• 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:
    Anti-inflammatory 1-substituted-4,5-diaryl-2-(substituted-thio) imidazoles and their corresponding sulfoxides and sulfones useful for treating arthritis and related diseases.
    公开号:SU867301A3
    申请号:SU782574555
    申请日:1978-02-08
    公开日:1981-09-23
    发明作者:Карль Черковски Сауль；Рей Шарп Томэс
    申请人:Е.И.Дюпон Де Немур Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new 1-substituted-4,5-diaryl-2 (substituted thio) imidazoles, their sulfoxides or sulfones of the general formula H b
    where η = 0 or 2J
    CF or CF 3 CHF a ; 15 and - the same or different and means water
    genus, CHAO or fluorine; Q, “Cd-alkyl, allyl CHjCH ^ NiRj) ^ -CH a 0R 4 , 20 2-tetrahydrofuranyl < 0 0 0 II II II cor 5 , - СЖ 6 , - - CW / H / Ja'j 25
    Ooh
    II IIII - GRfRdz ι 1 —CRg> · —SAG ”
    UAU — S0 2 Ar where R j “methyl;
    The poison is benzyl, -CH ^ CH ^ OCHgJ
    R 5 is ethyl or benzyl;
    R (, - methyl;
    R is ethyl; ‘*
    R® is methyl;
    Rg is methyl;
    R th - C-j-Cd - alkyl;
    provided that if R l P 'U ί H - C # ) S i — CN (R 3 ) 2ii - C0R s i-CN.R 6 ,
    0
    II | - __CAg - SOgRffl or —SOjfAe, or η = 0, with anti-inflammatory activity.
    4-alkyl-5-aryl-1-substituted 2-mercapto-imidazoles and 4-alkyl-2-alkylthio-5-aryl-1-substituted imidazoles having anti-inflammatory activity flj are known.
    The purpose of the invention is the synthesis of new compounds with active activity.
    The goal is that, according to the methods of this formula, anti-inflammatory is achieved by obtaining the compound formulas, compounds
    where n
    are as defined above, is reacted with a compound selected from the group consisting -Sd haloalkyl, haloallyl, halide dimethylaminoethyl, benzyloxymethyl halide, halide ^ -metoksietoksimetil, acyloxymethyl halide, wherein the acyl group is limited to alkyl or benzyl, -C 4 alkyl or benzyl, galogenformat , halo-35-iddimethyl and halo-dimethylcarbamoyl, dimethylthiocarbamoyl halide, 2-halo-tetrahydrofuran, haloaroyls, C ^ -Cd. halogen alkane sulfonyls, haloarylsulphonyls, C 1 -C alkylisocyan- 40 tons or alkane carboxylic acid anhydrides with alkyl groups with 1-4 carbon atoms, at a temperature of from -78 ° C to the boiling point of the solvent with the release of the target product. 45
    Example 1. 1-Benzyloxymethyl-4,5-diphenyl-2- (1,1,2,2-tetrafluoroethyl thio) imide sol. ''
    A mixture of 3.5 g (0.01 mol) of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) 50 imidazole, 2.1 g (0.013 mol) of benzyl chloromethyl ether, 3.6 g (0.026 mol) of potassium carbonate in 25 ml of dimethylformamide is stirred for 24 hours. According to thin-layer chromatography 55 there is still some starting material * so that another 0.5 g (0.003 mol) of benzylchloromethyl ether is added and stirring is continued.
    h. The mixture is poured into ice water, extracted three times with ether, and the ether layers washed three times with water. The ethereal solution was dried and concentrated on a rotary evaporator. The residue is chromatographed over 200 g of Stile ARCC-7, eluting with toluene, and obtained after recrystallization from hexane.
    3.6 g (76.6%) of a white product, mp. 70-70.5 ° C.
    Found: C, 63.10; H, 4.27; ’N, 6.10.
    C 25 H 2oW S
    Calculated: C 63.55 ^ H 4.27J N 5.93. Example 2. 4,5-Diphenyl-1-ethoxycarbonyl-2- (1, 1,2,2-tetrafluoroethylthio) imidazole.
    A mixture of 1.76 g (5 mmol) of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole, 1.1 g (10 mmol) of ethyl chloroformate in 10 ml of pyridine was stirred at room temperature overnight. temperature. According to thin-layer chromatography, there is still a little starting material, so that another 0.6 g (5 mmol) of ethyl chloroformate is added and stirring is continued for another 24 hours. The mixture is poured into water, neutralized with acetic acid and extracted three times with ether. The ether extracts are washed three more times with water, dried and 0 concentrated. The last traces of pyridine are removed by pumping at 50 ° C / 0.5 mm Hg. The residue was chromatographed over 150 g of SilieARCC-7, eluting with toluene, and after recrystallization from hexane, 1.05 g (55%) of a white product, mp. 126.5127 ° C.
    Found: C 56.76, 56.78; H 3.95, 3.88; N, 6.69, 7.01.
    Cqo H 1b Gd N 2 ° 2 s
    Calculated: C 56.60; H, 3.80; N, 6.60.
    Example 3. I-Benzyloxymethyl-
    4,5-diphenyl-2- (I, I, 2,2-tetrafluoroethylsulfonyl) imidazole.
