• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 优先权
    • 专利摘要:
    This invention relates to pharmaceutical compositions containing as active ingredient an aryltrifluoroethanol, and a process for producing the same. These pharmaceutical compositions are useful for treating or alleviating pain, hyperpyretic conditions and/or inflammatory states.
    公开号:SU925247A3
    申请号:SU792843404
    申请日:1979-11-02
    公开日:1982-04-30
    发明作者:Вэнсан Мишель；Ремон Жорж；Бюре Жак
    申请人:Сьянс Юньон Э Ко (Инофирма)；Сосьете Франсэз Де Решерш Медикаль (Инофирма)；
    IPC主号:
    专利说明:

    ί The invention relates to a method for producing new derivatives of 1 (-4-aminophenyl) -2,2,2-trifluoroethanol or their salts of the general formula
    where Ζ is hydrogen, C g . 6- alkyl, 10 lower cycloalkyl, an acyl residue of ((lower alkyl) -carboxylic acid, chlorobenzoic acid or pyridine-carboxylic acid of the formula
    Ν == γΰ0ΟΗ 18
    Ol and Ζ - hydrogen or Ζ and Ζ 'together with N form the remainder of Ν- (lower alkyl-piperidine, or Ν- (phenyl) - (lower alkyl) -piperidine,
    R is hydrogen or lower alkyl, and also salts of compounds of formula I.
    It is known that some aniline derivatives containing an oxy group (for example, phenacetin, paracetamol) have a strong antipyretic, analgesic and anti-inflammatory effect [1].
    The purpose of the invention is the expansion of means of influence on a living organism.
    This goal is achieved by the method of obtaining new derivatives of 1- (4aminophenyl) -2,2,2-trifluoroethanol or their salts, based on the known reactions of amination of aryl halides [2] and reduction of xetoHOB to alcohols by the action of sodium borohydride [3] and consisting in what amine
    general formulaZand where z - hydrogen, C | _ 6 -alkyl or lower cycloalkyl; Z 1 is hydrogen;
    or Z and Z together with N form the remainder of N- (lower alkyl) piperidine. or N- [henyl- (lower alkyl)] piperidine, are reacted with 4-fluoro-phenylketone of the formula
    O III »0 isolate the intermediate 4-aminophenyl ketone of the General formula
    where Z and Z'have the meanings given in formula II, 20 l are reduced with sodium borohydride and 4-aminophenylethanol of the general formula is isolated
    a "L · OH V
    ί 'where Ζ and Ζ * have the meanings indicated in formula II, in free form 30 or in the form of its salt and / or a compound of general formula IV, where Ζ and Ζ 1 are hydrogen, acylated with acid chloride (lower alkyl) - carboxylic, chlorobenzoic or pyridinecarboxylic Acids of the general formula A in the presence of an organic base and the intermediate is reduced with sodium borohydride and / or a compound of the general formula V, where Ζ and Ζ * are as indicated in. formula I values, alkylate (lower alkyl) - halide in the presence of sodium ethylate and isolate the target product in free form or in the form of its salt.
    'NBC rule, the interaction of the amine of General formula 11 with 4-fluorophenylketone : formula 111 is carried out in polar. an organic solvent, for example dimethyl sulfoxide. ΙΟ
    The acylation of the compound of general formula IV is carried out in the presence of an organic base, for example triethyl · amine.
    EXAMPLE 1. 1 - (4-Acetaminophen-5S nyl) -2,2,2-trifluoroethanol.
    Stage A. 4-Aminophenyl- (trifluoromethyl) -ketone.
    50 g of 4-fluoro- (U-, d, <4-trifluoroaceto) phenone and 500 ml of a solution of ammonia in ethanol saturated at ordinary temperature are placed in an autoclave and the mixture is heated to 140 ° with stirring for 30 hours.
    After cooling, the reaction mixture is unloaded, degassed and evaporated to dryness. 150 ml of ether are added to the residue and insoluble matter is filtered off. Then the ether phase is extracted 4 times with 100 ml of 2 N. hydrochloric acid. The aqueous phases are separated, they are combined and neutralized with a saturated solution of sodium bicarbonate. The precipitate was filtered off, washed with water and dried in vacuo. 15.4 g of dry product are obtained, which consists mainly of 4-amino ("C," I, <L-trifluoroacetophenone) ..
    As a result of repeated extraction of the ethereal solutions, an additional semi-crystalline portion of weights of 1.8 g is obtained.
    The mother liquors are evaporated to dryness and the resulting oil is recycled to the autoclave at 140 ’for • 20 hours. An additional amount of 4-aminated product weighing 4.7 g is obtained. Yield 52%.
