• 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:
    Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid derivatives and methods for their preparation and use are disclosed. The compounds are useful analgesic and anti-inflammatory agents. The derivatives are acids of formula I below or their salts. <CHEM> In formula (I) R<1>, R<2>, R<3>, R<4>, R<5> and R<6> are hydrogen or lower alkyl or R<3> and R<4> are joined together to form (CH2)m or R<5> and R<6> are joined together to form -CH=CH-CH=CH-, (CH2)n, -CH=CH=O- or -CH=CH-S-, R<8> and R<1><0> are independently hydrogen, lower alkyl or halogen, R<9> is hydrogen or lower alkyl, m is 2 to 3 and n is 2 to 4.
    公开号:SU1482915A1
    申请号:SU864027307
    申请日:1986-04-14
    公开日:1989-05-30
    发明作者:Мобилио Доминик；Александр Демерсон Кристофер；Джордж Хамбер Лесли
    申请人:Американ Хоум Продактс Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to new chemical compounds of the carbazole series, namely, to 2,3,4,9-tetra-hydro-1H-carbazole-1-acetic acid derivatives of the general formula
     TU
    (I)
    CH2COOH
    Mr. Rs
    R b) R, RG
    de a) R.J - benzyl; ethyl; hydrogen;
    hydrogen or 8-ethyl; 2-methyl-2-propenyl; ethyl;
    R R is hydrogen or Rj-7-chloro; R J is 8-methyl;
    c) R is 1,1-pimethyl-2 propenyl; Rg is ethyl;
    R3 is hydrogen;
    R is 8-fluoro or RJ is 7-chloro; R 4 - 8-methyl
    d) R - 2-propenyl; Rj. - methyl;
    Rs is hydrogen; K is hydrogen or 8-ethyl, or RJ h is ethyl, R is hydrogen, R is hydrogen, 8-methyl, 6-, 7- or 8-ethyl, 8-propi 8-isoprogash, 6-butyl, b or 8-fluoro, 5-s 6-, 7- or 8-hlrr, 5-, 6-, 7- or 8-bromo, 8-iodine, or RJ - 8-methyl, - 5-methyl, 7- fluorine,. 5- or 7-. chlorine 7-bromine, or RS ™ 8-chloro, E4-5-methyl, 5-, 6- or 7-chloro, or R3 - 8-bromine, R4 5-methyl, or RJ - 7-chloro, R4 - 5 chlorine or Ra is propyl, R3 is hydrogen, R is 8-ethyl, or benzmethanes are a new salt of compound 1, where RI is 2-propenyl, RJJ and R is ethyl, RJ is ROD,
    They have analgesic and anti-inflammatory effects, as well as 2,3,4,9-tetrahydro-1H-carbazol-1-acetic acid methyl ester of the general formula
    (Ii)
    s HR2 CH2COOCH3
    five
    0
    five
    0
    five
    0
    five
    0
    five
    where R15R2, RJ and R4 have the indicated meanings, which is an intermediate product for the synthesis of compounds that have an analgesic and anti-inflammatory effect.
    The purpose of the invention is to search in the carbazole range for new compounds with a higher analgesic and anti-inflammatory effect.
    The invention is illustrated by the following examples.
    Example 1: Cis-1,8-diethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1 H-carbazole-1-acetic acid.
    a) Preparation of 2-ethylcyclohexanone 2-Ztilcyclohexanol (1.6 mol,
    I204 g, 226 ml) is stirred in 3.2 l of acetone at 0 ° C and treated with 8N "Jones reagent (prepared from 106.8 g of Cr03e suspended in 92 ml of concentrated sulfuric acid and diluted with 400 ml of water) until a steady orange color appears (CHO ml ). Isopropanol is then added to the reaction mixture until it again turns green, and it is poured into 2 liters of ether. The resulting product is washed 6 times with brine, 500 ml portions, dried over MgSO4 and the solvent is distilled off. After molecular distillation (m.p. 80–85 ° C at 25 mmHg), 184 g (1.46 mol, 91% yield (2-ethylcyclohexanone as a colorless oily liquid) are obtained.
    b) Preparation of 1-ethyl-2-oxocyclohexanone acetic acid methyl ester.
    I
    Potassium hydride (417 mmol, 70 ml, -o
    L / 6M in mineral oil) is placed under a nitrogen atmosphere in a three-neck flask equipped with a mechanical stirrer and washed three times with petroleum ether (this washing is not necessary). Then tetrahydrofuran (200 ml, distilled from a mixture of sodium and Ph $, CO) is added to the flask, and then slowly over about 15 minutes a solution of 2-ethylcyclohexanone (VIII) (50 g, 396 mmol) in 200 ml of tetrahydride. rofurana. After 1 minute, 495 ml of 1 M EtjB in tetra-idrofuran were added to the flask, and after another hour, 594 mmol (91 g, 56 ml) of methyl bromoacetate. The yellow suspension is stirred for 2.5 hours, poured into 800 ml of water, carefully separated by decanting from excess KN and extracted
    4 times with petroleum ether in 300 ml portions. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The resulting product is distilled in a 6-inch Burpo column and the fraction boiling at 107-118 ° C is collected and
    0.8 mm Hg (two regioisomers from the alcoping stage). Purify the resulting product using flash chromatography (4 inch diameter column, eluent: 7.5% ethyl acetate in petroleum ether, 5.5 inch layer of silica gel), resulting in 35.33 g (178.2 mmol , 45% yield) colorless oily liquid. The target product is a product with less
    482915b
    Viscous phase: 15% ethyl acetate solution in petroleum ether) R 0.9.
