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    • 专利摘要:
    A thiazole compound of the formula: wherein R1 is amino optionally having suitable substituent(s), R2 is hydrogen, lower alkyl or aryl, R3 is hydrogen, nitro, amino optionally having suitable substituent(s), hydroxy or lower alkoxy, A is lower alkylene, Q is hydrogen or halogen, and a heavy solid line means a single or double bond, and a pharmaceutically acceptable salt thereof, processes for the preparation thereof and pharmaceutical composition comprising the same.
    公开号:SU1753948A3
    申请号:SU884356048
    申请日:1988-07-12
    公开日:1992-08-07
    发明作者:Уеда Икуо；Мацуо Масааки；Манабе Такаси；Мацуда Хироси
    申请人:Фудзисава Фармасьютикал Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of novel biologically active chemical compounds, specifically thiazole derivatives or their addition salts with acids, which have antiallergic activity, which can be used in medicine,
    The purpose of the invention is a method for producing new indolpiperidine thiazole derivatives having improved antiallergic activity in a series of indoliperidines.
    PRI me R 1. To a mixture of 2-amino-4- 4- (3-indolyl) pipiridinomethyl (1.73 g), triethylamine (3.1 ml) and 15 ml of NN-dimethylformamide in drops I added a solution of 0.86 ml of mesyl chloride in methylene chloride (1 ml) at temperature with stirring. This mixture was further stirred at the same temperature for 2 hours, after which a solution of mesyl chloride (0.34 ml) in methylene chloride (0.5 ml) was added. The reaction mixture is further stirred at the same temperature for 1.5 hours. After adding water (BO ml), the reaction mixture is extracted twice with a mixture of chloroform and methanol (60 ml, 10: 1 by volume). The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue is dissolved in 40 ml of tetrahydrofuran and then 10% is gradually added to the solution.
    VS
    cl
    (l 45 4 00

    Sl)
    an aqueous solution of sodium hydroxide (20 ml). The mixture is stirred at room temperature overnight. The reaction mixture is then acidified to pH 7.0 with dilute hydrochloric. acid and extracted with a mixture of chloroform and methanol (100 ml, 10: 1 by volume). The organic layer is separated, washed and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is fed to a silica gel chromatography column, after which the column is eluted with a mixture of chloroform and methanol (10: 1 by volume). 480 ml of 4- {4- (3-indolyl) piperidino-methyl -2-mesyl miniazolol are obtained from the eluate. M.p. 215-217 ° C (recrystallized from a mixture of chloroform-methanol 20: 1 by volume).
    IR Spectrum (nudzhol), 3310; 1380; 1260; 1116; 967; 743.
    Mass spectrum: 390 (M4).
    NMR (diterodimethylsulfoxide): 1.5-3.3 (9H, multiplet); 2.80 (3N, singlet); 3.50 (2H, singlet); 6.68 (1H, singlet); 6.8-7.7 (5H, multiplet); 10.72 (1H, singlet).
    Calculated,%: C 55.36; H 5.68; N 14.35.
    Found,%: C 55.13; H 5.48; N 14.03.
    C18H22N402S2
    Example 2. To a mixture of (3-indolyl) piperidinomethyl -2-aminothiazole (1.5 g), triethylamine (2.68 ml) and NN-dimethylformamide (15 ml) a solution of propionyl chloride (0 , 63 ml) in 1.2 ml of methylene chloride for 10 minutes under ice cooling and the mixture is stirred for 4.5 hours. The reaction mixture is dissolved in a mixture of chloroform and methanol (100 ml, 10: 1 by volume), solution washed with water (3 times 50 ml each time) and brine (50 ml) in the sequence indicated, dried over magnesium sulfate. The solvent is evaporated and the residue is fed to a silica gel column chromatography. The column was eluted with a mixture of chloroform and methanol (from 30: 1 to 15: 1 by volume). The fractions containing the desired product are combined and concentrated to give a residue which, upon recrystallization from ethanol, gives 0.72 g of (3-indolyl) piperidinomethyl} -2-propynyl aminothiazole. M.p. 191.5-195 ° C.
    IR (Nujol), 3380: 1673: 1540; 1180; 738.