    Stage B. 4-Acetamino - «<, o (^ .- trifluoro-cetophene.
    10 g of 4-aminophenyl- (trifluoromethyl) -ketone obtained in Step A, 5.86 g of triethylamine and 60 ml of benzene are placed in a three-necked flask. Then, 4.5 g of acetyl chloride are added over 20 minutes while stirring and keeping the temperature below 10 ’using an ice-water bath. After addition, the reaction mixture was kept under stirring for 3 hours at ordinary temperature. The excess acetyl chloride is decomposed by adding a few drops of 40% caustic soda alkali, then 10 ml of water. The benzene phase is separated, washed with water, then with saturated sodium bicarbonate solution, then with water until neutral. After that, the benzene phase is dried and evaporated to dryness under reduced pressure.
    Thus, 8.7 g of acetamino-et, <4, </ - trifluoroacetophenone are obtained. An analytical sample is recrystallized from isopropyl ether. Mp pure product 02 °.
    Step C: 1- (4-acetaminophen) -2; 2,2-trifluoroethanol.
    925247 6
    8.2 g of 4-Acetamino <X, o (, <2-trifluoroacetophenone obtained in step B) are dissolved in 120 ml of methanol and 2.85 g of sodium borohydride are added in small portions, keeping the temperature of the reaction medium below 10 ° in a bath with cold water .. After adding the entire amount of reagent, the mixture is kept for 1 h with stirring at 10 ° C. The excess reagent is destroyed by adding several ml of 50% acetic acid, then the mixture is diluted with an equal volume of water and extracted three times with 25 ml of ether. combine, washed with water until tral, dried over sodium sulfate and evaporated to dryness.
    A dry residue of 9.46 g was obtained, which was purified by recrystallization from cyclohexane. Receive
    6.84 g of 1 - (4-acetaminophenyl) -2,2,2 trifluoroethanol as colorless crystals, insoluble in water, but soluble in methanol and ethanol.
    T. pl ', pure product 157-158 C. Calculated,%: C 51.51; H 4.32;
    N, 6.00.
    C io H io FjNO 2 = 233.20. Found,%: C 51.33; H 4.50;
    N, 6.18.
    Example!. 1- (4-Isobutyraminophenyl) -2,2,2-trifluoroethanol.
    By the method described in the example
    1, receive sequentially:
    4-isobutyrami- "X, <<, <L.-trifluoroacetophenone;
    - (4-isobutyraminophenyl) -2,2,2 trifluoroethanol in the form of colorless, not · ”water-soluble crystals. T. pl. 150 °.
    Calculated,%: ’C 55.17; H 5.40; N, 5.36.
    C 12 H l4 F 3 . N0 2 = 261.25.
    Found,%: C 55.17; H 5.46;
    N, 5.40.
    LimerZ. 1 - (4-Butyraminophenyl) -2,2,2-trifluoroethanol.
    According to the method described in example 1, starting from 4-aminotrifluoroacetophenone receive sequentially:
    4-butyramino-Ζ, D, and, trifluoroacetophenone;
    1- (4-butyraminophenyl) -2,2,2-trifluoroethanol; so pl. 120 ° (methanol). Calculated,%: C 55.17; H 5.40; N, 5.36.
    Cfc N M F 3 N0 2 = 261,25
    Naideno,%: C 55.52; H 5.41;
    N, 5.37.
    PRI me R 4. 1- (4 · -ΠροπΗθΗ3ΜΗΗρ phenyl) -2,2,2-trifluoroethanol.
    By the method described in the example.
    1, starting from 4-aminotrifluoroacetophenone, one obtains sequentially: 4-propionamido- <4, "1," 1-trifluoroacetophenone;
    ju 1 - (4-propionamidophenyl) -2,2,2-trifluoroethanol as colorless crystals with a melting point of 166-167 ° (recrystallized from water).
    Calculated,%: C 53.44; H 4.89; is N 5.67
    Cu H t2 Fj N0 2 = 247.22.
    Found,%: C 53.35; H 4.89;
    N, 5.67.
    PRI me R 5. 1 [(4-Chlorobenzoyl20 amino) phenyl] -2,2,2-trifluoroethanol.
    By the method described in the example
    1, based on 4-aminotrifluoroacetophe • non receive:
    (4-chlorobenzoylamino) -tri25 fluoroacetophenone;
    1- [(4-chlorobenzoylamino-phenyl] -2,2,1-trifluoroethanol with a melting point of 175 ’176 ° (recrystallized from water).
    Calculated,%: C 54.64; H 3.36; Zo N 4.25; Ct 10.75
    C u H n CtF s NQ Z = 329.71.