    g) Preparation of cis-1-ethyl-2-oxo-4- (2-prolenyl) - cyclohexanoacetic acid methyl ester,
    The initial enon 6-carbomethoxy-methyl-6-ethyl-2-cyclohexan-1-one (X) (81.53 mmol, 16.0 g) is stirred in 82 ml of dry (distilled s) at -78 ° C. under a nitrogen atmosphere and thereto is added dropwise to it (122.30 mmol (23.2 g) TiCl, and then
    15.97.84 mmol (11.18 g, 15.55 ml) of allyl-trimethylthylsilane. After 1.5 h, the reaction is stopped, adding 50 ml of MeOH to the reaction mixture at -78 ° C, pouring it into 200 ml of water and four times
    HZ (out of two overlapping 20 water, extraction with ether is carried out in portions
    spot on thin layer chromatography) R 0.23 using a mixture of ethyl acetate and petroleum ether as the mobile phase. About 5-10% of the 2,6-regioisomer (top spot) can be extracted from the resulting product.
    c) Preparation of methyl 1-ETHYL-2-oxocyclohex-3-ene-acetic acid.
    The starting ketone, 2-carbomethoxy-methyl-2-ethylcyclohexanone (141 mmol, 28 g) is stirred in 1.25 l of ethyl acetate (dried using a molecular sieve FOR), and then treated with 169 mmol (32.5 g) of PhSeCl. The reaction mixture is stirred under nitrogen for 4 hours and treated with 250 ml of water. The mixture was vigorously shaken in a separatory funnel and the organic phase was returned to the reaction flask, to which 550 ml of tetrahydrofuran was added and then 35 ml of 30% aqueous hydrogen peroxide solution was added dropwise. The reaction mixture is stirred for 1 h and washed first with 500 ml of water and then with 500 ml of a saturated aqueous solution of NajCQj. The resulting product is dried over MgSO4 and concentrated in vacuo. Flash chromatography (4 inch diameter column, 20% ethyl acetate solution in petroleum ether as eluant, silica gel layer, 5.5 inch high) gives 15.3 g (78.0 mmol, 55% yield) of product in a pale yellow oily liquid. According to thin layer chromatography (under 30
    35
    100 ml. After drying () and flash chromatography (95 mm long column, 15% ethyl acetate in petroleum ether as eluent, 5.5 inch thick layer of 25 silica gel), 16.02 g (67.2 mmol, 82% colorless oily liquid. The resulting product consists mainly of a single diastereomer (with a ratio of not less than 9: 1 diastereomers). The main diastereomer is the cis isomer. According to thin-layer chromatography using 154% ethyl acetate in petroleum ether as the mobile phase C 0.39.
    e) Preparation of cis 1,8-diethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H-carbazole-1-acetic acid methyl ester.
    Initial ketone, cis-1-ethyl-2-oxo-4- (2-propenyl) -cyclohexane acetic acid methyl ester (51.14 mmol, 12.188 g) and 2-ethylphenylhydrazine (51.14 mmol, 6.965 g ) boil under reflux in 219 ml of MeOH for 120 hours. The reaction mixture is then cooled to 0 ° C, 102 mmol (8.0 g of 7.3 ml) of AcCl are added to it and refluxed in for another 45 minutes Thereafter, the solvent was distilled off, and the chromatography was carried out (95 mm long column, 12% ethyl acetate in petroleum ether as eluent, silica gel layer 5.5 inches), resulting in 7.0 g (20.64 mmol , yield 40%) oily liquid orange. According to thin layer hro40
    45
    50
    55
    0 water extraction with portions of ether
    0
    five
    100 ml. After drying () and flash chromatography (column 95 mm long, 15% ethyl acetate in petroleum ether as eluent, layer 5, silica gel, 5.5 inches thick), 16.02 g (67.2 mmol, 82% yield) are obtained colorless oily liquid. The resulting product consists mainly of a single diastereomer (with a ratio between diastereomers of at least 9: 1). The main diastereomer is the cis isomer. According to thin layer chromatography using 154% as a mobile phase. % ethyl acetate in petroleum ether C 0.39.
    e) Preparation of cis-1,8-diethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H-carbazole-1-acetic acid methyl ester.
    Initial ketone, cis-1-ethyl-2-oxo-4- (2-propenyl) -cyclohexane acetic acid methyl ester (51.14 mmol, 12.188 g) and 2-ethylphenylhydrazine (51.14 mmol, 6.965 g ) boil under reflux in 219 ml of MeOH for 120 hours. The reaction mixture is then cooled to 0 ° C, 102 mmol (8.0 g of 7.3 ml) of AcCl are added to it and refluxed in for another 45 minutes Thereafter, the solvent was distilled off and flash chromatography was carried out (95 mm long column, 12% ethyl acetate in petroleum ether as eluent, 5.5 inches silica gel), resulting in 7.0 g (20.64 mmol). , yield 40%) oily liquid orange. According to thin layer hro0
    five
    0
    five
    matography using 15% ethyl acetate as the mobile phase in petroleum ether Rj 0.54.
    e) Preparation of cis-1,8-diethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H-carbazole 1-acetic acid.
    Source ester, methyl ester cy.sup.1,8-diethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H-carbazole-1-acetic acid (20.64 mmol, 7.007 g) and CdCO3 (24.77 mmol, 3.433 g) was heated under reflux in 165 ml of MeOH j containing 21 ml of water under nitrogen for 27.5 hours. Most of the MeOH was distilled off in vacuo, and the residue was dissolved in 50 ml water. The solution is acidified to pH 311 with an aqueous solution of HC1 and extraction is carried out four times with 50 ml portions of ether. The combined organic phases are dried over MgSOij and concentrated. Flash chromatography (column 75 mm long, 40% ethyl acetate in petroleum ether as eluent, height of silica gel layer 5.5 inches) yields 5,0152 g (15.41 mmol, 75% yield) oil yellow liquid. According to liquid chromatography data, the resulting product consists mainly of one isomer (with a ratio of at least 9: 1 stereomers). The main diastereomer is the cis isomer. 3 g of the product obtained is recrystallized from 20 ml of a mixture of petroleum ether and benzene in a 2: 1 ratio, resulting in 1.3 g of acid-white needle-like crystals (mp 121-124 ° C). According to the liquid chromatography of the recrystallized material, its purity was 99.3%. After the second recrystallization, the purity was 99.6%.