    NMR spectrum (deuterodimethyl sulfoxide) 5: 1.07 (3N, triplet-J 7.2 Hz); 1.2-3.8 (13H, multiplet); 6.8-7.7 (6H, multiplet); 10.66 (1H, shir, singlet); 12.05 (1H, broad singlet).
    Mass spectrum: 368 (M4).
    Calculated,%: C 64.42; H 6.95; N 14.31.
    Found,%: C 64.62; H 6.66; N 14.63.
    C20H24N40S 1/2 C2NaOH
    Example 3. To a mixture of 3.0 f 4- {4- {3-indolyl) piperidinomethyl} - 2-aminothiazole, 5.4 ml of triethylamine and 30 ml / W-dimethylformamide
    a solution of 2.18 ml of cyclopropylcarbonyl chloride in methylene chloride (2.5 ml) is added dropwise over 30 minutes at 0 ° C in a stream of gaseous nitrogen with stirring. After
    after completion of the reaction, the reaction mixture is filtered and the filtrate is concentrated. The residue is purified on a chromatographic column with silica gel, which is eluted with a mixture of chloroform and methanol (20: 1 by volume) to give 2.9 g of 4 {4 {3-indolyl) piperidinomethyl} -2-cyclopropylcarbonylaminothiazole. M.p. 120-132 ° C (recrystallized from ethanol-water 1: 1 by volume).
    IR Spectrum (Nujol), 3560; 3420; 1673; 1550; 1270; 1190; 1000
    NMR spectrum (deuterodimethylsulfoxide) b: 0.6-1.3 (4H, multiplet); 10.90 (1H, singlet); 12.27 (1H, singlet).
    Example 4. To a mixture of 2-amino-4- {2- 4- {3-indolyl) piperidino ethyl} thiazole (1.24 g) and triethylamine (2.1 ml) in 10 ml of N.N-dimethylformamide, slowly add a solution of mesyl chloride (0.6 ml) in methylene chloride (2 ml) at a temperature of 0-6 ° C and the mixture is stirred for 1.5 hours. To the mixture is added another 0.3 ml of mesyl chloride and
    stirred for 2 hours. 0.13 g of 4- {2- {4- {3-indolyl) piperidino eTi} -2-mesyl minothiazole is obtained. M.p. 141-144 ° C.
    IR (Nujol), 1120; 1100; 968; 740.
    NMR spectrum (deuterodimethylsulfoxyl) d: 1.5-3.4 (13H, multiplet); 2.80 (SA, siglet); 6.41 (1 H, singlet); 6.8-7.8 (5H, multiplet); 10.70 (1H, broad singlet). Mass spectrum: 404 (M4).
    Calculated,%: C 53.23; H 5.57; N 12.89.
    Found,%: C 52.95; H 5.65; N 12.69.
    C19H24N402S2 1 / 4CHCI3
    Example 5. To a mixture of (3-indolyl) piperidinomethyl -2-aminothiazole (1 g), triethylamine (1.3 g) and M, 1-dimethylformamide (10 ml) was added dropwise a solution of 2-acetoxyacetyl chloride (0 , 87g) in methylene chloride (1 ml) in a stream of gaseous nitrogen with cooling
    ice and stirred for 20 min. After 3 hours, the reaction mixture is filtered and the residue on filter paper is washed with 10 ml of N.N-dimethylformamide. The filtrate and the washings are combined and concentrated under reduced pressure in order to remove the solvent. The residue is fed to a chromatographic column with silica gel and fusion elution with a mixture of chloroform and methanol (20: 1 by volume). Fractions
    containing the desired product is collected and concentrated under reduced pressure, and the residue is recrystallized from a mixture of water and ethanol to obtain 0.23 g of (3-indolyl) piperidinomethyl -2- (2 (2-acetoxy acetylamino) thiazole. mp. 140-144 ° s
    IR Spectrum (nujol), 3410; 1750; 1705: 1585.
    NMR spectrum (deuterodimethylsulfoxide) b; 1.5-2.4 (5H, multiplet); 2.13 (SA, singlet); 2.6-3.9 (4H, multiplet); 3.54 (2H, broad singlet); 4.75 (2H, broad singlet); 6.8 - 7.2 (2H, multiplet); 7.0 (1H, singlet); 7.08 (1H, doublet, J 2.0 Hz); 7.35 (1H, dw. Doublet, J - 2.0 Hz and 7.0 Hz).
    Mass spectrum (t / e): 412 (M4).