    Found,%: C 54.39; Η 3.54; N, 4.49; Ct 11.14.
    P p and m e p 6. 1- (4-Nicotinoyl35 aminophenyl) -2,2,2-trifluoroethanol.
    According to the method described in example 1 (stage B), based on 18.9 g of 4-amino-i, <= 1, D-trifluoroacetophenone and
    17.8 g of nicotinoyl chloride give 40 13.5 g of (4-nicotinoylamino) trifluoroacetophenone.
    By reduction with sodium borohydride according to the method described in example 1 (step C), 1- (4-no 4 5 cotinoylaminophenyl) -2,2,2-trifluoroethanol is obtained in 88% yield, mp. pure product 214-215 ° (water) ..
    Calculated,%: C 55.91; H 3.82;
    N.9.31.
    so C l4 H „F 3 N 2 0 2 = 300.75 50 Found,%: C 55.97; H 3.79;
    N, 9.36.
    Example/. 1 “[-4- (4-Methylpiperazinyl-) phenyl] -2,2,2-trifluoroethanol.
    55 According to the method described in example 1, starting from 4-fluoro-l, with {, about 1-trifluoroacetophenone and N-methylpiperazine are obtained sequentially:
    .4- (4-methylpiperazinyl-1) ~ d, d, a, trifluoroacetophenone with mp 54-55 °;
    -. [4- (4-methylpiperazinyl-1) -fe- ; nile] -2,2,2-trifluoroethanol with mp 192 C. Calcd: C, 56.93; H, 6.25;
    N, 10.21. C <5 H rr F, -N 2 0 = 274.29 Found,%: C 57.04; H 6.36;
    N, 10.20.
    Example 1 - (4-n-Hexadecylaminophenyl) -2,2,2-trifluoroethanol.
    Stage A. (4-n-Hexadecylaminophenyl) -2,2,2-trifluoroethanol.
    4-n-exadecylamino-2,2,2-trifluoroacetophenone.
    30 g of p-fluoro-a, a, a, trifluoroacetophenone, 44.5 g of freshly distilled n-hexadecylamine, 21.55 g of sodium carbonate and 75 ml of anhydrous dimethyl sulfoxide are placed in a three-necked flask. The mixture is heated to 100 ° with stirring and kept at this temperature for 6-7 hours. Then the suspension is allowed to cool to normal temperature and poured into 400 ml of water, stirred for 1 hour and then the mixture is extracted 3 times with 30 ml of ether. The ether phases are combined, washed with water, dried and evaporated to dryness. Get 58 ^ 5 g of an oily product, consisting mainly of 4- (n-hexadecylamino) - <£, ^. ^ - trifluoroacetophenone, which is used in this form in the next stage of synthesis.
    Stage B. (4-n-Hexadecylaminophenyl) -2,2,2-trifluoroethanol.
    g of 4- (n-hexadecylamino) - </, <4, Dtrifluoroacetophenone is dissolved in 260 ml of methanol and 9.97 g of sodium borohydride are added in small portions, maintaining the temperature of the medium 10 ° by external cooling. The reaction mixture is left under stirring for 4 hours, then the excess reagent is destroyed by adding acetic acid. After that, an equal volume of water was added to the reaction mixture, and after stirring for 1 h, the precipitate formed was filtered off. It is washed with water until the washings are neutral and dried at 60 ° under reduced pressure. 50.7 g of (4-n-hexadecylaminophenyl) -2,2,2-trifluoroethanol are obtained, which is recrystallized for analysis from isopropyl ether.
    1 pl. pure product 63-64. Calculated,% ·. C 69.36; H, 9.70;
    • N 3.37 '
    C 24 H 1B F 5 N0 = 415.59. 5 Found,%: C 69.40; H 9.39;
    N Z.Ts.
    The product is soluble in dilute solutions of acids, such as hydrochloric or acetic.
    Example!). 4- [(2,2,2-Trifluoro-1-hydroxyethyl) -4-aminophenyl] -1 - (phenyl-2-ethyl) piperidine.
    According to the method described in example 8, BASED ON 4-fluoro - </, at, ct-trifluoro15 acetophenone and -1 - (phenyl-2-ethyl) -4-aminopiperidine receive sequentially:
    4-) (2,2,2-trifluoro-1-ethanone) -4-amy nophenyl] -1 - (phenyl-2-ethyl) piperidine; M 4- [(2,2,2-trifluoro-1-hydroxyethyl) -4-aminophenyl] -1 - (phenyl-2-ethyl) piperidine with mp 120-122 ° (ether-pentane)
    This compound is dissolved in a precisely calculated equivalent amount of 0.1 N. of hydrochloric acid. The hydrochloride is isolated by evaporation of the solvent.