    NMR (CDCl1 (tetramethylsilane): 0.85 (t, 3N, J8, CHttCH9); 1.33 (t, J8, 3H, ArCHjCH,) j 1.6-2.5 (m, 6H, CsvSn, , cycle СНг); 2.5-3.4 (m, 711, CHS CHfcCOO,, С ССНа)
    & s
    4.9-5.3 (m, 2H,); 5.6-6.3 (m, 1H,) | 7.0-7.6 (m, 3N, aromatic), 8.98 (broad s, 1H, NH).
    IR (KBg): 3600-3100 (OH), 3400 (NH), 1710 (C - 0),
    Example 2. 1,8-Diethyl-2,3,4 ,, 9-tetrahydro-4- (phenylmethyl) - 1H-carbazole-1-acetic acid
    p g 0 5 0
    five
    five
    0
    five
    a) Preparation of 1-ethyl-2-oxo-4- (phenylmethyl) cyclohexane acetic acid methyl ester.
    The original enon, methyl ester 1-ethyl-2-oxocyclohex-3-enucetic acid, obtained in example 1, stage b, (56,26 mmol, 11,04 g), MeeS (11,25 ml) and 5,626 mmol (1 , 15 g) CuBr. MeeS was stirred in 165.5 ml of tetrahydrofuran at -40 ° C under nitrogen and 56.26 mmol (28.1 ml of a 2 M solution in tetrahydrofuran) PhCH / jMgCl was added dropwise to the mixture. The reaction is then stopped by adding 150 ml of 1M HC1 to the reaction mixture and extraction is carried out four times with petroleum ether in 100 ml portions. The combined organic phases are dried over and concentrated. Flash chromatography (95 mm high column, 12% ethyl acetate in petroleum ether as eluent) gave 11.20 g (38.84 mmol, 69% yield) of a mixture of isomers as a yellow oily liquid.
    b) Preparation of 1,8-distil-2,3,4,9-tetrahydro-4- (phenylmethyl) -1H-carbazole -1-acetic acid methyl ester.
    The mixture of ketone isomers obtained in stage a, (74.56 mmol, 17.775 g) and 2-ethylphenylhydrazine (74.56 mmol, 10.156 g) is refluxed in 320 ml of MeOH under a nitrogen atmosphere for 112 hours. the mixture is then cooled, 112 mmol (8.78 g, 8 ml) AcCl are added to it and boiled for another 45 minutes. The reaction mixture is then concentrated in vacuo and flash chromatographed (95 mm high column, 12% ethyl acetate in petroleum ether as eluent, 5.5 inches silica gel), resulting in 8.922 g (22.9 mmol, yield 31%) mixture of isomers in the form of a yellow oily liquid.
    c) Preparation of 1, 8-d. Ethyl-2,3,4,9-tetrahydro-4- (phenylmethyl) -1H-carba-sol-1-acetic acid.
    The mixture of ester isomers (22.9 mmol, 8.922 g) obtained in stage b, and K4C03 (27.48 mmol, 3.798 g) is refluxed in 183 ml and 23 ml of water under a nitrogen atmosphere for 26.5 The major part of MeOH is distilled off in vacuo, and the residue is dissolved in 50 ml of water. Podka solution obtained
    diluted to pH / 1 G with an aqueous solution of HC1, extraction is carried out four times with ether, in 50 ml portions, the organic phase is dried over MgSO4 and concentrated. As a result, flash chromatography (75 mm high column, 50% ethyl acetate in petroleum ether as eluent, 5.5 inch thick layer of silica gel), 6.7712 g (18.03 mmol, 79% yield) oily yellow liquid are obtained. Using reverse phase (C j) chromatography, approximately 1 g of each of the isomers is isolated, which is recrystallized from a mixture of petroleum ether and benzene in a ratio of approximately 2: 1. The result is white crystals. Both isomers are dried under vacuum (72 ° C, silica gel as a drying agent) for 8 hours. The first isomer eluted by reverse phase chromatography (a mixture of CH3C1 and NaO in a ratio of 60:40 with the addition of 0.001 M KH2PO, (), designated as isomer A , has a melting point of 185-186 ° C. The second eluted isomer, designated as isomer B, has a melting point of 181-184 ° C.
    Isomer A: NMR (CDC13 (tetramethylsilane): 0.9 (t, 3N, J 9, CHaCH); 1.36 (t, 3N; J 9, Lg CH 2 CH 3); 7.5-2.3 (m, 7H, cycl. CHg. And SI); 2.6 - 3.6 (m, Ph CHrj, ArCHrj,); 7.07, 6 (m, 8H, aromatic); 8.9 (broad s, 1H, NH ).
    IR (KBr): 3440 (NH); ZBOO-ZOOO (OH) 3060 (CH aromatic); 3000-2880 (CH alifatich.); 1710 ().
    Isomer B: H11R (CDClI / tetramethylsilane): 0.88 (t, J 9, 3N, CHaC3); 1.36 t, J 9, 3N, AgSM, CK4); 1.6-2.2 (m, 7H, cycl. SI, and CH); 2.7-3.5 (m, 6H, PhCHqi, ArCIU, CHa, COO); 6.9-7.6 (m, aromatic); 9.0 (broad, s, 1H, NH).