    Calculated,%: C 58; H 6.09; N 13.01.
    Found%: Ј. 58.71: H 6.21; N 12.90.
    C22H24N403S H20
    According to the method of examples 1-5, the following compounds were obtained (examples 6-35).
    EXAMPLE 6 (3-Indolyl) piperidinomethyl-2-isobutyryl-aminothiazole. M.p. 183-187 ° C.
    IR Spectrum (nudzhol), 3280; 3100; 1533; 1100; 758.
    NMR spectrum (deuterodimethyl sulphoxide), (5: 1.14 (6H, doublet); 1.2-3.7 (12H, multiplet); 6.8-7.7 (6H, multiplet); 10.70 (1H, br. Singlet); 12.05 (1H, br. Singlet).
    Mass spectrum: 382 (M +).
    Calculated,%: C 65,16; H 7.21; N 13.81.
    Found,%: C 65.31; H 7.15; N 13.75.
    C2tH26N40S 1/2 C2H5OH
    PRI me R 7. (3-Indolyl) piperidinomethyl -2-ethylsulfonylaminothiazole, m.p. 181-182 ° C (recrystallized from ethanol).
    IR Spectrum (nudzhol), 3270; 1465; 1110; 1017: 738.
    LMR spectrum (deuterodimethylsulfoxyl) 5: 1.22 (3N, triplet 7.6 Hz); 1.5-3.7 (11H, multiplet); 3.47 (2H, singlet); 6.57 (1H, singlet); 6.9-7.8 (5H, multiplet); 9.46 (1H, broad singlet); 10.73 (1H, singlet).
    Mass Spectrum (m / e): 404 (.
    Calculated,%: C 56,41; H 5.98; N 13.85.
    Found,%: C 56.13; H 5.93; N 13.52.
    Ci9H24N402S2
    Example (3-Indolyl) piperidinomethyl -2-isopropylsulfonylaminothiazole and its hydrochloride.
    The following physical data was obtained for the hydrochloride salt: so pl. 230 - 238 ° C (recrystallized from ethanol).
    IR (Nujol), 3365: 1540; 1460; 1118; 883; 740.
    NMR spectrum (deuterodimethylsulfoxide) 5: 1.24 (6H, doublet, J 4.2 Hz): 1.8-3.7 (12H, multiplet); 4.27 (2H, singlet); 6.8-7.0 (6H, multiplet).
    Calculated,%: C 52.75; H 6.45: N 11.50.
    Found,%: C 52.52; H 6.17, N 11.81.
    C20H26N402S2 HCI 7/10 C2H5ON Example 9. 4- {2- 4- (3-Indolyl) piperidino ethyl} -2-ethylsulfonylaminothiazole and its hydrochloride.
    5The following physical data was
    obtained for hydrochloride: so pl. 222-228 ° C (recrystallized from 70% ethanol).
    IR Spectrum (Nujol), 3250; 2650; 0 1544; 1298; 1117; 890; 743.
    NMR spectrum (deuterodimethylsulfoxide) d: 1.22 (3N, triplet J 7.8 Hz); 1.8-4.0 (17H, multiplet); 6.40 (1H, singlet); 6.7-7.8 (5H, multiplet); 10.75 (1H, broad singlet). 5Calculated,%: C, 52.78; H 5.98; N 12.31.
    Found,%: C 52.66; H 5.70; N 12.25. C2H26N402S HCI
    Example 10. 4- {3- 4- (3-Indolyl) piperidino propyl} -2-mesyl aminothiazole. M.p. 0 210-214 ° C (recrystallized from a mixture of ethanol and water).
    IR Spectrum (Nujol), 3350; 1535. NMR spectrum (deuterodimethylsulfoxide) d: 1.5-3.3 (15H, multiplet); 2.72 (3N, 5 singlet); 5.80 (1H, broad singlet); 6.25 (1H, singlet); 6.9-7.5 (5H, multiplet); 10.7 (1H. Shir. Singlet).
    Mass spectrum (m / e): 418 (M +), 339. Calculated,%: C 57.39; H 6.26; N 13.39. 0 Found,%: C 56.99; H 6.21; N 12.23.
     Szo
    PRI me R 11. (3-Indolyl) piperidinomethyl -2- (2-methoxy-acetylamino) thiaz ol and its hydrochloride.