    Calculated, ^ C 66.65; H, 6.66;
    N 7.40 30 C 21 H 25 F 3 N 2 0 = 378.44
    Found D: C, 66.68; H 6.85; N, 7.27.
    Example 10. 1- (4-Acetaminophenyl) -1-ethoxy-2,2,2-trifluoroethane. 35 6.6 g of 4-p-acetaminophenyl-2,2,2 trifluoroethanol obtained in Example 1 is dissolved in 75 ml of ethanol and a solution obtained by the action of 0.5 g of sodium per 40 2 5 g of ethanol is added to it. The mixture was left at room temperature for one hour, then evaporated to dryness in vacuo.
    Thus obtained sodium salt is dissolved in 30 ml of dimethyl · 4 $ formamide at ambient temperature, then after complete dissolution, the solution is cooled to 10 ° and 4.2 ml of ethyl bromide pre-cooled to 0 ° are added to it. m. When ethyl bromide was added, the reaction mixture was cooled in a bath of water and ice. Then the temperature of the reaction mixture was allowed to rise to room temperature and stirring was continued for 4 hours.
    After that, the mixture was diluted with an equal volume of water and extracted 3 times with methylene chloride. The organic phases are separated925247, washed with 5% sodium carbonate solution, then with water, dried and the solvent is distilled off to dryness.
    The oily residue gradually crystallizes. 6.35 g of crude product are obtained, which is dissolved in benzene, then cyclohexane is added. The precipitated 1- (4-acetaminophenyl) -1-ethoxy-2,2,2 trifluoroethane is chromatographed on a silica column and eluted with a mixture of equal cyclohexane and ethyl acetate. 2.9 g of pure product are obtained with mp.
    Calculated,%: C 55.17; N, 5.36.
    C, 2 N m F } N0 = 261.25 Found,%: C 55.33; AND
    N, 5.43.
    132-1344. H 5.40;
    5.48;
    solvents.
    This compound is insoluble in water, but soluble in ordinary organic
    Example P. dM- [(4-Cyclobutylamino) phenyl] -2,2,2-trifluoroethanol.
    By the method described in the example *
    8, starting from 4-φτορ-οζо4, о »-triftor. acetophenone and cyclobutylamine receive [(4-cyclobutylamino) phenyl] -2,2,2 trifluoroethanol with so pl. 90 “92 °
    Calculated,%:
    H 5 ^ 82;
    C 12 H n F, N0 =
    Found,%: C
    N
    C 57.71; N, 5.62,246.75. 57.60; H, 5.31.
    5.79;
    PRI me R 12. d -1- [(4-Cyclopentylamino) phenyl] -2,2,2-trifluoroethanol.
    According to the method described in example 8, starting from 4-fluoro-a1, 1- ((4-cyclopentyl) phenyl] -2,2,2-trifluoroethanol with so pl. 100-101 °.
    Calculated,%:
    C u H ie F 5 N0 Found,%:
    C, 60.22; H, 6.22; N, 5.40; 259.27; 59.96; H 6.47,
    5.40.
    PRI me R 13. 1- (4-Tert-butylaminophenyl) -2,2,2-trifluoroethanol.
    By the method described in example 8 starting from 4-fluoro-a1, D, at-trifluoroacetophenone and tert-butylamine, are obtained sequentially:
    - (4-tert-butylaminophenyl) -b (, s (, s (- 5S “trifluoroacetophenone (b.p. 120 / 0.05 mm)
    1- (4-tert-butylaminophenyl) -2,2,2 trifluoroethanol with mp 87-89 *.,
    Calculated,%: C 58.53; H, 6.14; N, 5.69; F 29.14
    C " 2 Hte F t N0 = 247.26
    Found,%: C 58.39; H, 6.21; N, 5.74; F 23.09.
    A pharmacological study of the compounds is as follows.
    Acute toxicity is determined in batches of 10 mice to which test compounds are orally administered in gradually increasing doses. Mice were observed for 8 days and the number of dead was counted.
    The administered doses are gradually increased from 800 mg / kg to 4 r / kg. In most cases, death is detected only starting with doses of 1.5 g / kg. The average lethal dose is usually somewhere around 2 g / kg.
