). Mass spectrum - shows expected molecular ion at mass to charge ratio / e 137. Elemental analysis: Calculated,%: From 61.28; H 5.14; N 10.21. Found,%: C 61.43; H 5.44; N 10.48. Preparation of 4-chlorothiobenzamide. Following the procedure of Example 2, 4-chlorothiobenzamide is prepared using 25 g (0.187 mol) of 4-chlorobenzonitrile as the starting material. The product has a melting point of 128-130.5 ° C and is 15.4 g (48% yield). The mass spectrum shows the expected molecular ion at m / e 171. Elemental analysis: Calculated,%: C 48, 98; H 3.52; N 8.16. ° Found,%: C 49.02; H 3.54; N 8.30. Preparation of 4-bromothiobenzamide Following the procedure of Example 2, 4-bromothiobenzamide is prepared using 25 g (o, 137 mol) of 4-brOmbenzonitrile as the starting material. The product has a melting point of 142-144 s and is 15.8 g (B3% yield). The mass spectrum shows the expected molecular ions at m / e 215 and 217.
    Elemental analysis: Calculated,%: C 38.91; H 2.80;
    N 6.48 ..
    CyHgBrNS
    -Found,%: C 39.16; H 2.90; b, 24. Example. 2- {4-Bromophenyl) -4, 5-bis- (4-methoxyphenyl) -thiazole,
    7.43 g (-0.034 mol) of 4-bromothiobenzamide is dissolved in 50 ml of dioxane during heating to 200 mg. Then 10.0 g of C0f034 mol) of 4,4-dimethoxydesyl chloride in 50 ml of dioxane is added and the mixture is heated at 100 ° C for 2 4i The mixture is cooled and acidified with 1N. hydrochloric acid. Most of the dioxane is removed under vacuum and the resulting precipitate is filtered off. The solid is purified by chromatography on silica gel (400 g) using benzene as eluent1. The product has a melting point of 155-157 ° C and is 8.83 g (57% yield). The mass spectrum shows the expected molecular ions at m / e 451 and 453. The NMR spectra (deuterated chloroform) show the following: S. (ppm) 3.80 singlet (6H) methoxy; 8 (ppp) 7.40 multiplet (12H) phenyl.
    Elemental analysis:
    Calculated,%: C 61.07; P 4.01; N 3.10; S 7.09; Br 17.66.
    Ci HlgBrNOjS -,
    Found,%: C 61,32; H 3.71; n 3.27; S 7.00; Br 17.90.
    Example 2. 2- (4-fluorophenyl-4, 5-bis- (4-methoxyphenyl-thiazole.
    Following the procedure of the first example, 2- (4-fluorophenyl) -4,5-bis- (4-methoxyphenyl) -thiazole is obtained using f 5.34 g / 0.034 mol) 4-fluoro ± iobenzamide and 10.0 g (0.034 mol) 4,4-dimethoxydisyl chloride as a starting material. The product has a melting point of 140-142 ° C and is 8.74 g (yield) after chromatography on silica gel. The mass spectrum shows the expected molecular ion at m / e 391. The NMR spectrum (deuterated chloroform) shows the following: 8 (ppl) 3.80 singlet (6H) methoxy; S (rri) 7.30 multiplet (12H) phenyl.
    Elemental analysis:
    Calculated,%: C, 70.57; H 4.63; F 4.85; N 3.58; S 8.19
    CzjH gFNOjS
    Found,%: C, 70.48; And 4.41; F 5.05; N, 3.44; S 8.09.
    Froze 2- (4-Chlorophenyl) -4, 5-bis- (4-methoxyphenyl) -thiazole.
    Following the procedure of the first example, 2- (4-chlorophenyl) -4,5-bis- (4-methoxyphenyl) -thiazol is prepared using 5.90 g (0.034 mol) of 4-chlorothiobenzamide and 10.0 g (O, 034 col. A) 4,4-dimethoxydesyl chloride as a starting material
    ethanol-sodium acetate mixture. A cationsite amount of piperidine is added to the solution and refluxed for 16 hours.
    After chromatography on silica gel, the product is 5.4 g (38% yield) and has a melting point of 134-137 ° C. The mass spectrum shows the expected molecular ions at m / e 407 and 409.
    0
    Elemental analysis:
    Calculated. %: C, 67.72; H 4.45; N 3.43.
    Cjj H (g ClNOjS
    Found,%: C 67.59; H 4.73;
    5 N 3.13 ..,
    Example 4. 2- (4-Fluorophenyl) -4, 5-bis- (4-methoxyphenyl) -thiazole.
    3 ml of concentrated sulfuric acid, 250 ml of dioxane, 27.2 g (0.1 mol) of anisoin, and 15.5 g (0.1 mol) of 4-fluorothibenzamide are placed in a round bottom flask. The mixture is stirred at reflux for 3 days,
    5 is then cooled to room temperature and poured into ice water. The mixture is then extracted with ethyl acetate, washed with water and dried with sodium sulfate. Thereafter, ethyl acetate is evaporated to obtain in the remainder 35 g of a crude solid. The solid is then recrystallized from ethyl acetate, which results in 27.5 g (70% yield). The product has a temperature
    Melting 5 140-141.5 s. The mass spectrum shows the expected molecular ion at m / e 391. S (ppm) 3.80 singlet (Gil) methoxy; S (ppm) 7.40 multiplet (12H) phenyl
    0 Elemental analysis:
    Calculated,%: C, 70.57; H, 4.63; .N3.58.