    5 Below are the physical data for hydrochloride: m.p. 190-205 ° C,
    IR Spectrum (nudzhol), 3400; 2650; 2550; 1695; 1550.
    NMR spectrum (deuterodimethylsulfox-d): d: 2.08 (3N, singlet); 4.20 (2H, singlet); 4.33 (2H, broad singlet); 1.9-3.8 (9H, multiplet); 6.8-7.8 (6H, multiplet); 10.88 (1H, broad singlet). 12.15 (Sh. Singlet).
    Mass spectrum (m / e): 384 (M +), 266, 199. 5 Calculated,%: C 57.28; H 6.18; N 12.72.
    Found,%: C 56.75; H 5.96; N 12.45. C2H24N402S HCI 1/3 CH3CO2-CH3 EXAMPLE 12 (3-Indolyl) piperidinomethyl -2-acryloylaminothiazole. 0 IR spectrum (nudzhol), 3300 (broad band); 1670; 1630; 1555.
    NMR spectrum (deuterodimethyl sulfoxide) d: 1.3-2.4 (4H, multiplet); 2.8-3.1 (2H,
    multiplet); 3.2-3.4 (3N multiplet); 3.57
    5 (2H, singlet); 5.87 (1H, dw. Doublet, J 8.0 and
    4.0 Hz); 6.45 (1 H, doublet, J 4.0 Hz); 6.47 (1 N,
    doublet, J 8.0 Hz); 6.8-7.15 (2H, multiplet);
    7.0 (1 H, singlet); 7.08 (1 H, doublet, J 2.0 Hz);
     7.35 (F, dw. Doublet. J 7.0 and 2.0 Hz); 7.53 (1 N,
    dv doublet, J = 7.0 and 2.0 Hz); 10.7 (1H, broad singlet); 12.3 (1H, burstsignal).
    Mass spectrum (m / e): 366, (M), 199, 167.
    PRI me R 13. (3-Indolyl) piperidinomethyl -2-crotonoylaminothiazole. M.p. 115-118 ° C.
    IR spectrum (nudzhol), cm 1: 3250; 1690; 1650; 1550.
    NMR spectrum (deuterodimethyl sulphoxide) (5: 1.4-2.35 (7H, multiplet); 1.87 (ZN, doublet, J 6.0 Hz); 2.8-3.1 (2H, multiplet ); 3.52 (2H, singlet); 6.16 (1H, double doublet, J = 1.0 Hz and 15.0 Hz); 6.8-7.2 (5H, multiplet); 7.31 ( 1H, twin doublet, 0n 2.0 Hz); 7.51 (1H, twin doublet, J 8.0 Hz and 2.0 Hz); 10.69 (1H, broad singlet); 12, Yu (1H, broad singlet).
    Mass spectrum (t / e): 380 (M4); 262; 199.
    Calculated,%: C 64.76; H 7.08; N 13.13.
    Found,%: C 64.99; H 6.89; N 13.27.
    C21H24N40S С2Н5ОН
    EXAMPLE 14. 2-Acetylamino-4-4- (3-indolyl) piperidinomethyl-thiazole. M.p. 204-207 ° C.
    IR (Nujol), 3400: 3165; 1686; 1263; 1004; 758; 747.
    NMR spectrum (deuterodimethyl sulphoxide) d: 2.32 (3N, singlet); 1.4-3.2 (9H, multiplet); 3.52 (2H, singlet); 6.8-7.65 (6H, multiplet); 10.70 (1H, singlet); 12.08 (1H, singlet).
    Example 15. 2-Acetylamino-4 {2- 4- (3-indolyl) piperidino ethyl} thiazole. M.p. 203-204 ° C.
    IR Spectrum (Nujol), 3275; 1663; 1560; 1305; 1106; 740.
    NMR (deuterodimethylsulfoxide) 5: 2.13 (GN, singlet); 1.4-3.4 (13H, multiplet); 6.80 (1H, singlet); 6.8-7.7 (5H, multiplet); 10.79 (1H, singlet); 12.03 (1H, broad singlet).