    A mixture of 1.92 g (5 mmol) of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole, 1.6 g (10 mmol) of benzyl chloromethyl ether and 2.8 g (20 mmol) ) carbonate, potassium in 20 ml of tetrahydrofuran for 6 hours, stirred at room temperature, then pouring into ice water. The aqueous mixture was extracted three times with ether. The ether extracts are washed three more times with water, then dried and concentrated. Os-; chromatography chromatography on 150 g of Si lie. ARCC-7, eluting with toluene, and obtained by recrystallization from hexane
    2.5 g (100%) of a white product, mp 97.5-98 ° C.
    Found: C 59.73} H 3.70} N 5.58.
    N qOgS.
    Calculated: C 59.52 ’, H 4.00’, N 5.55.
    Example 4. 1-Ethoxycarbonyl-4,5-bis (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) imidazole.
    Ethyl chloroformate (1.3 g) was added to an ice-cooled mixture of 4,5-bis (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylthio) imidazole (1.5 g) in pyridine (20 ml) . The progress of the reaction is recorded by thin layer chromatography. Then add 7.0 g (in three portions) of ethyl chloroformate additionally and in order to complete the reaction, warm to room temperature. The reaction mixture was then poured into water, the crystalline tricky product was collected and washed with water to obtain 1.2 g of a colorless product, mp. 137-139 ° C.
    Found: C, 52.08; H 3.24 ’, N 5.95.
    Calculated: C 52.17} Η 3.07ζ N 6.09. Example 5. A mixture of 1-ethoxycarbonyl-4- (4-fluorophenyl) -5-phenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole and 1-ethoxycarbonyl-5 ~ (4-fluorophenyl) -4- phenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole.
    Mixture of 1-ethoxycarbonyl-4- (4-fluorophenyl) -5 ~ phenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole. .
    To a mixture of 4- (or 5) - (4-fluorophenyl) -5 (or 4) -phenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole (5, / g, 0.014 mol), pyridine ( 2.2 g, 0.028 mol) and methylene chloride (75 ml) ethyl chloroformate (3.0 g, 0.028 mol) was added dropwise. The mixture is refluxed for 30 minutes, then another 5 g of ethyl chloroformate are added in 3 portions. After each portion of the added chloroformate, the mixture was refluxed for 30 minutes. The cooled mixture was washed twice with water, dried with magnesium sulfate and concentrated. The residue was recrystallized from methylcyclohexane to give 4.3 g (72%) of colorless crystals, mp. 132-135 ° C. According to the NMR spectrum, the product is a mixture of these compounds.
    Found: C 54.67, ’H 3.70} N 6.32.
    Calculated: C 54.30, H 3.42} N 6.33.
    EXAMPLE 6 4,5-bis (4-fluorophenyl) -1-methyl-2- (1,1,2,2-tetrafluoroethyl ulphonyl) imidazole.
    A mixture of 4,5-bis- (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole (3.0 g, 0.0071 mol), methyl iodide (1.5 g, 0.011 mol ), potassium carbonate (1.5 g, 0.011 mol) and dimethylformamide (30 ml) are stirred for 50 hours. room temperature in a clogged flask. The mixture was then poured into water and after the oil crystallized out, the solid product was collected and washed with water to obtain 2.9 g of colorless crystals,
    so pl. 122-124 ° C. Recrystallization from heptane (1 ^ 25 ml) gives 2.5 g (81%) of colorless prisms, so pl. 125 126.5 ° C.
    Found: C, 49.92; H, 2.97; 'N, 6.52'.
    C <e H
    Calculated: C 49.77} H 2.78} N 6.45. Example 7. 1- (N, N-Dimethylthiocarbamoyl) -4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole.
    To a solution of 5.0 g (0.014 mol) of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole in 50 ml of tetrahydrofuran is added dropwise 15 ml of a 1.6 M solution of methyl lithium, and then a solution
    5.5 g (0.045 mol) of dimethylthiocarbamoyl chloride in 25 ml of tetrahydrofuran. The reaction mixture is heated for several hours under reflux, then concentrated on a rotary evaporator. The residue was shaken with ether and 1N hydrochloric acid. The ether layer was washed with 10% sodium bicarbonate solution, dried and concentrated. The residue (7.8 g) was purified by silica gel chromatography, eluting with toluene, and 0.8 g of product was obtained, mp. 133133.5 ° C (with recrystallization from methylcyclohexane).
    Found: C 54.30, ’H 3.84} N 9.38.
    Calculated: C 54.67} H 3.87} N 9.57. ^ Example 8. 1- (Ν, Ν-Diethylcarbamoyl) -4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole-1-carboxamide.
    A mixture of 2.0 g (0.006 mol) of 4,5'-diphenyl-2- (1,1,2,2-tetrafluoroethyl) imidazole and 10.0 g (0.074 mol) of diethylcarbamoyl chloride is heated under reflux for 2 hours. diethylcarbamoyl chloride is removed in high vacuum. The residue was chromatographed on silica gel, eluting with toluene, to give 1.5 g of product, mp. 108-.
    109 ° C (from methylcyclohexane).
    Found: C 58.33 ’, H 4.72, * N 9.27. CqjF ^ NjOS.
    Calculated: C 58.54] Η 4.66, * Ν 9.31. Example 9. N-Methyl-M- (methyl, aminocarbonyl) -4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole-1-carboxamide.