    IR (KBr): 3600-2500 (CH); 3420 (NH); 1700 ().
    PRI me R 3. Cis-1-ethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H-carbazole 1-acetic acid.
    a) Preparation of cis-1-ethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H-carbazole-1-acetic acid methyl ester.
    5 g (20.98 mmol) of cis-1-ethyl-2-oxo-4- (2-propenyl) cyclohexane acetic acid methyl ester obtained in Example 1, step g, and 2.27 g
    ten
    -, 25
    .
    . „
    0
    five
    five
    five
    (21 mmol, 2.07 ml) 2-phenylhydrazine is refluxed under nitrogen in 21 ml of toluene to remove water (azeotropic distillation). After 24 hours, toluene was distilled off in vacuo, and the residue was dissolved in 15 ml of acetic acid. To the resulting solution was added 27.27 mmol (3.87 g, 3.35 ml) of boron trifluoride, and the mixture was heated under reflux in a nitrogen atmosphere for 20 minutes. It is then poured into 40 ml of water and extracted four times with 40 ml portions of ether. The combined organic phases are washed twice with a saturated aqueous solution of sodium bicarbonate in 20 ml portions each and dried over magnesium sulfate. After flash chromatography (75 mm high column, 7% ethyl acetate in petroleum ether as eluent, 5.5 inches silica gel), 3.04 g (9.81 mmol, 47% yield) of an oily orange liquid are obtained. . Rr 0.65 when using as the mobile phase 15% ethyl acetate in petroleum ether.
    IR (pure) 3490 (NH); 2850-3050 (CH); 1715 ().
    NMR (CDCl3 / tetramethylsilane, 200 MHz): 0.836 (t, J 7.5, 3N CH 3 CN.SCH); 1.258 (t, J 7.15, ZN, AgSngSNe); 1.6-2.4; 2.6-2.8 (m, 8K, CLUCH}, CHQCHcC, .e); 2,664 (5, 2Н, СНвСООМе); 3.05 (m, CH); 3,703 (s, 3N, OSNg); 5.0-5.1 (m, 2H, C-CHi); 5.8-6.0 (m, 1H,); 7.0-7.6 (m, 4H, aromatic); 9.3 (broad s, 1H, NH). I
    b) Preparation of cis-1-ethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H-carbazole-1-acetic acid.
    A solution of the starting ester, cis-1-ethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H-carbazole-1-acetic acid methyl ester (9.71 mmol, 3.01 g) and Potassium carbonate (14.57 mmol, 2.01 g) is refluxed under nitrogen in 78 ml of methanol and 9.7 ml of water for 24 hours under reflux. After that, most of the methanol is distilled off in vacuum, and the residue suspended in 15 ml of water. The suspension is acidified to pH 1 with 1M HCl and extraction is carried out four times with 60 ml portions of ether. The combined ether phases are dried over magnesium sulphate and concentrated. After flash chromate
    1114
    a decanter (a column with a diameter of 50 mm, 25% ethyl acetate in petroleum ether as eluent, a layer height of silica gel 5.5 inches) gives 2.72 g (9.19 mmol, 95% yield) of the product in the form of an oily liquid. Crystallizing it from a mixture of petroleum ether and benzene in a ratio of 85:15 gives 2.2 g of a very white powdery product. Dried at 78 ° C over phosphorus pentaoxide for 7 hours, it has a melting point of 207 ° C. 103-105 C.
    Calculated,%: C, 76.74; H 7.79; N 4.71.
    Found,%: C 76.84; I 7.70; N 4.73.
    IR (KBr): 3420 (NH); 3600-3000 (OH); 2860-3100 (-CH); 1715 ()
    In examples 4-7, 11, 10, 12-19, 21, 24, 25-30, 32, 34, - 36, 37 to 39, methyl cis-1-ethyl-2-oxo-4- (2-propenyl a) -cyclohexane acetic acid (obtained by the method and in accordance with Example 1, step d) was reacted with the corresponding arylhydrazine at reflux in toluene for 12-100 hours to form a hydrazine, after which the resulting product was concentrated under vacuum and dissolved in acetic acid. After adding boron trifluoride to the solution and boiling the mixture under reflux for 5 to 260 minutes, compounds of formula (41) were obtained, which were then subjected to hydrolysis using sodium hydroxide in an aqueous solution of ethanol, thereby forming compounds of formula (1) ).
    In the case of examples 8 and 11, methyl 1-methyl-2-oxo 4- (2 propenyl) - cyclohexane acetic acid ester (obtained by the method in accordance with Example 1, step d, with the difference that instead of 2-ethylcyclohexanone as the starting material 2-methylcyclohexanone was used in accordance with Example 1, step b) was reacted with the corresponding hydrazine followed by hydrolysis,
    In the case of Example 20, the process was carried out as in Examples 8 and 11, and 2-progpsyclohexanone was used as the starting material for 2-methylcyclohexanone.
    In the case of examples 22 and 33, methyl 4- (1,1-dimethyl 2-prope
    five
    0
    five
    9
    50
    50
    five
    0
    1512.
    nyl) -1-e-2-oxo-cyclohexane-acetic acid (obtained by the method in accordance with Example 1, step d, with the difference that (3-methyl-2-butenyl) -tributylin was used instead of aplyltrimethylsilane with the corresponding hydrazine followed by hydrolysis.
    In the case of examples 23 and 38, the process was carried out as in examples 22 and 33, with the difference that (2-methyl-2-propenyl) tributylin was used instead of (3-methyl-2-butenyl) -tributylin.