    The anti-inflammatory effect is determined using a test for carrageenin according to the method described by Winter. Rats previously starved are given a subcutaneous test compound as a suspension or as a solution in water. After half an hour, in the plantar aponeurosis of the right paw of the rat, administer a 1% solution of carrageenin. The rat paw volume is measured 3 hours after the injection; otherwise, the dose is administered in doses of 20 to 320 mg / kg. As a wakada, a 50% reduction in the volume of an inflamed paw compared to a normal paw is approximately 150 mg / kg.
    and compared with the volume of the paws. The studied rules, dose, and pain reliever are determined by the method of seizures after peritoneal injection of phenylbenzoquinone according to the method described by Hendershot. Batch of 10 mice receive an intraperitoneal dose of 1 μ / kg phenylbenzoquinone. Previously, prior to injection, mice receive orally in the form of a solution or suspensions in an aqueous vehicle test compound c. gradually increasing dose from 25 to 400 mg / kg. The average active dose, which causes a decrease in the number of twists by 50% compared with control animals receiving only phenylbenzoquinone, is depending on the compounds from 50 to 100 mg / kg. ,
    In the same conditions, the average asset. The dose of acetylsalicylic acid * 925247 is approximately 150 mg / kg phenylbutazone 140 μg / kg and diphenyl pyramide approximately 100 mg / kg. The antipyretic effect of the compounds of general formula I is investigated using the test described by Pu et al. This test consists in causing a hyperthermic crisis in the rat by subcutaneous administration of brewer's yeast.
    R is hydrogen or lower alkyl, as well as salts of compounds of the formula I, characterized in that the amine of the general formula I I
    Test compounds are orally administered as a suspension in water mixed with resin 19 hours after brewing yeast. The temperature is measured 1-5 hours after 15 doses of compounds using a thermal probe. Doses of 25 to 200 mg / kg are administered. Temperature changes of the order of 2 ° are observed in animals that received ONLY BEER YEAST, in ANIMALs treated with the test compounds, only a limited increase in temperature is observed, namely, 3 and 4 hours after administration of the test Compound. The highest 25 high doses cause the animals to drop to the initial temperature.
    A batch of animals receives, under the same conditions, an aqueous suspension of paracetamol in doses of 50 to 500 mg / kg. M naya useful dose is clearly twice d <| PS compounds of formula I.
    权利要求:
    Claims (3)
    [1]
    8.2 g of α-Acetamino-CH, B1, o-trifluoroacetophenone, obtained in Step B, is dissolved in 120 ml of methanol and in 2.75 g of sodium borohydride in small portions, maintaining the temperature of the reaction medium below 10 ° C using baths with cold water ,. After adding the total amount p of the agent, the mixture is incubated for 1 hour with stirring at 10 °. Excess reagent current is destroyed by adding a few ml of 50 acetic acid. The mixture is then diluted with an equal volume of water and extracted three times with 25 ml of ether. The ether extracts are combined, washed with water until neutral, dried over sulfate for three and evaporated to dryness. A dry residue of weight g is obtained, which is purified by recrystallization from cyclohexane. 6 g are obtained in g 1 - (-acetaminophenyl) -2,2,2 trifluoroethanol in the form of colorless crystals, insoluble in water, but soluble in methanol and ethanol. M.p. pure product 157-158 Calculated: С 51.51; H k, 32; N 6.00. CioH, oFjN02 233.20. Found,%: C 51.33; H 4.50; N 6.18. EXAMPLE 2. 1- (-Isobutyraminophenyl) -2,2,2-trifluoroethanol. According to the method described in Example 1, the following is obtained: -isobutyramino - “) (, o (., A.-trifluoroace tofenone; 1- (4-isobutyraminophenyl) -2.2,2,2 trifluoroethanol as colorless Heit water-soluble crystals. Mp 150 °. Calculated, 55.17; H 5.0; N 5.36. CizHuFj. N0 261.25. Found: C 55.17; And 5.6; N 5.0. 