    To a solution of 15.0 g (0.263 mol) of methyl isocyanate and 5.0 g (0.014 mol) of 4,5-diphenyl ~ 2- (1,1,2,2-tetrafluoroethylthio) imidazole in 50 mp tetrahydrofuran is added a catalytic amount of tert-butoxide potassium. Reactionary
    - the mixture is stirred for several hours at room temperature, then concentrating on a rotary evaporator. The residue was shaken with ether and 1N. hydrochloric acid. The ether layer was washed with 10% sodium bicarbonate solution, dried and concentrated. The residue was triturated with petroleum ether and collected to obtain 4.8 g of crystals. A sample (2.5 g) was purified by chromatography on silica gel, etched with chloroform, and 1 * 3 g of a crystalline product was obtained (from methylcyclohexane), so pl. 107-108.5 ° C.
    Found: C 54.19 ^ H 3.86, 3 ^ 91]
    N, 11.92; 12.01. ' ^ 24 ^ 19 F4N4P1S Calculated: C 54.07] H 3.86, 'N 12.01.
    Example 10. 1-Benzyloxycarbonyl-4,5-diphenyl-2- (1, I, 2,2-tetrafluoroethylthio) imidazole.
    To a solution of 5.0 g (0.014 mol) of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole in 50 ml of glyme was added 1.7 g (0.015 mol) of potassium tert-butoxide. The mixture was cooled and a solution of 5.0 g (0.029 mol) of benzyl chloroformate in 25 ml was added dropwise. The reaction mixture was stirred at room temperature overnight, then poured onto water. The mixture was then extracted with ether, and the collected ether extracts were washed, dried and concentrated to obtain 12.1 g of crystals. The product was purified by silica gel chromatography, eluting with toluene: scrap, and (from hexane), 2.1 g of colorless crystals were obtained, mp. 110–111 ° С.
    Found: C 61.85! H 3.82, ’N 5.62.
    C ^ H ^ F ^ NqOaS.
    Calculated: C 61.73! H 3.73.
    Example 11. 4,5-bis (4-Fluorophenyl) -1- (pivaloyloxymethyl) -2- (1,1,
    2,2-tetrafluoroethylsulfonyl) imidazole.
    To a solution of 5.0 g (0.012 mol) 4,5-bis (4-fluorophenyl) t-2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole in 50 mp 1.7 g (0.015 mol) are added dropwise. potassium tert-butoxide, followed by a solution of 4.6 g (0.031 mol) of chloromethyl pivalate in 25 ml glyme and a catalytic amount of potassium iodide. Reaction mixture overnight With reflux condenser, then pour into water. The aqueous mixture was extracted with ether. The collected ether extracts were washed, dried and concentrated to give 13.4 g of a crude oily product. The product was purified by silica gel chromatography, eluting with toluene, and (from methylcyclohexane), 4.1 g of crystals were obtained, 0 mp. 121-125,5¾ ..
    Found: C 52.10, ’H 3.80] N 5.10.
    Calculated: C 51.69, 'H 3.75,' N 5.24. Example 12.1-Benzenesulfonyl-4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole
    To a stirred solution of 7.0 g (0.02 mol) 4,5-diphenyl-2- (1,1,2 ^ 2-tetrafluoroethylthio) imidazole in 50 ml glyme at 0 ° C, add 3.4 g (0.03 mol) potassium tert-butoxide. The mixture was stirred for 5 minutes at 0 ° C, then a solution of 5.3 g (0.03 mol) of benzenesulfonyl chloride was added dropwise. The mixture was stirred for 1 h at 0 ° C, then overnight at room temperature. The mixture was drunk on ice water, the crude solid was collected and washed with water and hexane to obtain 12.4 g of a tan solid, which was purified by silica gel chromatography, eluting with toluene, to give
    7.2 g of white crystals, so pl. 171.5- /
    172.5 ° C (from methylcyclohexane).
    Found: C 56.45, * H 3.32] N 5.65.
    Cqi Ν οθ 2 $ 2, · Calculated: C 56.09 ’, H 3.27] N 5.69.
    Example 13. 1-Acetyl-4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthioimidazole).
    A mixture of 1.8 g (0.005 mol) of 4,5-di 'phenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole and 25 ml of acetic anhydride is heated under reflux for 7 hours, cooled and stirred at room temperature 4 days.
    Most of the acetic anhydride and acetic acid are removed under reduced pressure (about 0.5 mmHg). The resulting white solid product is chromatographed on silica gel 5, eluting with toluene, and 0.8 g of a white product is obtained, mp. 143-144 ^ 0 (from hexane).
    Found: C, 57.80; H 3.47; N, 7.25.
    F ^ N ^ OS. 10
    Calculated: C 57.86; H 3.58, 'N 7.10. Example 14. 4,5-Diphenyl-2- (1,1,2,2-tetrafluoroethylthio) -1- (2 and tetrahydrofuranyl) imidazole.