    In the case of example 25, 1-ethyl-2-oxo-4- (phenyl-methyl) -cyclohexane-acetic acid methyl ester (obtained by the method in accordance with Example 2, step a) was reacted with phenylhydrazine followed by hydrolysis
    Example 40: Benzmethanamine salt of (W-cis) -1,8-diethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H-carbazole-1-acetic acid.
    a) Preparation of 2,3-dimethoxy-strichnidin-10-one salt (1: 1) (1K-cis) -1,8-DIETHIL-2,3,4,9-tetrahydro-4- (2-propenyl ) -1I-carbazole-1-acetic acid,
    6 mmol (1.947 g) of cis-1, 8-diethyl-2,3,4,9-tetrahydr0-4- (2-propenyl) -1H-carbazole-1-acetic acid (prepared according to the method of Example 1, step e) and 6.0 mmol (2.583 g) of 2,3-dimethoxy-strichinidin-10-one dihydrate (brucine dihydrate) are dissolved in 25 ml of hot ethanol. To the resulting clear solution was added 6.25 ml of water and left overnight at room temperature. The precipitated white crystals of the salt are filtered off and washed with 5 ml of a mixture of ethanol and water in a 1: 1 ratio. The mother liquor is used to isolate the second enantiomer in Example 45 in step a. The resulting salt (1.94 g) is again placed in hot ethanol (14 ml) and 3.5 ml of water are added dropwise, without allowing the solution to cool. The solution is then left overnight at room temperature. The resulting crystals (1.73 g) are filtered off, washed with 5 ml of a mixture of ethanol and water in a 1: 1 ratio, and dried overnight in a vacuum. The yield of the obtained compound is 80% of the theoretical value; m.p. 128-130 00
    b) Benzmethanamine salt (1: 1) (1R-cis) -1,8-DIETHIL-2,3,4,9-tetrahydro-4- (2-propenyl) - 1H-carbazole-1-acetic acid.
    The original 2,3-dimethoxy-strichnidine 10-one salt (1: 1) (1K-qi) -1,8-diethyl-2,3,4,9-tetrahydro-4- (2-propyl) -1H -carbazole-1-acetic acid (1.73 g) is suspended in 100 ml of ether and 1M hydrochloric acid is added to the suspension with stirring. After separation of the organic salt, it is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and the colorless oily liquid is evaporated (765 mg, 99% yield). The product obtained is dissolved in 5 ml of ether and a solution of benzmethanamine (255 mg) in 2 ml of ether is added to the solution. The result is a clear solution. After 2 hours at room temperature, a crystalline product precipitates from it. The solution is placed in the refrigerator overnight. After that, the crystals are filtered off, washed with a small amount of ether and dried under high vacuum at room temperature. The result is 715 mg of the target compound (mp 133.5-134 ° C (V) ъ -93). The chiral purity of the product obtained, determined by high-speed liquid column chromatography on free acid methyl ester on a chiral chromatographic column, was 99.9%. The absolute and relative configuration was determined by X-ray crystallography.
    Calculated,%: C 77.74; H 8.39; N 6.48.
    Found,%: C 77.58; H 8.16; N 6.51.
    IR (KBg): 3340 (NH): COOH (broad); 3080-2850 (CH); 640 ().
    NMR (CDC13, 200 MHz): 0.85 (t, 3N, J 7.5); 1.32 (t, 3N, J 7.6); 1.6-2.3 (m, 7H); 2.6 (m, 2H); 2.7 (m, 1H; 2.80 (q, 2H, J 7.6); 3 (m, 1H); 3.86 (s, 2H); 4.3 (wide s); 5.5, 2 (m, 2H); 5.8-6 (m, 1H), 6.9-7.1 (m, 2H); 7.2-7.4 (m, 6H), 9.9 (wide with , 1H).
    Example 41: Benzmethanamine salt (1: 1) (15-cis) -1 „8-diethyl-2,3,4,9-tetrahydro-4- (2-propenyl) - 1H-carbazole-1- acetic acid.
    0
    five
    0
    five
    0
    five
    0
    five
    0
    five
    a) Preparation of 2,3-dimethoxy-strichnidine-10-one salt (1: 1) (15-cis) - 1,8-diethyl-2,3,4,9-tetrahydro-4 (2-propenyl) -1H-carbazole-1-acetic acid.
    The mother liquor after the first crystallization in Example 44, at stage a, is saturated with water (5 ml) and placed in a refrigerator overnight. The precipitated crystals are filtered and washed with a mixture of ethanol and water (10 ml) in a 1: 1 ratio. The result is an enriched salt mixture. Brucicadas which are dissolved in 10 ml of hot ethanol. 1 ml of water is added to the solution and the seed of the product obtained in Example 44 is introduced into it. on the stage . The seed solution is left overnight at room temperature. Drop-down crystals (385 mg) are filtered off and the mother liquor is saturated with water (30 ml). The precipitate (1.5 g) is dissolved in 8 ml of hot ethanol, 3 ml of water are added to the solution and left overnight at room temperature. The precipitated crystals are filtered off and 5 ml of water is added to the filter. During crystallization, which proceeds overnight (the solution is left in the refrigerator), a white crystalline compound C (1.1 g) is formed. After double recrystallization from hot ethanol (3 ml) and water (1.5 ml) at room temperature, brucine salt (600 mg) is obtained (yield 28%). The chiral purity determined by high speed liquid column chromatography on the free acid methyl ester is 99.9%.
    b) Benzmetanamine salt (1: 1)
    (18-cis) -1,8-diethyl-2,3,4,9-tetrahydro-4- (2-propenyl) -1H) -carbazole-1-acetic acid.