    PRI me R 16. (3-Indolyl) piperidinomethyl -2-pivaloylaminothiazole. M.p. 93-96 ° C
    IR Spectrum (Nujol), 3235; 1684; 1165; 1148; 1045; 750
    NMR (deuterochloroform) 5: 1.33 (9H, singlet); 1.5-3.4 (9H, multiplet); 3.56 (2H, singlet); 6.73 (1 H, singlet); 6.9-7.8 (5H, multiplet); 8.10 (1H, broad singlet); 9.00 (1 H, multiplet); 8.10 (1H, singlet); 9.00 (1H, broad., Singlet).
    EXAMPLE 17 (3-Indolyl) piperidinomethyl-2- (3-methylureido) thiazole. M.p. 222-224 ° C (decomposed).
    IR Spectrum (Nujol), 3550; 1750; 1680; 1550.
    NMR spectrum (deuterodimethylsulfoxide) d: 1.5-3.2 (12H, multiplet); 3.50 (2H, broad singlet); 6.50 (1H, multiplet); 6.8-7.2
    (2H, multiplet); 7.05 (1 H, doublet, J 2.0 Hz);
    7.08 (1H, singlet); 7.38 (1H, double doublet, J
    2.0 and 7.0 Hz); 7.55 (1 N, dw. Doublet, J 2.0 and 7.0
    Hz); 10.7 (1H, br. Singlet), Example 8. 2-Acetylamino-4 {3-4 (indolyl) piperidino propyl} thiazole. M.p.
    168.5-170 ° C.
    IR Spectrum (Nujol), 3300; 3100;
    1670; 1570; 1300; 985; 750. NMR spectrum (deuterodimethylsulfoxide) d: 1.4-3.3 (15H, multiplet); 2.12 (MN,
    singlet); 6.70 (1H, singlet); 6.8-7.7 (5H,
    multiplet); 10.70 (1H, broad singlet), 12.00
    (1H, broad singlet), Example 9. (3-Indolyl) piperidinomethyl -2- (3,3-dimethylbutyrylamino) thiazole. M.p. 224.5-226 ° C.
    IR Spectrum (nudzhol), 3390; 3248;
    1650; 1548; 1327; 740. NMR spectrum (deuterodimethylsulfoxide) d: 1.03 (9H, singlet); 2.33 (2H, singlet);
    1.3-3.3 (9H, multiplet); 3.53 (2H, singlet);
    6.95 (1H, singlet); 7.0-7.8 (5H, multiplet);
    10.75 (1H, singlet); 12.03 (1H, singlet). PRI me R 20. 4 4- 3-Indolyl) piperidinomethyl -2-valerylaminothiazole. M.p.
    142-144 ° C.
    IR Spectrum (Pujol), 3240; 1693;
    1553; 1105: 745. NMR spectrum (deuterodimethyl sulfoxide) d: 0.8-3.7 (18H, multiplet), 3.55 (2H,
    singlet); 6.92 (1H, singlet); 6.9-7.7 (5H,
    multiplet); 10.73 (1H, singlet); 12.05 (1H,
    wide singlet). PRI me R 21. (3-Indolyl) piperidinomethyl -2-formylaminothiazole. M.p.
    217-221c.
    IR Spectrum (nudzhol), 3460, 1690;
    1562; 1280; 852; 755. NMR spectrum (deuterodimethyl sulfoxide) 5: 1.5-3.8 (9H, multiplet); 3.51 (2H,
    singlet); 6.8-7.7 (6H, multiplet); 8.45 (1H,
    singlet; 10.70 (1 H, broad singlet); 12.13 (1 N,
    wide singlet). PRI me R 22. (3-Indolyl) piperidinomethyl -2-butyrylaminothiazole. M.p.
    163-165 ° C.
    IR spectrum (nudzhol), 3200 (wide band); 1690; 1555: 745.
    NMR spectrum (deuterodimethyl sulfoxide) d: 0.90 (3N, triplet, J 7.5 Hz); 1.07
    (ZN, triplet, J 7.5 Hz); 3.53 (2H, singlet);
    4.33 (1 H, singlet); 6.92 (1 H, singlet); 6.9-7.7 (5H, multiplet); 10.71 (F, singlet); 12.02
    (1H, singlet).
    PRI me R 23. (3-Indolylpiperinomethyl -2- ethoxycarbonylaminothiazole.
    M.p. 85 ° C (decomposed).
     IR Spectrum (nudzhol), 3400; 1725; 1563; 1075: 740.
