• 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:
    Antiinflammatory4,5-diaryl-2-(substituted-thio)-pyrroles and their corresponding sulfoxides and sulfones, useful for treating arthritis and related diseases.
    公开号:SU1160934A3
    申请号:SU813248461
    申请日:1981-02-19
    公开日:1985-06-07
    发明作者:Карл Черковски Саул
    申请人:Е.И.Дюпон Де Немур Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of novel pyrrole derivatives with anti-inflammatory effects. A known method for producing thioethers by reacting sulfenyl chlorides with compounds containing a mobile hydrogen atom of 1 J. The aim of the invention is to develop compounds based on the well-known method of the method of obtaining novel compounds with valuable pharmacological properties. This goal is achieved by the method of obtaining 2-thio-substituted pyrroles of the general formula {X}. RI1 $ (0) pSPRs, where K 4-CH3 (0) PS (, R 4-PC H4ILI and 4-CH3 8 H4;), which means that the compound of the general formula (IO Y H where R. and i have the indicated values are treated trifluoromethiolsulfenyl chloroids in the presence of sodium carbonate in an inert organic solvent at a temperature of from -78 ° C to room temperature followed by or injecting the target product as a compound of the general formula (1) where, or by oxidizing it with m-chloroperbenzoic acid. (4-fluorophenyl) 2- (4-methoxythiophenyl) -5- (trifluoromethylthio) -1H-pyrrole. A. 2- (4-fluoropensch1) -1- (4-methylthiophenyl) -ethane to a stirred mixture of 75.4 g (0.438 mol) of 4-fluorofensh-acetyl chloride and 54.4 g (0.438 mol) of thioanisole in 500 ml of methylene chloride, cooled in an ice bath, 58.3 g (; 0.438 mole) aluminum chloride for about 20 minutes, The mixture was stirred for another 1.5 h in an ice bath, then drank in 1 liter of 1N hydrochloric acid. The mixture was extracted three times with methylene chloride. The combined organic layers were washed with saturated aqueous sodium bicarbonate, 5% sodium hydroxide solution, saturated salt solution, dried and concentrated m on a rotary evaporator. The residue is triturated with cold ethanol and collected to give 99.7 g (88%) of an off-white solid, i.e. 135-138C. B. 2- (4-fluorophenyl) -4- (dimesh1hydrazon) -1- (4-methylthiophenyl) -2-butene-1-one. To a mixture of 52 g (0.2 mol) of 2- (4-fluorophenyl) -1- (4-methylthiophenyl) ethanone and 22 g (0.22 mol) of glyoxalmono (dimethyl hydrazone) in 200 ml of ethanol, a solution is added dropwise sodium ethoxide, crawled from 5.1 g (o, 22 mol) of sodium in 200 ml of ethanol. The mixture was heated under reflux for 3 h, then stirred at room temperature overnight. The mixture is concentrated on a rotary evaporator. The residue is diluted with water and extracted three times with methylene chloride. The organic layers are combined, dried, and concentrated. The residue is recrystallized from methylcyclohexane to give 46.4 g (68%) of a yellow solid, m.p. 129ISO C. B. 3- (4-fluorophenyl) -1H-pyrrole. 46.4 g {O, 136 mol) 2- (4-fluorofensch1) -4- (dimethylhydrazon) -1- (4-methylthiophenyl) -2-butene-T-one in 400 ml of ethanol and 250 ml of water were immediately added to the stirred mixture. 153.8 g (0.884 mol) of sodium hydrogen sulfate. The mixture is heated under reflux for 3 h, then cooled to room temperature. 50 ml of water are added, then the mixture is drunk in 2 l of ice water, the precipitated solid is collected, washed with water, dried, then recrystallized from ethanol / water to give 28.2 g (87%) of a white solid, mp. 164-165C. G. 3- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (trifluoromethylthio) -1H-pyrrole. Into a stirred mixture of 2.8 g (0.01 mol) of 3- (4-fluorophenyl) -2- (4-methylthiophenyl) -1H-pyrrole and 2.1 g (0.02 mol) of sodium carbonate in 50 ml of ether at reflux. A solution of 1.5 g (0.011 mol) of trifluoromethanesulfenyl chloride in 2 ml of cold ether is added by nickname with dry ice. The mixture was stirred at -78 ° C for 1 h, then warmed to room temperature. The mixture is filtered to remove inorganic salts. The filtrate is concentrated and the residue is purified chromate. graphing on silica gel, eluted with hexane / toluene mixtures (60 / 4.0). The xp matched product is recrystallized from ethanol / water to give 3.5 g of a white solid, mp: 106-107 s. Calculated,%: C 56.39; H 3.42; N 3.65. Found X: C 56.30; H 3.52-, N 3.71. Example 2. 