1- {4-Butyraminophenyl) -2,2,2-trifluoroethanol. According to the method described in the example, starting from t-aminotrifluoroacetophenone, the following is obtained successively: -butyramino-o4, ot, "i, -trifluoroaceto-phenone; 1- (4- butyraminophenyl) -2,2,2-trifluoroethanol; t, pl 120 (methanol). Calculated,%: C 55.17; H 5, N 5.36. SG2 HM RE3 N02 261.25 Found: C 55,52; H 5,4l; N 5,37. Example 1- (-propionaminrenyl) -2,2,2-trifluoroethanol. According to the method described in example 1, starting from "-aminotrifluoroacetophenone are obtained successively: -propionamido-o, ""., - trifratracetophenone; 1 - (+ -propionamidophenyl) -2,2,2-trifluoroethanol as colorless crystals with mp, 166-167 ° (recrystallized from water). Calculated , I: C 53, tt; H +, 89; N 5.67 Ci H, 2Fi N02, 22. Found,%: C 53.35; H ti, 89; N 5.67. PRI me R 5. 1 (-chlorobenzoylamino) phenyl -2,2,2-trifluoroethanol. According to the method described in Example 1, starting from 4-aminotrifluoroacetophenone, the following is obtained: (-chlorobenzoylamino), "с o (-trifluoroacetophenone; 1 (-chlorobenzoylamino-phenyl -2, 2,1-trifluoroethanol with mp. 1775176 ° ( recrystallized from water.) Calculated,%: C 5, H 3.36; N "4.25; CF 10.75 ,, CEFjNOj, 329.71. Found: C 5.39; H 3, N, E, CE 11.1. EXAMPLE 6: 1- (-Nikotin9Ilaminophenyl) -2,2,2-trifluoroethanol. According to the method described in Example 1 (stage c), starting from 18.9 g + -amino o (i, cA-trifluoroacetophenone and 17.8 g of nicotinoyl chloride get 13) 5 g of (α-nicotinoyl amino) trifluoroacetophenone. By reduction of borohydride sodium according to the method described in example 1 (stage c), the TC-nicotinoyl-aminophenyl) -2,2,2-trifluoroethanol is obtained with a yield of 885, mp of pure product 21-215 ° (water). Calculated: C 55.91; H 3.82; N.9.31. C14No 300.75 Found: C 55.97; H 3.79; N 9.36. Example 7: 1-1 - "- (-Metylpiperazinyl-) -phenyl -2,2,2-trifluoroethanol. According to the method described in Example 1, starting from 4-Fluoro-B1, O1, O1-TRIPTOracetophenone and N-methylpiperazine. 7 A- (4-methylpiperazinyl-1) -o4, 3 (, O1, triftrracetophenone with mp. 1 -.- (-methylpiperazinyl-1) -feNyl -2, 2,2-trifluoroethanol with m. mp 192 Calculated D: C 56.93; H 6.25; N 10.21 C, iH, 7F, N. jO 27.29; Found D: C 57, H 6.36; N 10.20. p 8 1- (A nn Hexadecylaminophenyl) -2,2,2-trifluoroethanol. Stage A. ("n Hexadecylaminophenyl) -2,2,2 trifluoroethanol. n Hexadecylamino-2,2,2 -triftoacetophenone. In a three-necked flask, 30 g of p-fluoro-o (., C1, oL, trifluoroacetophenone, 5 g of freshly distilled n-hexadecylaiine, 21.55 g of sodium carbonate and 75 ml of anhydrous dimethylsulfoxyde are placed. The mixture is heated to 100 ° with stirring and maintained at this temperature for 6-7 hours. The suspension is then allowed to cool to ambient temperature and poured into UOO ml of water, stirred for 1 hour, and then the mixture is extracted 3 times with 30 ml of ether. they are washed with water, dried and evaporated to dryness to give g of an oily product consisting mainly of 4- (n-hexadecylamino) - «i,, ((b1-trifluoroacetophenone, which is used as such in the next stage of the synthesis. Stage B. (-Ne “Saddecyl aminophenyl) -2,2,2-trifluoroethanol. 5 g of - (n-hexadecylamino) -o, A, L trifluoroacetophenone is dissolved in 2O of methanol and sodium borohydride is added in small portions, maintaining the temperature of the medium 10 ° by external cooling. The reaction mixture is left under stirring for 4 hours, then the excess reagent is destroyed by the addition of acetic acid. Thereafter, an equal volume of water is added to the reaction mixture, and after stirring for 1 hour, the precipitate formed is filtered off. It is washed with water until neutral. The washes are washed and dried at 60 under reduced pressure. 50.7 g of {t-n-hexadecyl-aminophenyl) 2,2,2-trifluoroethanol are obtained, which is recrystallized for analysis from isopropyl ether. eight . pure product 63-6D. Calculated D: C 69.36; H 9.70; N 3,, N0, 59. Found: C 69.0; H 9.39; N З ,. The product is soluble in dilute solutions of acids, for example hydrochloric or acetic. Example9. - (2,2,2-Trifluoro-1-hydroxyethyl) - -aminophenyl -1 - (phenyl-2-ethyl) -piperidine, According to the method described in Example 8, starting from "-fluoro-d1, a1, o ( -TrIftoracetophenone and -1- (phenyl-2-ethyl) -α-aminopiperidine receive the sequence - 1 (2,2,2-trifluoro-1-ethanone) -k-at V (nophenyl -1- (phenyl-2-ethyl) -piperidine; C- (2,2,2-trifluoro-1-hydroxyethyl) -U-aminophenyl -1 - (phenyl-2-ethyl) -piperidine with mp 120-122 (ester-pentane). This compound dissolved in an exactly calculated equivalent amount of 0.1 N. hydrochloric acid. The hydrochloride is isolated by evaporation of the solvent. Calculated,%: C 66.65; H 6.66; N 7, to C2, H, .sF, H20 378 , i Found ,: C, 66.68; H, 6.85; N, 7.27. EXAMPLE 10. 