    NMR spectrum (deuterodimethylsulfoxide) 5: 1.27 (3N, triplet, J 6.4 Hz); 1.5-3.5 (9H, multiplet); 3.52 (2H, singlet); 4.23 (2H, quartet, J 6.4 Hz); 6.94 (1H, singlet); 7.0 - 7.8 (5H, multiplet); 10.75 (1H, singlet); 11.60 (1H, broad singlet).
    PRI me R 24. (1-Methyl-3-indolyl) piperidinomethyl -2-acetylaminothiol. M.p. 17b-177 ° C.
    IR Spectrum (Nujol), 3150; 1690; 1550; 1279: 743.
    NMR spectrum (deuterodimethylsulfoxide) d; 1.5-3.7 (9H, multiplet); 2.16 (SA, singlet); 3.55 (2H, singlet); 6.8-7.8 (6H. Multiplet).
    Example 25 (5-Nitro-3-indolyl) piperidinomethyl -2-propionylamino-thiazole, m.p. 222-224 ° C.
    IR Spectrum (nudzhol), 3290; 1670; 1575; 1520; 1330; 1250; 1100; 735.
    NMR spectrum (deuterodimethylsulfoxide) d: 1.10 (3N. Triplet, J 7.5 Hz); 2.40 (2H, quartet, J 7.5 Hz); 1.4-3.5 (9H, multiplet); 3.50 (2H, singlet); 6.85 (1H, singlet); 7.3-8.5 (4H, multiplet); 11.48 (1H, broad singlet); 11.91 (1H, broad singlet),
    PRI me R 26. (3-Indolyl) piperidinomethyl -2- (2P) -2-acetoxypropionyl amine thiazole.
    IR Spectrum (nudzhol), 3430; 1744; 1692; 1550; 1463.
    NMR spectrum (deuterochloroform) d: 1.55 (3N, doublet, J 6.9 Hz); 1.6-3.3 (9H, multiplet); 2.17 (3N, singlet); 3.55 (2H, singlet); 5.38 (1E, quartet, J .6.9 Hz); 6.8-8.1 (8H, multiplet). 12.0 ° (concentration 0.1 mol / L, dimethylformamide).
    PRI me R 27. (3-Indolyl) piperidinomethyl -2- (2P) -acetoxypropionylamino-thiazole.
    IR spectrum (needs), 3430; 1744; 1692; 1550; 1463.
    PRI me R 28. (5-amino-3-indolyl) piperidinomethyl -2-propionylamino-thiazole. M.p. 115-118 ° C (decomposed).
    IR Spectrum (nudzhol), 3400; 3300; 3200; 1685; 1555; 1350; 1330; 1275; 1200
    NMR spectrum (deuterodimethylsulfoxide) d: 1.05 (3N, triplet, J 7.0 Hz); 2.41 (2H, quartet, J 7.0 Hz); 1.3-3.6 (9H, multiplet); 3.50 (2H, singlet); 4.30 (2H, broad singlet); 6.3-7.0 (5H, multiplet), 10.10 (1H, shir, singlet); 11.88 (1H, broad singlet).
    EXAMPLE 29 (5-Acetylamino-3-indolyl) piperidinomethyl -2-propionidamine-nohiazole. M.p. 263-267 ° C.
    IR spectrum nudzhol), 3370; 1680: 1650; 1590; 1560.
    NMR spectrum (deuterodimethyl sulphoxide) d: 1.08 (3N, doublet. J 9.0 Hz); 2.0 (SN, singlet); 2.35 (2H, quartet, J 9.0 Hz); 1.4 - 3.2 (9H, multiplet); 3.48 (2H, singlet); 6.8 - 9.56 (5H, multiplet); 10.55 (1H, broad singlet); 11.93 (2H, broad singlet).
    PRI me R 30. (3-Indolyl) piperidinomethyl -2- (0-lactoylamino) thiazole, m.p. 213-216.5 ° C.
    IR Spectrum (nudzhol), 3360; 3190, 1663; 1570; 1138.
    NMR spectrum (deuterodimethyl sulphoxide) d: 1.27 (3N, doublet, J = 6.6 Hz); 1.4-3.6
    (9H, multiplet); 3.52 (2H, singlet); 4.30 (1 N,
    quartet, J 6.6 Hz); 5.6 (1H, broad singlet);
    6.8-7.7 (6H, multiplet); 10.68 (1 H, singlet);
    11.50 (1H. Shir. Singlet). 5 ° (concentration 0.1 mol / L, dimethylformamide).