3- (4-fluorophenyl) 2- (4-methylsulfonylphenyl) -5- (trifto methylthio) -1H-pyrrole. A. 3 -, (4-fluorophenyl) -2- (4-methylsul fonylphenyl) -1H-pyrrole. In a stirred mixture of 28.3 g (0.1 mol). 3- (4-fluorophenyl) -2- (4-me .thylthiophenyl) -1H-pyrrole in 850 ml of ethyl acetate in an ice bath, is added dropwise a solution of 50 g (, 25 mol) of 85% ln-chlornadoc sibenzoic acid in 500 ml of ethyl acetate. The mixture is stirred at 3 hours, then at room temperature overnight. The mixture is again cooled to 0 ° C, the crystalline product is collected, washed cold with ethyl acetate, then dried. The NMR spectrum detected the content of 80% sulfone and A20% sulfoxide, the solid substance was dissolved in 2 liters of hot ethyl acetate (at 65 ° C) and the amount of 4.0 g of chloroacetic benzoic acid was added. The mixture is cooled to room temperature, then cooled in an ice bath. The crystalline precipitate is collected, washed with cold ethyl acetate, then dried in air to obtain 17.1 g of 4-BSbH4. In 4-CH5 $ 02СбН4 Product of Example 2. For Example 3, item 1, for Example 4 is 55. 3.7 g (9 mmol) of the compounds of Example 2 were measured under nitrogen in ethyl acetate (200 ml) at room (54%) of a colorless product, mp. 268-270C. B. 3- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) -5- (trifluoromethylthio) -1H-pyrrole. To a mixture of 15.8 g (0.05 mol) of 3- (4fluorophenyl) -2- (4-methylsulf6nylphenyl) -H-pyrrole and 10.6 g (0.1 mol) of sodium carbonate in 300 ml of tetrahydrofuran and 300 ml of ether at -78 ° C and under reflux with dry ice in the form of a gas, 2.8 g (0.095 mol) of trifluoromethanesulfenyl chloride are added. The mixture was heated to room temperature (with reflux with dry ice) and stirred for 3 hours. The mixture was again cooled to -78 ° C and / - 3.0 g of trifluoromethanesulfenyl chloride was added as a gas. The mixture was stirred overnight at room temperature (with refluxing with dry ice for several hours). An additional 3.0 g of trifluoromethanesulfenyl chloride was added, as indicated above, and the mixture was stirred for three days at room temperature. The mixture is filtered to remove inorganic substances and the filtrate is concentrated to give 21.8 g of a solid. It is purified by chromatography on silica gel, eluted with toluene containing 4-8% ethyl acetate to obtain, after recrystallization from ethanol / water, 18.2 g (88%) of the product as a white solid with mp. 204-206 C. The sample obtained in a similar way, gives so pl. 203-204 s and the following microanalytical results. Calculated C, 52.04; H 3.15; N 3.37 ,, C, 8H, 3F NOjb-i Found: C, 52.29; H 3.17; N 3.25. Example zi4. 4-RSbN4 :, iT –sn5 $ 02SbN4 15g $ (o) „at 5 ° C, adding 85% l-chloroperoxybenzoic acid (2.0 g in 50 ml of ethyl acetate) to the solution. Then it is stirred at room temperature for 5.5 hours after which the reaction mixture is diluted with ethyl acetate, washed three times with 10% sodium bicarbonate solution, dried with magnesium sulfate and evaporated.
    The residue is purified by high-performance liquid chromatography (95: 5 5 methylene chloride-ethyl acetate eluent). Two fractions of the pure product are obtained by recrystallization from a solution of ethanol in water (80% by volume).
    O, .6 g (16% yield) of the compound at Primer 3, m.p. 220-22I C.
    Calculated,%: C 50.11; H 3.04; N 3.27 .SF
    Found,%: C 50.6-, H 3.1; N 3.3. 15
    0.75 g- (yield 19%) of the compound of Example 4, m.p. 280-282 ° C; PMR, A 3.2 (s, 3N); 6.9-7.5 (m. 5K) 7.5-8.0 (AB squ., 4H).
    Example 5. 2- (trifluoromethyl- 20 thio) -4- (4-fluorophenyl) -5- (4-methylsulfinylphenyl) -pyrrole.