    To a “stirred solution” 1.8 g of 15 (0.005 mol) 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole and 5 g (0.05 mol) of triethylamine in 20 ml of tetrahydrofuran are added dropwise at room temperature solution 2- 2 0
    -chlortetrahydrofuran obtained by adding 2.4 g (0.018 mol) of sulfuryl chloride to 30 ml of tetrahydrofuran, and it is expected that the temperature of the exothermic reaction reaches 25 ° C. The reaction mixture was stirred for 4 days at room temperature, then poured into ice water containing excess sodium bicarbonate. The aqueous mixture was ekst- 30 ragiruyut with methylene chloride, dried and concentrated. Crystal where η = 0 or 2; · Or and Y j - independently from each other, selected from the group consisting of hydrogen, CHjO - or fluorine;
    R / χ-C “C 4 alkyl, allyl, CH ^ CH ^ N (R 3 ) t , -CH a OR 4 , 2-tetrahydride £ ofuranyl,
    0 '0g
    -SOY 5 , -CN%, ~ CN (R e ) 2r
    Oh r Ni ~ CC 9, -Sat, —SO ^ o im — — SO a Ar, where Rj is methyl;
    R4 is benzyl or -CH ^ CH ^ OCHg; Ry is ethyl or benzyl;
    R 7 is ethyl;
    Rg, Rg ,, Rg is methyl;
    Ry 0 - C 7 -C 4 alkyl,
    provided that if R ^ -.
    O ® θ, θ
    —CN (R 7 ) lt —CN (C 0 ) 2 , __ c ORj ( —CNfQg), the residue was purified by silica gel chromatography, eluting with toluene, and 1.6 g of product was obtained, m.p. 145146 ° C (from methylcyclohexane).
    Found: C, 60.05; H 4.41; N, 6.66. c ai H i6 F 4 N a 0S
    Calculated: C 59.71; H 4.30; N, 6.63.
    The anti-arthritic and analgesic agents of the present invention may be administered for the treatment of arthritis and / or analgesia in any way that causes the active ingredient to come into contact with the body of the mammal.
    权利要求:
    Claims (1)
    [1]
    or n O with anti-inflammatory activity. 4-alkyl-5-aryl-1-substituted 2-mercapto-imidazoles and 4 alkyl-2-alkylthio-5-aryl-1-substituted imidazoles with anti-inflammatory activity 1} are known. The purpose of the invention is the synthesis of new compounds with anti-inflammatory activity. This goal is achieved by the fact that, according to the method for producing compounds of the indicated formula, compounds of the formula where n, k, Y, Y, j have the indicated values, interact with the compound selected from the group containing haloalkyl, haloallyl, halide dimethylaminoethyl, benzyloxymethyl halide , halide -methoxyethoxymethyl, halide acyloxymethyl, where the acyl group is limited to alkyl or benzyl, C-C jj. alkyl or benzyl the dynasty to the boiling point of the solvent to isolate the desired product. Example 1. 1-Benzyloxymethyl-4,5-diphenyl-2- (1,1,2,2-tetrafluoroethyl thio) imide sol. A mixture of 3.5 g, (0.01 mol) of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole, 2.1 g (0.013 mol) of benzyl chloromethyl ether, 3.6 g (0.026 mol) of potassium carbonate in 25 ml of dimethylformamide is stirred for 24 hours. According to thin-layer chromatography, there is some more starting material j so that another 0.5 g (0.003 mol) of benzyl chloromethyl ether is added and another 1 is stirred. The mixture is poured into ice water, three times extracted with ether, and the ether layers washed three times with water. The ether solution is dried and concentrated on a rotary evaporator. The residue is chromatographed on 200 g of Si lie ARCC-7, eluting with toluene, and obtained after recrystallization from hexane, 3.6 g (76.6% J of a white product, mp 70-70.5 ° C. Found: C 63, 10; H 4.27; N 6.10. Calculated: C 63.55, H 4.27; N 5.93. Example 2. 4,5-Diphenyl-1-ethoxycarbonyl-2- (1,1,2 , 2-tetrafluoroethylthio) imidazole. A mixture of 1.76 g (5 mmol) of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole, 1.1 g (U mmol) of methyl chloroformate in 10 ml pyridine is stirred at room temperature overnight. According to thin layer chromatography, there is still a bit of starting material, so that another 0.6 g (5 mmo or) ethyl chloroformate and continue stirring for another 24 hours. The mixture is poured into water, neutralized with acetic acid and extracted three times with ether.The ether extracts are washed three times with water, dried and concentrated.The last traces of pyridine are removed by pumping at 50 ° C / 0.5 mm Hg. senior The residue is chromatographed on 150 g of Si ieARCC-7, eluting with toluene, and 1.05 g (55%) of a white product is obtained after recrystallization from hexane, mp. 126.5127C. Found: C, 56.76, 56.78; H 3.95, 3.88; N 6.69, 7.01. CaoHibF4N OjS: C, 56.60; H 3.80; N 6.60. Example 3.1-Benzyloxymethyl4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole. A mixture of 1.92 g (5 mmol) of 4,5-difesh1L-2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole, 1.6 g (10 mmol) of benzyl chloromethyl ether and 2.8 g (20 mmol ) potassium carbonate in 20 ml of tetrahydrofuran is stirred at room temperature for 6 hours, then poured into ice water. The aqueous mixture is extracted three times with ether. The ether extracts are washed three times with water, then dried and concentrated. The residue is chromatographed on 150 g Sllle. ARCC-7, eluting with toluene, and obtained by recrystallization from hexane, 2.5 g (100%) of a white product, so pl. gy.s-ge-c. Found: C 59.731 H 3.70; N 5.58,. . Calculated: C 59.52, H 4.00; N 5.5 Example 4. 