    The brucine salt (600 mg) obtained in step a is suspended in ether and hydrochloric acid is added to the suspension III. After separation, the organic elephant is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and evaporated, to give a colorless oily liquid (265 mg, 99% yield). The resulting product is dissolved in 1.5 ml of ether and added to a solution of benzmethanamine (88 mg) in 0.5 ml of ether. When standing for 2 hours at room temperature and then overnight in a refrigerator, a precipitate of crystalline product precipitates from the solution. The crystals are filtered, washed with a small amount of ether and dried under vacuum at room temperature. The result is 248 mg of the target compound (yield 70%, mp 133-134 ° C, (oOjj + 91.5 ° chiral purity determined by high-speed liquid column chromatography on the free acid methyl ester) ,9%.
    Calculated,%: C 77.74; And 8.39; N 6.48.
    Found,%: C 77.75; H 8.29; N 6.49.
    IR (KBr): 3340 (NH); SOOI (wide); 3080-2850 (CH); 1640 ().
    NMR (CDC13, 200 MHz): 0.85 (t, 3N, J 7.5); 1.3 (t, 3N, J - 7.6); 1.6-2.3 (m, 7H); 2.5 (m, 2H) 2.65 (m, 1H); 2.8 (q, 2H, J 7.6); 3 (m, 111), 3.85 (s, 2I); 4.63 (wide s); 5-5.2 (m, 2H); 5.8-6 (m, 1H); 6.9-7.1 (m, 211); 7.2-7.4 (m, 6H); 10 (broad s, 1H).
    The melting points of compounds (I) are listed in Table. one.
    The anti-inflammatory effects of compounds (I) are illustrated using standard pharmacological tests, for example, a test called puffiness prevention. The purpose of this test is to determine the ability of the tested drugs to have an anti-inflammatory effect on rats. The results of this test are used for primary anti-inflammatory drugs.
    Male Sprague Dawley rats weighing 180–200 g were used as experimental animals. For 18 hours before the test, the animals were no longer fed, but were given plenty of water.
    Freund's total adyrant was prepared by suspending 5 mg of dead dried microbacteria butyricum (Difeo) in 1 ml of liquid paraffin. Test compounds were dissolved in distilled water or suspended in distilled water with the addition of a few drops of Tween 80, depending on their solubility. For the initial selection, all the preparations were administered orally after washing.
    stomach in the amount of 0.5 ml / 100 g of weight at a dose of 100 mg / kg. Each group consisted of 10 animals.
    Animals were injected intradermally in the left hind paw with 0.1 ml of complete adyu anta Freund. A test compound or an indifferent carrier was administered immediately before the adjuvant and 24 and 48 hours later (after 0.1 and 2 days) after the adjuvant. The volume of the hind paw that was injected was measured using a plethysmometer (Buxco Electronic Inc.) before administering the adjuvant and 24 hours after the last injection of the test preparation (after three days). The difference between the last and originally measured hind paw volume is the volume of the swelling. Phenylbutazone was used as a control drug (administered orally in an amount of 50 mg / kg).
    The volume of puffiness (in ml + SEM) for each group of experimental animals was calculated and the percentage of protection (as a result of the effect of the drug) was calculated using the formula
     (c-t) 100% protection 1
    where c is the volume of puffiness for control animals (which were not injected with medication), t is the volume of puffiness for animals that were injected with the test drug.
    Another test conducted to determine the usefulness of the compounds in accordance with the present invention was called the Effect of drugs on the writing movement in mice, induced by phenylquinone.
    The purpose of this test is to determine the ability of test drugs to inhibit the pain-sensitive response in mice that have been injected with a chemical irritant. This test is used for the initial selection of pain medications that act on both the peripheral and central systems.
    Male Swiss white mice weighing 15–25 g were used as experimental animals. For 18 hours before the beginning of the test, animals were not fed, but they were given plenty of water.
    Test drugs were dissolved or suspended depending on
    their soluble. i in 0.5% methylcellulose or 0.5% tween 80 solution. The drugs were administered by washing the stomach in an amount of C, 5 ml / kg. For the initial screening, the dose of all drugs administered was 200 mg / kg. Each group of experimental animals consisted of 10 mice.
    TO ANIMAL TRIPS, STANDING OUT
    5 mice were injected with the test compound or control indifferent carrier. After 60 minutes thereafter, a 0.02% phenylquinone solution (PBQ, 2-phenyl-1, 4-benzoquinone) was injected intraperitoneally in quantities of 0.3 ml per 2D g of weight and placed in individual boxes for observation. At the same time, the number of writing movements and convulsive abdominal movements performed by each mouse over the next 15 minutes was counted. The experiment was repeated with another group of 5 mice and the number of movements per mouse was calculated for a group of 10 mice.
    Experiments were compared with control mice and mice that were injected with the drug, and the results of the experiments were calculated by the percentage of protection according to the formula
     (c-t) IOO% protection)
    where c is the number of writing movements in mice from the control group,
     t is the number of writing motions in mice injected with medication.
    In addition, to determine the usefulness of the proposed compounds, a test called the Paw Pressure Test on rats was carried out. The purpose of this test is to assess the ability of drugs that have an effect on the peripheral and central system, inhibiting the reaction to pain caused by the effect on the inflamed paw.
    Male Spraque Dawiey rats weighing 180-200 g were used as experimental animals. At night, before the administration of the medicine, the animals were not allowed to eat.
    Freund's complete adjuvant (PAF) was prepared by suspending butiri- dead and dried microbacteria
    | n
    20 5
    0
    five
    0
    .with
    0
    five
    cum (Difeo) 1 ml of liquid paraffin. Test compounds were dissolved or suspended, depending on their solubility in distilled water with the addition of a few drops. Tween 80. Prepared preparations were administered by washing the stomach in the amount of 0.5 ml per 100 g of weight. Each group consisted of 10 animals.