    A slurry of 2- (4-methyl-1-sulfinylphenyl) 3- (4-fluorophenyl) -pyrrole (2.5 g, 8 mmol) in 100 ml of DIELETRATE 10THE ether and 100 ml of tetrahydrofuran is treated with sodium carbonate (1.7 g, 16 mmol), cooled to and treated with gaseous trifluoromethylsulfenyl chloride, (1.4 g, 10 mmol). 30 The reaction mixture was then stirred at 7.5 hours and then allowed to warm to room temperature overnight. The reaction mixture is filtered and concentrated in vacuo. Chromatography on; silica gel and recrystallization from methylcyclohexane / toluene to give the title compound (2.1 g) with mp. 226-228 C. The IR, proton and fluorine 40 NMR spectra correspond to the proposed structure. Mass spectrum: t / g 399 (M)., Yield 66%.
    Calculated,%: C 54.14-, H 3.28i N.3.51.45
    c; n
    Found,%: C 54.3 j 54.5; H 3.4,4, 3; N 3.4; 3.4.
    . Example 6. 2- (trifluoromethylthio) -4, (4-methylthiophenyl) pyrrole, 50
    A solution of 2,3-bis- (4-methyl 1-pyrene) 1 pyrrole (4 g, 13 mmol) in 100 ml of diethyl ether and 50 ml of tetrahydrofuran is treated with sodium carbonate (2.8 g, 26 mmol), cooled to 55 and then treated with gaseous trifluoromethylsulfenyl chloride ( 2.1 g, 15 mmol). Reaction mixture
    stirred at for one and a half hours, filtered and concentrated in vacuo. Chromatography on:. silica gel and recrystallization from hexane to give the title compound (3.6 g), mp. 110-111 6. The ICT of the proton and fluorine-H1-1-R spectra correspond to the proposed structure of the Mass Spectrum: rn / z 411 (M), yield 68%. Calculated,%: C 55.48 ", H 3.92; N 3.40J
    С;, ЭН, 4Ы8зРз
    Found,%: C 55.8; 55.6, H 4.0; 4.0; N 3.7; 3.7.
    Example 7. 4- (4-fluorophenyl) 5- (4-methylsulfonylphenyl) -2- (methylthio) -1H-pyrrole.
    4- (5-fluorofensch1) -5- (4-methylsulfonylphenyl) -2-thiociano-1H-pyrrole (24.0 g) are weighed in methanol (200 ml) and treated with KOH (1.1 eq. In water (100 ml) After stirring for 1 hour and removing the solid by filtration, the filtrate is concentrated and the residue is dissolved in toluene (150 ml). After holding the solution overnight, a precipitate is formed in an amount of 4.0 g. Chromatography of the mother liquor (SiOj; 6: 4 toluene-ethyl acetate), an additional product is obtained which is combined with the first portion, triturated with ether and petroleum ether and dried, yielding 11.8 g per . Vannogo product, m.p. 168-171S (with decomposition) This product is also prepared .If adding methyl iodide in methanol, the reaction mixture after zabuferoni Coj. Yield: 51%, MS: m / z 361 (M).
     The method for determining and comparing the anti-inflammatory effects of the compounds obtained is a test in rats in which arthritis is caused by the administration of a special agent. The method for determining and comparing the analsetic effect of the compounds is the phenylquinone paw reaction test. Methods for testing the anti-inflammatory and analgesic effects are described below.