1-Ethoxycarbonyl-A, 5-bis (4-fluorophenyl) -2- (1,1,2,2-tet rafluoroethylthio) imidazole. To an ice-cooled mixture of 4,5-bis (4-fluorophenyl) -2- (1, 1,2,2-tetrafluoroethylthio) imidazole (1.5 g) in pyridine (20 ml) is added ethyl chloroformate (1, 3 g). The progress of the reaction is detected by thin layer chromatography. 7.0 g (in three portions) of ethyl chloroformate is added in addition and heated to room temperature in order to complete the reaction. The reaction mixture is then poured into water, the crystalline three products are collected and washed with water to obtain 1.2 g of a colorless product, m.p. 137-139 0. Found: C, 52.08; H 3.24, N 5.95. , OiS. Calculated: C 52,17; H 3.07; N 6.0 Example 5. A mixture of 1-ethoxy carbonyl-4- (4-fluorophenyl) -5-phenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole and 1-cytoxycarbonyl-5- (4- Fluorophenyl) -4-phenyl-2- (1,1,2,2-tetrapoftortillo) imidazole. A mixture of 1-ethoxycarbonyl-4- (4-fluorophenyl) -5-phenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole,. To the mixture of 4- (or 5) - (4-fluorophenyl-5 (or 4) -phenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole (5, / g, 0.014 mol of pyridine (2, 2 g, 0.028 mol) and methylene chloride (75 ml) ethyl chloroformate (3.0 g, 0.028 mol) was added dropwise. The mixture was refluxed for 30 minutes, then another 5 g of ethyl chloroformate was added in 3 portions. After each portion of the chloroformate added, the mixture is treated under reflux for 30 minutes. The cooled mixture is washed twice with water, dried with magnesium sulfate and concentrated. The residue is recrystallized from methylcyclohexaca to give 4.3 g (72%) of colorless crystals, mp 132-135 C. According to the NMR spectrum, the product is a mixture of the named compounds Found: C 54.67, H 3.70; N 6.32. O “S, B1: C 54.30; H 3.42; N 6.33. Example 6. 4,5-bis (4-fluorophenyl) -i-methyl-2- (1,1,2,2-tetrafluoroethyl ulfa NIL) imide az ol. A mixture of 4,5-bis- (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole (3.0 g, 0.0071 mol), methyl iodide ( 1.5 g, 0.011 mol), potassium carbonate (1.5 g, 0.011 mol) and dimethylformamide (30 ml) are stirred for 50 h. room temperature in a sealed flask. The mixture is then poured into water and after the oil crystallizes, the solid product is collected and rinsed with water to obtain 2.9 g of colorless crystals, m.p. 122-1. Recrystallization from heptane (ml) gives 2.5 g (81%) of colorless prisms, mp 125126, 5 C. Found: C 49.92; H 2.97, N 6.52. Calculated: C 49.77 H 2.78) N 6.45. Example 7. 1- (M, M-Dimethylthiocarbamoyl) -4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole. To a solution of 5.0 g (0.014 mol) of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole in 50 ml of tetrahydrofuran, add dropwise 15 ml of a 1.6 M solution of methyl lithium, and then a solution of 5.5 g (0.045 mol) of dimethylthiocarbamoyl chloride in 25 ml of tetrahydrofuran. The reaction mixture is refluxed for several hours, then concentrated on a rotary vysarny apparatus. The residue is shaken with ether and 1N hydrochloric acid, the ether layer is washed with 10% sodium bicarbonate solution, dried and concentrated. The residue (7.8 g) is purified by chromatography on silica gel, eluting with toluene, to give 0.8 g of product, mp. 133133, 5 ° C (with recrystallization from methylcyclohexane). Found: C 54.30, H 3.84; N 9.38. Calculated: C 54.67; H 3.87, N 9.57. Example 8. 