    EXAMPLE 31, (3-Indolyl) piperidinomethyl 2- (lactoylamino) thiazole. M.p. 212-216 ° C. "L 24 5 -5 ° (concentration 0.1 M, dimethylformamide).
    PRI me R 32. (3-Indolyl) piperidinomethyl -2 glycosyl aminothiazole. Mp: 185-188 ° C.
    IR Spectrum (Nujol), 3250; 1680, 1530.
    NMR spectrum (deuterodimethyl sulphoxide) d: 1.4-3.4 (9H, multiplet); 3.51 (2H, singlet); 4.10 (2H, singlet); 6.8-7.2 (2H, multiplet); 6.96 (1 H, singlet); 7.07 (1 N. doublet, J 2.0 Hz); 7.35 (1H, dw. Doublet; J - 2.0 Hz and 7.0 Hz); 7.58 (1 N, dw. Doublet, J 2.0 and 7.0 Hz); 10.65 (1H, broad singlet).
    EXAMPLE 33. (3-Indolyl) piperidinomethyl -2- (3-methoxypropionylamino) thiazole. M.p. 157-158 ° C. IR Spectrum (Nujol), 3200; 1696; 1554; 1108: 740.
    NMR spectrum (deuterodimethylsulfoxide) d: 1.5-3.5 (9H, multiplet). 2.65 (2H, triplet, J 6.0 Hz); 3.23 (SA, singlet); 3.52 (2H, singlet); 3.63 (2H, triplet, J 6.0 Hz); 6.8-7.6 (6H, multiplet); 10.7 (1H, singlet); 12.06 (1H, singlet).
    PRI me R 34. (3-Indolyl) piperidinostil 2- (3-acetoxypropionylamino) thiazole. M.p. 73-75 ° C.
    IR Spectrum (nudzhol), 3610; 3430; 1714; 1680; 1565.
    NMR spectrum (deuterodimethylsulfoxide) d: 1.5-2.4 (6H, multiplet); 2.0 (SN, singlet); 2.76 (2H, triplet, J 6.0 Hz); 2.6 - 3.25 (ЗН, multiplet); 3.54 (2H, singlet); 4.28 (2H, triplet, J = 7 Hz); 6.95 (1 N. singlet); 7.06 (1 H, doublet, J 2.0 Hz); 6.8-7.15 (2H, multiplet); 7.33 (1H. Dw. Doublet, J 2.0 and 7.00 Hz);
    7.51 (1H, dw. Doublet, J 2.0 and 7.0 Hz); 10.71 (1H, broad. Signal); 12.17 (1H, broad. Signal).
    PRI me R 35. (3-Indolyl) piperidinomethyl 2- (3-hydroxypropionylamino) thiazole, m.p. 212-218 ° C (decomposed).
    IR spectrum (nudzhol), cm: 3200; 1650; 1550.
    I M P-spectrum (deuterodimethylsulfoxide) d: 1.3-2.3 (6H, multiplet); 2.55 (2H. Triplet, J 6.0 Hz); 2.6-3.1 (3N, multiplet); 3.51 (2H, singlet); 3.70 (2H, triplet, J 6.0 Hz); 4.60 (1H, broad. Signal); 6.90 (1 H, singlet); 7.05 (F, doublet, J 2.0 Hz); 6.8-7.1 (2H, multiplet); 7.30 (1H, dw. Doublet, J 7.0 Hz and 2.0 Hz); 10.67 (1H, broad. Signal); 11.9 (1H, wide signal).