    Artificially induced arthritis in rats. Charles River Lewis male rats (weighing 130-150 g each) were subcutaneously injected into the region of the base with a right hind leg 0.1 ml of auxiliary .711 body agent, destroyed by heating, the lyophilized microorganism Mycobacterium butyricum, suspended in mineral oil, 4.5 mg / ml Experimental animals hold 2 weeks to allow arthritis to develop. 20 non-arthritic control animals are injected with mineral oil. Then, the volume of the untreated left hind paw is measured, animals treated with the agent are selected and divided into groups in 10 rats of the same stage of the disease. Untreated control animals are divided into two groups of 10 copies each. The wings themselves are administered orally by a compound or a mixture,%: polyvinyl alcohol 1, gum arabic 5, methyl paraben 0.5 in an amount of 10 ml / kg on this day and for the next 6 days. One day after the last dose, paw volume (untreated posterior left) was measured using a differential volume meter 7101. Processed Control. (average volume group (average paw volume, ml) paws, ml) Control (non-arthritic control (arthritic) | rhythmic) (average volume. (average paw volume, ml) of the paw, ml)% decrease compared to control by average paw volume. Curves to reduce the response to the input doses in% are plotted on millimeter paper according to visual observation, the decrease compared to the control (paw volume) is determined by checking. The results are shown in table 1. Table Biological Activity Continued Table. 1 „.L AA, 51 mg / kg of Example 3 AA, 8 mg / kg of Example 4 The compound of Example 2 has an effect on rats after its oral administration for 12 days, with a therapeutic ratio greater than 40 (the therapeutic ratio means the maximum no effect in toxicity testing for 12 days in rats with an ED value relative to arthritis caused by Mycobacterium butyricum in mineral oil). In addition, the compound of Example 2 is not mutagenic in the Ames in vitp mutagenicity test. 2-alkyl-4,5-diphenyl-pyrrole used as anti-inflammatory agents is known. As can be seen in Table 2 below, the obtained -ED value is 0.6 mg / kg, which means an activity comparable to the compounds according to the invention. table 2
    2
    0.5
    3 0.6 4 8.4 5 1 6
    6. 7
    1,2 nE 2-methyl4, 5-5is (p-methoxyphenyl) pyrrole 2-ethyl4, 5-5c (p-methoxyphenyl) pyrrole 2-H-butyl 4,5-5is (p-methox phenide) pyrrole O 4 Continued tab. 2 2-ysobutyl-4, 5bis- (pmethoxyphenyl) pyrrole The compound of Example 2 of the present invention was tested in an experiment with edema caused by carrageenin, and you dreamed that it possessed ED5 .. It follows that with the experience with edema caused by carrageenin, it is better The distinctive signs of various kinds of activities are revealed. After conducting this experiment, the great strength of the compounds of the present invention is drawn especially clearly compared to lime compounds.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING 2-THIOSAME · HYDROGEN PYRROLES of general formula (T)
    AND
    S (O) n CF 3 .
    where K 4-CH 3 S (0) h C b H 4 ; R <4-FC b H 4 or 4-CH 3 SC € H 4; η = 0-2, characterized in that the compound of general formula (s)
    And where are R and Rn have the indicated values are treated with trifluoromethiosul phenyl chloride in the presence of sodium carbonate in an inert organic solvent at a temperature from -78 ° C to room temperature, followed by isolation of the target product in the form of a compound of general formula (i), where n = 0 ,: or oxidation with chloroperbenzoic acid.
    SU <„, 1160934
    1 1160934
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    同族专利:
    公开号 | 公开日
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    JPS56150060A|1981-11-20|
    CA1144550A|1983-04-12|
    FI804028L|1981-08-20|
    ZA808109B|1982-07-28|
    AU6403280A|1981-08-27|
    YU279080A|1983-10-31|
    GR70770B|1983-03-16|
    ATA73981A|1983-10-15|
    EP0034798A2|1981-09-02|
    ES499559A0|1983-01-01|
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    PH17299A|1984-07-18|
    ES8302652A2|1983-01-01|
    EP0034798B1|1985-05-22|
    AT374796B|1984-05-25|
    JPH0250902B2|1990-11-05|
    引用文献:
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    US3709906A|1968-07-26|1973-01-09|Sankyo Co|2-alkyl-4,5-diphenylpyrrole derivatives|
    DK75779A|1978-03-13|1979-09-14|Du Pont|4,5-DIARYL-2- PYRROLES AND SULFOXIDES AND SULPHONS THEREOF AND PROCEDURES FOR THEIR PREPARATION AND USE|US4495196A|1980-07-17|1985-01-22|E. I. Du Pont De Nemours And Company|Antiinflammatory 4,5-diaryl-α-polyfluoroalkyl-1H-pyrrole-2-methanols and method for use thereof|
    US4438117A|1980-09-03|1984-03-20|E. I. Du Pont De Nemours And Company|2-Substituted thio-4,5-diarylpyrimidines|
    US4652582A|1985-01-09|1987-03-24|E. I. Du Pont De Nemours And Company|Antiinflammatory-2-halo-4,5-diarylpyrroles|
    US5284863A|1991-12-04|1994-02-08|American Cyanamid Company|Haloalkylthio, -sulfinyl and -sulfonyl arylpyrrole fungicidal agents|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/122,501|US4267184A|1979-02-08|1980-02-19|Antiinflammatory 4,5-diaryl-2-pyrroles and their corresponding sulfoxides and sulfones|
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