1- (M, M-Dietsh1carbamoyl) -4,5-diphenyl-2- (1, I, 2,2-tetrafluoroethylthio) imidazole-1-carboxamide, Mixture of 2.0 g (0.006 mol) 4, 5-Diphenyl-2- (1,1,2,2-tetrafluoroethyltich) imidazole and 10.0 g (0.074 mol) of diethylcarbamoyl chloride are heated under reflux for 2 hours. The Exile diethylcarbamoyl chloride is removed under high vacuum. The residue is chromatographed on silica gel, diluted with toluene, and 1.5 g of product are obtained, mp. 108109 C (from methylcyclohexane). Found: С 58, ЗЗ; H 4.72, N 9.27. . Calculated: C 58.54, H 4.66, N 9.3 PRI me R 9. M-Methyl-H- (methylaminocarbonyl) -4,5-diphenyl-2- (1,1,2, - tetrafluoroethylthio) imidazol-1-carbox amide. To a solution of 15.0 g (0.263 mol) of methyl isocyanate and 5.0 g (0.014 mol) of 4,5-diphenyl 2- (1,1,2,2-tetrafluoroethyl) imidazole in 50 ml of tetrahydrofuran and add a catalytic amount potassium tert-butoxide. The reaction mixture is stirred at room temperature for several hours, then concentrated on a rotary evaporator. The residue is shaken with ether and 1N hydrochloric acid. The ether layer is washed with 10% sodium bicarbonate solution, dried and concentrated. The residue is triturated with petroleum ether and collected to give 4.8 g of crystals. A sample (2.5 g) is purified by chromatography on silica gel, ether, chloroform, and a crystalline product is obtained (from methylcyclohexane), mp. 107-108.5С. Found: C, 54.19; H 3.86, N 11.92, 12.01: C, 54.07; H 3.86; N, 12.01. Example 10. 1-Benzyloxycarbonyl-4, 5-difesh-2- (1,1,2,2-tetrafluoroethylthio) imidazole. To a solution of 5.0 g (0.014 mol) of 4.5 gdiphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole in 50 ml of glyme was added 1.7 g (0.015 mol) of potassium t-butoxide. The mixture is cooled and a solution of 5.0 g (0.029 mol) of benzyl chloroformate in 25 ml is added dropwise. The reaction mixture is stirred at room temperature overnight, then poured onto water. The mixture is then extracted with ether, and the collected ether extracts are dried, dried, and concentrated to give 12.1 g of crystals. The product is purified by chromatography on silica gel eluting with toluene, and (from hexane) 2.1 g of colorless crystals are obtained, mp. 110lll c. Found: C, 61.85; H, 3.82; N 5.62. Cj5H aF4NriOrtS. Calculated: C 61.73, H 3.73. 18 Example 11, 4,5-Lis (4-Fluorophenyl) -1- (pivaloylximethyl) -2- (1,1, 2,2-tetrafluoroethylsulfonyl) imidazole. In a solution of 5.0 g (0.012 mol) of 4,5-bis (4-fluorophenyl) -2- (1,1,2,2-tetrafluoroethylsulfonyl) imidazole in 50 ml, 1.7 g are added dropwise in a drop (O, 015 mol) tert-butoxide potassium, and then a solution of 4.6 g (0.031 mol) of chlorotethylpivalate in 25 ml of glyme- “catalytic amount of potassium iodide. The reaction mixture was heated at reflux overnight, then poured onto water. The aqueous mixture is extracted with ether. The collected ether extracts are washed, dried and. concentrated, giving 13.4 g of a crude oily product. The product is purified by chromatography on silica gel, eluting with toluene, and (from methylcyclohexane) 4.1 g of crystals are obtained, v. Mp. 121-125.5C., Found: C 52.10, H 3.80; N 5.10. Calculated: C 51.69, H 3.75, N 5.24. Example 12.1-Benzenesulfonyl-4, 5-diphenyl-2- (1,1, 2,2-tetraft-ethylthio) imidazole. To a stirred solution of 7.0 g (0.02 mol) of 4,5-diphenyl-2- (1,1,2, c2-tetraf orethylthio) imndazole in 50 ml of glyme, 3.4 g (o, 03 mol) are added. a) tert-butoxide potassium. The mixture was stirred for 5 minutes, then a solution of 5.3 g (0.03 mol) of benzenesulfonyl chloride was added dropwise. The mixture was stirred for 1 h at, then overnight at room temperature. The mixture is suspended on ice water, the crude solid is collected and washed with water and hexane to give 12.4 g of a tan solid, which is purified by chromatography on silica gel, eluting with toluene, and prepared. 7.2 g of white crystals, so pl. 171.5172, 5С - (from methylcyclohexane). Found: C 56.45, H 3.32; N 5.65. In isleno: C 56.09; H 3.27; N 5.69. Example 13. 1-Acetyl-4,5-dienyl-2- (1,1,2,2-tetrafluoroethylthioemica eol). A mixture of 1.8 g (0.005 mol) of 4,5-dew-2- (1,1,2,2-tetrafluoroethi1Tio) imidazole and 25 ml of acetic anhydride is heated under reflux for 7 h, cooled and stirred at room temperature 4. days The main amount of acetic anhydride and acetic acid is removed under reduced pressure (about 0.5 mm Hg). The resulting white solid product is chromatographed on a shaker gel eluting with toluene, and 0.8 g of a white product is obtained, mp. 143-144C (from hexane). Found: C, 57.80; H 3.47; N 7.25, C, gH ,. Calculated: C 57.86; H 3.58, N 7.1 Example 14. 