    C HfgPNOaS
    Found,%: C 70.34; H 5, J38,
    five
    nj3 and mep 5. 2-Phenyl-4, bis- (4-methoxyphenyl) -thiazole.
    Following the procedure of Example 4, 2-phenyl.-4,5-bis- (4-methoxyphenyl) -thiazole is obtained using 25 g (0.18 mol)
    0 thiobenzamide as a starting material, toluene as a solvent, and P-toluenesulfonic acid as a catalyst. The product is 47.7 g (70% yield) and
    5 has a melting point of 117-118 s,
    Elemental analysis:
    Calculated,%: C 73.97; H 5.13; N 3.75; S 8.59.
    CjgH (()
    0
    Found,%: C 73.87; H 4.95; N 3.80; S 8.79.
    Example 6: Compounds of formula. (I) are effective analgesic agents, as demonstrated in pain tests on us.
    权利要求:
    Claims (6)
    [1]
    Claim
    1. The method of producing substituted 1 triarylthiazoles of the general formula I where X is an atom of hydrogen, bromine, chlorine or fluorine, characterized in that. Thiobenzamide of the general formula II
    X where X has the indicated meanings, ^ are they reacted with a dimethyl si substituted benzoin of general form
    III mules
    I
    Hj <0—
    - where R is hydroxyl or a chlorine atom in an organic solvent at. 20-150 ° C, provided that when R is hydroxyl, the process is conducted in the presence of an acid · catalyst:.
    □ s
    [2]
    2. The method according to π. 1, characterized in that as an organic solvent using dioxane or toluene.
    [3]
    3. The method according to PP. 1 and 2, different; so that when
    40 R - chlorine atom, the process is carried out at 100 ° C.
    [4]
    4. The method according to p. 3, characterized in that the process is carried out for 2-3 hours
    45
    [5]
    5, The method according to paragraphs. 1 and 2, characterized in that when R is hydroxyl, the process is carried out at 60-150 r C.
    [6]
    6. The method of claim 5, wherein the process is conducted for 3 days.
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    同族专利:
    公开号 | 公开日
    AU6881081A|1981-10-08|
    CA1157864A|1983-11-29|
    JPS56152469A|1981-11-26|
    RO81686A|1983-04-29|
    PT72757B|1982-03-23|
    HU182705B|1984-03-28|
    GB2073189A|1981-10-14|
    US4322428A|1982-03-30|
    NZ196625A|1983-09-30|
    IL62491D0|1981-05-20|
    FI810935L|1981-10-03|
    PT72757A|1981-04-01|
    ZA812019B|1982-11-24|
    BG35045A3|1984-01-16|
    YU80281A|1983-09-30|
    EP0037274A1|1981-10-07|
    DK142381A|1981-10-03|
    ES500870A0|1982-06-01|
    RO81686B|1983-04-30|
    AR226098A1|1982-05-31|
    ES8205210A1|1982-06-01|
    PH16945A|1984-04-24|
    PL230426A1|1981-12-23|
    GR73694B|1984-04-03|
    CS217994B2|1983-02-25|
    PL128570B1|1984-02-29|
    DD157799A5|1982-12-08|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    IE32084B1|1967-06-07|1973-04-04|Wyeth John & Brother Ltd|Thiazole derivatives|
    US3558644A|1966-09-26|1971-01-26|Upjohn Co|2-substituted-4,5-dianisylthiazoles|
    US3560514A|1966-09-26|1971-02-02|Upjohn Co|2--4,5-dianisylthiazole|
    US3458526A|1966-09-26|1969-07-29|Upjohn Co|Certain 2-amino-4,5-bisthiazoles|
    GB1145884A|1966-11-18|1969-03-19|Wyeth John & Brother Ltd|Thiazole derivatives|
    GB1539450A|1976-06-08|1979-01-31|Wyeth John & Brother Ltd|Thiazole derivatives|
    US4197306A|1977-06-30|1980-04-08|Uniroyal, Inc.|Aryl-substituted thiazoles|
    US4168315B1|1977-09-28|1985-05-28|US4500533A|1983-06-22|1985-02-19|Eli Lilly And Company|2,4,5-Triaryl pyrimidines and a method of treating pain, fever, thrombosis, inflammation and arthritis|
    US4533666A|1983-06-22|1985-08-06|Eli Lilly And Company|6-Phenyl-2,3-bis--pyridine derivatives having anti-inflammatory activity|
    US4495202A|1983-06-22|1985-01-22|Eli Lilly And Company|Terphenyl derivatives and pharmaceutical uses thereof|
    US4659726A|1984-04-19|1987-04-21|Kanebo, Ltd.|Novel 4,5-Bis -2- thiazoles and pharmaceutical composition containing the same|
    CA2074933C|1990-11-30|2002-12-03|Masatoshi Chihiro|Thiazole derivatives as active superoxide radical inhibitors|
    MY128323A|1996-09-30|2007-01-31|Otsuka Pharma Co Ltd|Thiazole derivatives for inhibition of cytokine production and of cell adhesion|
    CN100383131C|2005-06-15|2008-04-23|浙江大学|Process for synthesizing 2-p-trifluoro toluene-4-methyl-5-thiazolyl ethyl formate|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/136,591|US4322428A|1980-04-02|1980-04-02|2-4,5,-bisthiazole and method of use|
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