    Each group of experimental animals consisted of 10 rats. An apparatus is a device that creates a force, increasing with a constant speed. This force is continuously monitored using a dial device moving along a linear scale and is measured in grams. The inflammatory response was excited in rats by injecting 0.1 ml of Freund's adjuvant intracutaneously into the left hind paw. A test compound or an indifferent carrier was administered 24 hours after the adjuvant. Before the administration of the drug, rats were selected for their paw sensitivity. In the experiments, only rats were used, which reacted to a pain threshold below 10 g (force applied to the inflamed paw). The pain threshold (squeak, made with the sensation of pain) was determined after 1 and 3 hours on the inflamed and sore paw in animals from the control group and in animals that were injected with the medicine. In assessing the effect of the drug on the pain threshold, the larger of the two values obtained was used.
    It was assumed that the administered compound has an effect if a certain pain threshold was one and a half times higher than in animals from the control group. In each group, the number of animals in which the analgesic effect of the administered compounds was observed was determined.
    The EDgo value was then determined (the dose at which the pain relief effect was observed in 50% of the animals) using at least 3 doses.
    The data of biological tests are presented in table. 2-5.
    Compound (I) at the tested doses showed no signs of toxicity.
    Thus, compounds (I) possess high analgesic and anti-inflammatory activity,
    ascending known 4-propyl-1,8-β-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid (III) ..
    权利要求:
    Claims (2)
    [1]
    1. Derivatives of 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid of general formula (I)
    AT
    h n R2 CH-POOH
    de a) E.C. - benzyl R - ethyl1, RS - hydrogen; R 4 is hydrogen or 8-ethyl;
    b) R is 2-methyl 2-propenyl; E.J - ethyl;
    RS R /) is hydrogen or
    7-chloro, R / 1 - 8-methyl,
    c) R ,, - 1,1-dimethyl-2-propenyl; RQ is ethyl,
    RJ t hydrogen}
    R4 is 8-fluoro or R3 is 7-chloro, R is 8-methyl;
    g) Ry - 2-propenyl, Rg - methyl,
    R3R.
    hydrogen.
    R4 is hydrogen or 8-ethyl, or rjj
    ethyl, RJ is hydrogen, R / S is hydrogen, 8-methyl, 6-s 7- or 8-ethyl, 8-propyl, 8-isopropyl, 6-butyl, 6- or 8-fluoro, 5-, 6-, 7- or 8-chloro, 5-, 6-, 7- or 8-bromo, 8-iodo or Ry - 8-methyl, - 5-methyl, 7-fluoro, 5 or 7-chloro, 7-bromo, or RJ is chlorine, R4 is 5-methyl, 5-, 6-, or 7-chloro, or R, is 8-bromo, R4 is 5-methyl, or Ry is 7-chloro, R $ is 5-chloro, or Rg is propyl, RJ is hydrogen, R / J is 8-ethyl, or benzvm of the tanamine salt of compound (I), where R (is 2-propenyl, RJ. And R is ethyl, R3 is hydrogen,
    analgesic and analgesic
    inflammatory action.
    [2]
    2. 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid methyl ester of the general formula
    ten
    cd n kg sn2co3
    five
    0
    five
    0
    five
    0
    five
    0
    five
    where a) R is benzyl; Ru is ethyl; R3 is hydrogen; R4 is hydrogen or 8-ethyl;
    b) R is 2-methyl-2-propenyl; Rt is ethyl;
    Rj R o, is hydrogen or Ra 7-chloro; R4 8-methyl,
    c) R - 1, 1-dimethyl-2-propenyl, R4 - ethyl,
    R is hydrogen, R4 is 8-fluoroJ or RS 7-chloro; R is 8-methyl,
    d) Rf is 2-propenyl; - methyl;
    R is hydrogen,
    RJI is hydrogen, 8-methyl, 6-,
    7- or 8-ethyl, 8-propyl, 8-isopropyl, 6-butyl,
    6- or 8-fluoro, 5-, 6-,
    7- or 8-chloro, 5-, 6-, 7- or 8-bromo, 8-iodo or RJ - 8-methyl, R - - 5-methyl, 7-fluoro, 5- or 7-chloro, 7- bromine, or RJ - 8-chloro, RJ - 5-methyl, 5-, 6- or 7-chloro, or RS - 8-bromine, R l - 5-methyl, or RJ - 7-chloro, RH - 5- chlorine, or RJ. - propyl, R, - hydrogen,
    & l - 8-ethyl,
    as an intermediate product for the synthesis of 2,3,4,9-tetra-hydro--1H-karabazole-1-acetic acid derivatives, which have an analgesic and anti-inflammatory effect.
    Priority signs: 22.04.85 with R - 2-propenyl or benzyl, R $. - ethyl, Rg - hydrogen, R # n hydrogen or 8-ethyl,
    11/13/85 all other values of the radicals Rx, RG, R and R.
    # 3 n 2 CH2COOH
    2-PropeTable 1
    Continued table. one
    2S Continuation of table 3
    -1482915
    26 Continuation of table 3
    Table 4
    27148291528
    Continuation of table 4
    Note. The values shown are the percent inhibition at doses, mg / kg, given in brackets, or the value of ED5v, mg / kg.