4,5-Diphenyl-2- (1,1,2,2-tetrafluoroethylthio) -1 - (2-tet rahydrofuranyl) imidazole. In a stirred solution of 1.8 g (0.005 mol) of 4,5-diphenyl-2- (1,1,2,2-tetrafluoroethylthio) imidazole and 5 g (0.05 mol) of triethylamine in 20 ml of tetrahydrofuran are added dropwise At room temperature, a solution of 2-chloro-tetrahydrofuran obtained by adding 2.4 g (0.018 mol) of sulfuryl chloride to 30 ml of tetrahydrofuran is expected, and the temperature of the exothermic reaction is expected to drop to room temperature. The reaction mixture was stirred at room temperature for 4 days, then poured into ice-cold water containing sodium bicarbonate in excess. The aqueous mixture is extracted with methylene chloride, dried, and concentrated. The crystalline residue is purified by chromatography on silica gel, eluting with toluene, to give 1, 6 g of product, mp. 145 Nb C (from methylcyclohexane). Found: C, 60.05; H 4.41; N 6.66. Ca HiftF N OS. Calculated: C, 59.71; H 4.30; N 6.6 The anti-arthritis and analgesic agents according to the proposed invention can be administered for the purpose of treating arthritis and / or anesthesia by any means that determine the corresponding contact of the active ingredient with the body of the mammal. Claims of the invention A method for producing I-substituted-4,5-diaryl-2 (substituted thio) imidazolone, their sulfoxides or sulfones of the general formula: p O or 2; RY - Cp2 or CFjCHFjI Y and Y 2 independently of each other, selected from the group | containing hydrogen, CHjO- or fluorine; R / j. alkyl, allyl, (Yaz) -1, —CH.NW, 2-tetrahid1) ofuranyl, and —CNfife —I-t NiR). CQg ,, -50,3,0 -SO, jAr, Rj methyl R - benzyl, or-CH / j CHi OCHg; RC - Ethyl or Benzyl; R-7 - ethyl; RQ, Rf ,, Rg methyl; - WITH; - C d. Alkyl. provided that if Rn tR), (CQ) 2 ,, -CN {Qj,), O9 C "9, -CKr, -50.0. 0 ,. I deny the fact that the formula of formula),; , R, Y, Y, have the indicated meanings, interact with the one selected from the group, containing -C,. haloalkyl, haloallyl, projectile loader dimetilaminoztil, galoidenziloksimetil, halide |. 4 mettoksimetil, halogen acyloxy, wherein the acyl group ogranichekilom or benzyl, alkyl enzil, galogenformat, and galoiddimetil galoidtsimetilkarbamoil, dimetiltiokarbamoilgaloid, 2-galogentetragiDrofuran, galoidaroily, galoidalkansulfonipy, galoidarilsulfonily, C -C 2 alkyl isocyanates or alkane carboxylic anhydrides with alkyl groups with 1-A carbon atoms, at temperatures from -78 s to the boiling point of the solvent with the release of the target product that Priority signs: 09.0-2.77 when p is O or 2; Y ;, and each H, F, where Ld - benzyl; R5 is ethyl. 05.01.78 with p O or 2; Y and YQ are the same or different H, F, CHjO; R - - C, -C. - alkyl, allyl, CH, jCH.N (R3) i, -CHjOR, 2-tetrahydrofuranyl, C-ORg, -CNIQ,), CNlPg), and "9 Jiftr, -" v or methyl; R 4- is benzyl or R 5 is ethyl or benzyl; R6 is methyl; R is ethyl; Rg is methyl, Rg is methyl. Sources of information that are considered in the examination. US patent 3505350, 210-309, published. 1970.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU867301A3|1981-09-23|Method of preparing 1-substituted-4,5-diaryl-2-substituted thioimidazoles their sulfoxides or sulfones
    US5079264A|1992-01-07|Chemical process
    US4267184A|1981-05-12|Antiinflammatory 4,5-diaryl-2-|pyrroles and their corresponding sulfoxides and sulfones
    SU622405A3|1978-08-30|Method of producing 1-aryl-2|-alkyl ethers, thioethers or their salts
    HU211296A9|1995-11-28|Lignan analogues, methods of preparation thereof and anti-hyperlipemic agents
    DE69922009T2|2005-04-07|IMIDAZOL COMPOUNDS AND THEIR USE AS ADENOSINDEAMINASE INHIBITORS
    DE3044794C2|1990-02-15|
    US4294972A|1981-10-13|1,2-Disubstituted oxo triazolidine
    EP0541594A1|1993-05-19|Cyclopentane derivatives, process for producing them and their pharmaceutical use.
    CA1126275A|1982-06-22|Antiinflammatory 4,5-diaryl-2-|- pyrroles and their corresponding sulfoxides and sulfones
    EP1112265B1|2004-01-14|2-arylalkylthio -imidazoles, 2-arylalkenyl -thio -imidazoles and 2-arylalkinyl -thio -imidazoles as anti -inflammatory substances and substances inhibiting the release of cytokine
    US4702763A|1987-10-27|Herbicidal 1-aryl-delta2-1,2,4-triazolin-5-ones
    EP0273528A1|1988-07-06|Benzophenones and their preparation
    EP0350437B1|1995-09-06|3,4-Disubstituted phenyl-heterocycles and their use
    WO1985001637A1|1985-04-25|Herbicidal 1-aryl-delta2-1,2,4-triazolin-5-ones
    US5493032A|1996-02-20|Process for the preparation of substituted difluorobenzo-1,3-dioxoles
    US4888338A|1989-12-19|5-Methoxy alkyl ammonium tetrahydrofurans and tetrahydrothiophenes as anti-PAF agents
    US5068390A|1991-11-26|1,1,1-trifluoro-2-propene compounds
    US4079145A|1978-03-14|Certain pyrrolidone derivatives and pharmaceutical use thereof
    US6936632B2|2005-08-30|Fused pyrrole compounds, pharmaceutical agents containing the same, and the use thereof
    US5010100A|1991-04-23|Certain 2,5-diaryl tetrahydrofurans and analogs thereof as PAF antagonists
    US4262008A|1981-04-14|2,4-Disubstituted 5-oxo-5H-hexahydrofuro[3,2b]pyrroles
    JPH0830063B2|1996-03-27|Novel imidazole derivative and its salt