1- (A-Acetaminophenyl) -1-ethoxy-2,2,2-trifluoroethane, 6.6 g 4 -p-acetaminophenyl-2,2,2-trifluoroethanol prepared in Example 1 was dissolved in 75 ml of ethanol and a solution prepared with 0.5 g of sodium, 5 g of ethanol was added to it. The mixture was left at P at room temperature is then evaporated to dryness in vacuo. The sodium salt thus obtained is dissolved in 30 ml of dimethyl formamide at ambient temperature, then after complete dissolution, the solution is cooled to 10 and 2 ml of pre-cooled water are added to it. about 0 ° ethyl bromide. When ethyl bromide is added, the reaction mixture is cooled in a bath of water and ice. The temperature of the reaction mixture was then allowed to rise to room temperature and stirring continued for an hour. After that, the mixture was diluted with an equal volume of water and extracted 3 times with methylene chloride. The organic phases are separated, washed with 5% sodium carbonate solution, then with water, dried and the solvent is distilled off to dryness. The oily residue gradually crystallizes. 6.35 g of a crude product is obtained which is dissolved in benzene, then cyclohexane is added. The trifluoroethane precipitated in 1- (t-acetaminophenyl) -1-ethoxy-2,2,2 is chromatographed on a silica column and eluted with a mixture of equal amounts of cyclohexane and ethyl acetate. Obtain 2.9 g of pure product with so pl. T32-13 ° C. Calculated: C 55,17; H 5, “O; N 5.36. C | 2 Neither FJ N0 261.25 Found: C 55.33; H 5, "in; N 5, This compound is insoluble in water, but soluble in common organic solvents. PRI me R 11. d8-l - (- Cyclobutylamino) phenyl -2,2,2-trifluoroethane. According to the method described in Example 8, starting from -fluoro-o, o4, o (-trifluoroacetophenone and cyclobutylamine, (- cyclobutylamino) phenyl -2,2 trifluoroethanol with a melting range of 90-92. Numerous: C 57.71; H 5.82; N 5.62 ,, 75. Found: C 57.60; H 5 , 79; H 5.31. Example 12. d {-1- (-Cyclopentylamino) -phenyl -2,2,2-trifluoroethanol. According to the method described in Example 8, starting from -fluoro1, in (., L - tofenone and cyclopentylamine trifluorose get 1- (U-cyclopentyl) -phenyl -2,2,2-three fluoroethanol with mp 100-101 °. Calculated: C 60.22, H 6.22; N 5, Yu "259.27 B b Found,%: C 59.96; And 6 ,, N 5 ,. P Example 13. 1- (-T-butylaminophenyl) -2,2,2-trifluoroethanol. According to the method described in the example, starting from -fluoro (., 1, and (-trifluoroaceto-phenone and tert-butylamine is obtained sequentially: 1- ("-Tert-butylaminophenyl), o (, N. Trifluoroacetophenone (b.p., 05 1- (-tert-butylaminophenyl) -2,2,2 trifluoroethanol with mp. 7 Calculated,%: C 53, 53; H 6; IV; N 5.69; F 29, I, 6 F, N0, 26 Found: C 58.39; H 6.21; N 5, F 23.09. A pharmacological study of the compounds is carried out as follows. Acute toxicity is determined on batches of 10 mice to which test compounds are administered rarelno gradually (their doses. Mice are observed for 8 days, and the number of dead is counted. The administered doses gradually increase from 80 pg / kg to C g / kg, In most cases, death is ascertained only starting with doses of 1.5 g / kg. The average lethal dose is usually somewhere around 2 g / kg. The anti-inflammatory effect is determined using the carrageenin test according to the method described by Winter. Pre-starved rats t subcutaneously test the compound as a suspension or as a solution in water. Half an hour later, carrageenin solution is injected into the plantar aponeurosis of the right paw of the rat. The volume of the rat paw is measured 3 hours after the injection and compared with the untreated paw volume. from 20 to 320 mg / kg. Typically, the dose causing a decrease in the volume of the inflamed paw by 505 compared with the normal paw is approximately 150 mg / kg. The analgesic effect of the compounds was determined by the method of convulsions after peritoneal injection of phenylbenzoquinone according to the method described by Henderschott. Lots of 10 mice received a dose of 1 micron / kg of phenylbenzoquinone intraperitoneally. Previously, prior to injection, mice receive orally in the form of a solution or suspensions in an aqueous vehicle, the test compound in a gradually increasing dose of 25 to kQQ mg / kg. The average active dose, which causes a 50% reduction in the number of twists compared with control animals that received only phenylbenzoquinone, varies from 50 to 100 mg / kg, depending on the compounds. Under the same conditions, the average dose of acetylsalicylic acid 119252 is about 150 mg / kg of phenylbutazone - 140 µg / kg and diphenylpyramid - about 100 MI / KT. The antipyretic effect of compounds of general formula I is investigated using the 5 test described by Lou et al. This test is that in a rat they cause a hyperthermic crisis by subcutaneous administration of brewer's yeast. 