    Table 5
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1482915A1|1989-05-30|Derivatives of 2,3,4,9-tetrahydro-1n-carbazol-1-acetic acid having pain-relieving and antiinflammation effect
    US3420851A|1969-01-07|Novel dibenzoxepines
    EP0170213B1|1990-01-10|Glutarimide antianxiety and antihypertensive agents
    KR910002583B1|1991-04-27|Piperazine derivative or its salt,process for producing the same and pharmaceutical composition comprsing the same as active ingredient
    US3821249A|1974-06-28|Dibenzothiazefin derivatives
    US2489235A|1949-11-22|Synthesis of biotin
    DK171641B1|1997-03-03|Disubstituted proline derivatives, processes for their preparation and their use
    CS248035B2|1987-01-15|Production method of the|1|carboxyle acides
    DK160820B|1991-04-22|ANALOGY PROCEDURE FOR THE PREPARATION OF 1,2,3,4,4A, 5,10,10A-OCTAHYDROBENZO | QUINOLINE DERIVATIVES
    US4904690A|1990-02-27|Chromone derivatives useful as antitumor agents
    KR20170032328A|2017-03-22|Pyrazole derivative manufacturing method
    US4690932A|1987-09-01|Coumarins with imidazolyl group or pyridyloxy group having plateletes aggregation inhibiting activity
    EP0149419B1|1988-08-17|Acylindole derivatives and pharmaceutical compositions containing them
    EP0230020B1|1990-09-19|1,2,3,4,4a,9b-hexahydro-4a-aminoalkyldibenzofurans, a process for their preparation and their use as medicaments
    SU858570A3|1981-08-23|Method of preparing derivatives of 3-|-1-azaxanthone or their salts
    SU1091859A3|1984-05-07|Process for preparing derivatives of 2,3,6,7-tetrahydrothiazolo| pyrimidin-5-one |
    US3086972A|1963-04-23|Aza-thiaxanthene derivatives
    US4709048A|1987-11-24|Production of substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid derivatives
    EP0433064A1|1991-06-19|Naphthylsulfonylalkanoic acid compounds
    US5922739A|1999-07-13|5-Naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutical use thereof
    JP3207017B2|2001-09-10|Method for producing benzylsuccinic acid derivative and intermediate for producing the same
    FI62531B|1982-09-30|PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC 3-YAN-N- | -IMINOBENSYL OCH SYRAADDIT IOSSALTER DAERAV
    EP0057337B1|1984-03-14|4h-benzo|cyclohepta|furan derivatives, process for their preparation and their use as medicines
    JPH0635458B2|1994-05-11|Pyridonecarboxylic acid derivatives, their esters and their salts
    US4564685A|1986-01-14|Diphenylmethane compounds
    同族专利:
    公开号 | 公开日
    IL78431D0|1986-08-31|
    PT82384A|1986-05-01|
    ES8706632A1|1987-07-01|
    FI861561A|1986-10-23|
    KR900001183B1|1990-02-27|
    HUT40789A|1987-02-27|
    EP0247701A2|1987-12-02|
    US4616028A|1986-10-07|
    EP0200391A2|1986-11-05|
    PH21978A|1988-05-02|
    DE3664910D1|1989-09-14|
    EP0200391B1|1989-08-09|
    DK170986D0|1986-04-15|
    FI861561A0|1986-04-14|
    CS254348B2|1988-01-15|
    GR860945B|1986-07-23|
    PT82384B|1987-09-10|
    AU583909B2|1989-05-11|
    AU5572886A|1986-10-30|
    ES554211A0|1987-07-01|
    HU195484B|1988-05-30|
    DK170986A|1986-10-23|
    EP0200391A3|1987-06-03|
    KR860008138A|1986-11-12|
    EP0247701A3|1988-01-13|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    RU2515895C2|2008-03-27|2014-05-20|Грюненталь Гмбх|Spiroundecane derivatives|ZA715217B|1970-08-20|1972-04-26|Org Nv|Anti-inflammatory preparations|
    US4057559A|1973-10-01|1977-11-08|American Home Products Corporation|Carbazole acetic acid derivatives|
    GB1511169A|1975-08-29|1978-05-17|American Home Prod|Trycyclic acetic acid derivatives|
    US4578398A|1985-05-31|1986-03-25|American Home Products Corporation|Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid, compositions and use|IL81325A|1986-01-23|1990-11-29|Merck Frosst Canada Inc|Tetrahydrocarbazole 1-alkanoic acids and pharmaceutical compositions containing them|
    US4701533A|1986-08-26|1987-10-20|American Home Products Corporation|Process for preparing substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid|
    US4687860A|1986-02-18|1987-08-18|American Home Products Corporation|Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid|
    EP0239306B1|1986-03-27|1993-06-02|Merck Frosst Canada Inc.|Tetrahydrocarbazole esters|
    US4748266A|1986-05-28|1988-05-31|American Home Products Corporation|Substituted 2-oxocyclohexaneacetic acid esters|
    US4782076A|1988-03-01|1988-11-01|American Home Products Corporation|Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid derivatives, composition and use|
    US4873257A|1988-04-21|1989-10-10|American Home Products Corporation|Susbtituted fused tetrahydrocarbazole acetic acid derivatives|
    US4886826A|1989-06-01|1989-12-12|American Home Products Corporation|Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid derivatives, composition and use|
    US4988726A|1989-06-01|1991-01-29|American Home Products Corporation|Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid derivatives, composition and use|
    EP0405602A1|1989-06-30|1991-01-02|Laboratorios Vinas S.A.|New Zinc derivatives of anti-inflammatory drugs having improved therapeutic activity|
    US5055590A|1989-09-29|1991-10-08|American Home Products Corporation|Preparation of 2,3,4,9-tetrahydro-1H-carbazole acetic acid derivatives|
    US4927842A|1989-09-29|1990-05-22|American Home Products Corporation|2,3,4,9-tetrahydro-1H-carbazole acetic acid derivatives, composition and use as anti-inflammatories|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US72619785A| true| 1985-04-22|1985-04-22|
    US06/797,561|US4616028A|1985-04-22|1985-11-13|Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid derivatives, compositions and use|
    [返回顶部]