    DE4021007A1|1992-01-09|Amino diol DERIVATIVES
    US4241074A|1980-12-23|Prostaglandin analogues
    同族专利:
    公开号 | 公开日
    SE7801466L|1978-08-10|
    IL53996D0|1978-04-30|
    ATA87078A|1980-12-15|
    NO149813C|1984-06-27|
    DE2805166A1|1978-08-10|
    AU3309778A|1979-08-16|
    IT7820079D0|1978-02-07|
    IE46454B1|1983-06-15|
    PT67625A|1978-03-01|
    IL53996A|1982-04-30|
    FI68619B|1985-06-28|
    FI68619C|1985-10-10|
    GB1587373A|1981-04-01|
    DK16878A|1978-08-10|
    NO780432L|1978-08-10|
    AT363076B|1981-07-10|
    LU79028A1|1979-05-25|
    CA1107286A|1981-08-18|
    PT67625B|1979-07-17|
    JPS53130665A|1978-11-14|
    MX5934E|1984-08-30|
    HU181868B|1983-11-28|
    IE780280L|1978-08-09|
    NO149813B|1984-03-19|
    GR64157B|1980-02-05|
    FI780429A|1978-08-10|
    NL7801454A|1978-08-11|
    AR221590A1|1981-02-27|
    FR2380264A1|1978-09-08|
    IT1092439B|1985-07-12|
    CH643834A5|1984-06-29|
    ES466793A1|1979-08-01|
    US4182769A|1980-01-08|
    NZ186411A|1981-03-16|
    AU524360B2|1982-09-16|
    YU28978A|1983-01-21|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    SE345453B|1965-10-21|1972-05-29|Ciba Geigy Ag|
    US3929807A|1971-05-10|1975-12-30|Ciba Geigy Corp|2-Substituted-4--5--imidazoles|
    US3707475A|1970-11-16|1972-12-26|Pfizer|Antiinflammatory imidazoles|
    JPS5343958B2|1972-07-29|1978-11-24|DE2823197A1|1978-05-24|1979-11-29|Schering Ag|NEW IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM|
    US4308277A|1978-08-10|1981-12-29|Ciba-Geigy Corporation|2,4,5-Trisubstituted imidazolines and pharmaceutical compositions containing same|
    CY1344A|1978-08-10|1987-01-16|Ciba Geigy Ag|Substituted anthranilic acid amides,process for their preparation,and pharmaceutical compositions containing them|
    US4199592A|1978-08-29|1980-04-22|E. I. Du Pont De Nemours And Company|Antiinflammatory 4,5-diaryl-2-nitroimidazoles|
    DK337779A|1978-10-02|1980-04-03|Du Pont|METHOD FOR PREPARING ANTI-INFLAMMATORY 2-SUBSTITUTED 1H-PHENANTRO-IMIDAZOLES|
    DE2856909A1|1978-12-28|1980-07-17|Schering Ag|NEW IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM|
    IT1110282B|1979-02-19|1985-12-23|Acraf|BASIC THIO-INDAZOLS|
    DE3025484A1|1980-07-03|1982-02-04|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM|
    US4438117A|1980-09-03|1984-03-20|E. I. Du Pont De Nemours And Company|2-Substituted thio-4,5-diarylpyrimidines|
    US4355041A|1982-01-04|1982-10-19|E. I. Du Pont De Nemours And Company|4,5-Bis--1--2-[sulfonyl]-1H-imidazole, composition and use|
    US4503065A|1982-08-03|1985-03-05|E. I. Du Pont De Nemours And Company|Antiinflammatory 4,5-diaryl 1-2-halo imidazoles|
    ZA826501B|1982-09-06|1984-04-25|Du Pont|Anti-hypertensive imidazole derivative|
    DE3504678A1|1985-02-12|1986-08-14|A. Nattermann & Cie GmbH, 5000 Köln|Novel imidazolyl-oxyalkanoic acids and -thioalkanoic acids, derivatives thereof, and processes for their preparation|
    DE3508665A1|1985-03-12|1986-09-18|Hoechst Ag, 6230 Frankfurt|HETEROCYCLIC SULFIDES AND THEIR USE AS IMMUNO MODULATORS|
    US4686231A|1985-12-12|1987-08-11|Smithkline Beckman Corporation|Inhibition of 5-lipoxygenase products|
    US4780470A|1986-08-19|1988-10-25|Smithkline Beckman Corporation|Inhibition of interleukin-1 by monocytes and/or macrophages|
    US5300519A|1988-07-06|1994-04-05|The University Of Sheffield|Immunosuppressive agents|
    US5030644A|1989-07-31|1991-07-09|Merck & Co., Inc.|Imidazole compounds and their use as transglutaminase inhibitors|
    US5098707A|1989-07-31|1992-03-24|Merck & Co., Inc.|Imidazole compounds and their use as transglutaminase inhibitors|
    JPH03145473A|1989-10-27|1991-06-20|Hisamitsu Pharmaceut Co Inc|New imidazoleacetic acid derivative|
    GB9005966D0|1990-03-16|1990-05-09|May & Baker Ltd|New compositions of matter|
    DE4010797A1|1990-04-04|1991-10-10|Hoechst Ag|SUBSTITUTED AZOLES, METHOD FOR THE PRODUCTION THEREOF, MEANS CONTAINING THEM AND THE USE THEREOF|
    IL133766D0|1997-06-30|2001-04-30|Ortho Mcneil Pharm Inc|2-substituted imidazoles useful in the treatment of inflammatory diseases|
    FR2823747B1|2001-04-24|2003-05-23|Oreal|NOVEL COMPOUNDS OF THE FAMILY OF 3-ALKYL-AND THEIR USE AS ANTI-INFLAMMATORY|
    CA2955582C|2014-07-18|2021-03-16|Ohio University|Imidazole and thiazole compositions for modifying biological signaling|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US76721977A| true| 1977-02-09|1977-02-09|
    US05/865,831|US4182769A|1977-02-09|1978-01-05|Anti-inflammatory 1-substituted-4,5-diaryl-2- imidazoles and their corresponding sulfoxides and sulfones|
    [返回顶部]