10 Test compounds are administered orally as a suspension in water mixed with resin 19 hours after the introduction of brewer's yeast. The temperature is measured 1-5 hours after is taking compounds with a thermal probe. Dosages of between 25 and 200 mg / kg are administered. Changes in the temperature of the pores of dKa 2 ° are observed in animals that have submerged only brewer's yeast, in animals treated with the test compounds, only a limited temperature increase is observed, namely 3 and h after ingestion of the Compound. The highest doses cause lowering the temperature of animals to the initial. A batch of animals receives, under the same conditions, an aqueous suspension of paracetamol in doses from 50 to 500 mg / kg. A useful dose is clearly twice as much as D (| for compounds of formula I. Claims 1. Invention method for producing 1 - (α-aminophenyl) -2,2,2-trifluoroethanol of general formula I - "F,
    where Z is hydrogen, C, -b-alkyl, lower cycl / zralkyl ,. acyl residue (lower alkyl) - carboxylic acid, chlorobenzoic acid or pyridinecarboxylic acid of formula A
    and
    And Z is hydrogen
     or Z and Z together with N form a N- (lower alkyl) -piperidine residue or N-phenyl- (lower alkyl) -piperidine residue; 35
    where Z and Z are as defined in formula I, in free form or as its salt, and / or a compound of general formula IV, where Z and Z are hydrogen, are acylated with a (lower alkyl) -carboxylic, chlorobenzoic or pyridinecarboxylic acid chloride with the general formula In the presence of an organic base, the intermediate is reduced with sodium borohydride and / or a compound of general formula V,. where Z and Z have the values indicated in formula I, alkylate the (lower alkyl) -halide in the presence of sodium ethylate and isolate the desired product in free form or its salt. 7 R is hydrogen or lower alkyl, as well as salts of compounds of the formula f, characterized in that the amine of the general formula II wherein Z is hydrogen, C, alkyl or lower Z cycloalkyl; hydrogen, or Z and Z together form the residue - (lower alkyl) -piperidine or phenyl- (lower alkyl) -piperidine, is brought into interaction with the α-fluorophenyl ketone of formula III and the intermediate 4-aminophenyl ketone of general formula IV is selected, where Z and Z have the formula II, is reduced with sodium borohydride and-aminophenyl ethanol of general formula V -CF is isolated:
    13,92521 7k
    Information sources,
    [2]
    2. Bühler, K., Pearson, D. Organic, taken into account in the examination of. Synthesis. M., Mir, 1973, m.1, p.50 “1. Mashkovsky M. D. Medicinal. 507. means. M., Medicine, 1972, v.1, p.109-111.
    [3]
    3. Ibid, p.223.
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    引用文献:
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    US3142683A|1961-08-14|1964-07-28|Parke Davis & Co|1-pyridyl-1, 2-diaryl-3-trifluoro-propan-2-ols and a process for their preparation|
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    DE1618007A1|1967-05-09|1970-10-29|Thomae Gmbh Dr K|Process for the production of new amino-monohalophenylaethanolamines|
    US3821231A|1971-10-15|1974-06-28|E Lavrinovich|Method for preparation of n-substituted 4-aniline piperidines|
    GB1411783A|1972-02-24|1975-10-29|Wyeth John & Brother Ltd|Piperidine derivatives|
    FR2340734B1|1976-02-13|1978-11-10|Roussel Uclaf|
    DE2659117A1|1976-12-28|1978-07-06|Consortium Elektrochem Ind|TRICHLOROMETHYL CARBINOL|
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    法律状态:
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    FR7831096A|FR2440353A1|1978-11-03|1978-11-03|NOVEL ARYLETHANOLS, PROCESSES FOR OBTAINING THEM AND THEIR USE AS A MEDICINAL PRODUCT|
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