    EXAMPLE 36 A mixture of (5-nitro-3-indolyl) piperidinomethyl-2-propionyl aminothiazole (1.39 g) and 60 ml of ethanol is added to a solution of ammonium chloride (1.08 g) in water (20 ml), then stirred at 80 ° C. 1.13 g of iron was added to the mixture and the mixture was heated under reflux for 2 hours, after which it was filtered. The residue is washed with hot ethanol, the filtrate and the washings are combined and concentrated under reduced pressure. The residue is alkalinized (by litmus paper) 2n. sodium hydroxide solution in water and extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was applied to a silica gel column chromatography and elution was carried out with a mixture of chloroform and methanol, to obtain 0.92 g (5-amino-3-indolyl) piperidinomethyl -2-propionylaminothiazole. M.p. 115-118 ° C (decomposed). Recrystallized from ethanol. IR spectrum (nudzhol), cm-1: 3400; 3300; 3200; 1685; 1555; 1350; 1330; 1275; 1200
    NMR spectrum (deuterodimethylsulfoxide) d: 1.05 (3N, triplet, J 7.0 Hz); 2.41 (2H, quartet, J 7.0 Hz); 1.3-3.6 (9H, multiplet), 3.50 (2H, singlet); 4.30 (2H, broad singlet); 6.3-7.0 (5H, multiplet); 10.10 (1H, broad singlet); 11.88 (1H, broad singlet).
    Mass spectrum (m / e): 383 (M4).
    Calculated,%: C 61.51; H 7.27; N 16.30.
    Found,%: C 6i, 63; H 86; N 15.98.
    C2oH25N5OS C2H5OH
    Example 37. To a solution of (5-amino-3-indolyl) niperidinomethyl -2-propionyl minothiesol (0.5 g) in 5 ml of pyridine gradually add 0.16 ml of acetic anhydride while stirring and cooling with ice. . After stirring for 2.5 h, the reaction mixture was poured into ice water and extracted with a mixture of chloroform and methanol (10: 1 by volume). The extract is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was fed to a silica gel column chromatography, elution being carried out with a mixture of chloroform and methanol. 0.27 g of 4- {4- (5-acetylamino-3-indolyl) piperidino -2-propionylamino-thiazole is obtained. M.p. 263-267 ° C (recrystallized from aqueous ethanol).
    IR Spectrum (nudzhol), 3370; 16380; 1650; 1590; 1560.
    NMR spectrum (deuterodimethylsulfoxide) d: 1.08 (3N, doublet. J 9.0 Hz); 2.0 (SN, singlet); 2.35 (2H, quartet, J 9.0 Hz); 1.4 - 3.2 (9H, multiplet); 3.48 (2H, singlet); 6.8 - 9.56 (5H, multiplet); 10.55 (1H, broad singlet); 11.93 (1H, broad singlet). Mass spectrum (m / e): 425 ().
    Calculated. %: C 62.09; H 6.39; N 16.46.
    Found,%: C 61.98; H 6.23; N 16.16.
    C22H27N502S
    EXAMPLE 38 1 g of 4-4- {3-indolyl) piperidinomethyl} - 2- (2P) 2-acetoxy-propionylamino-thiazole is dissolved in 5 ml of ethanol and 1N is added while cooling with ice. sodium hydroxide solution in water (2,3,4 ml). The mixture is stirred for 1 h at the same temperature and
    then for 1.5 hours at room temperature. After this, 0.7 ml of 1N is additionally introduced. sodium hydroxide solution in water1 and the mixture is stirred at room temperature for another 2 hours. Then the reaction
    the mixture is neutralized with 1N. hydrochloric acid and concentrated under reduced pressure. The residue is extracted with a mixture of chloroform and methanol (10: 1 by volume) and the extract is washed with saturated aqueous
    a solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue is fed to a chromatographic column with silica gel, and elution is carried out with a mixture
    chloroform and methanol (10: 1 by volume). 0.39 g of (3-indolyl) piperidinomethyl-2- (O-lactoylamino) thiazole is obtained. M.p. 213-216.5 ° C (recrystallized from ethyl acetate).
    IR Spectrum (nudzhol), 3360; 3190; 1663; 1570; 1138.
    NMR spectrum (deuterodimethylsulfoxide) b: 1.27 (3N, doublet, J 6.6 Hz); 1.4-3.6 (9H, multiplet); 3.52 (2H, singlet); 4.30 (1H,
    quartet, J 6.6 Hz); 5.6 (1H, broad singlet); 6.8-7.7 (6H, multiplet); 10.68 (1H, singlet); 11.50 (1H, broad singlet). ajj -S 5 ° (concentration 0.1 mol / l, dimethylformamide). Mass spectrum (m / e): 384 (m.
    Calculated,%: C, 62.48; H 6.29; N 14.57; Found: C 62.80; H 6.22; N 14.48.
    C20H24N402S
    EXAMPLE 39 Analogously to Example 38, 4- {4- (3-indolyl) piperidinomethyl 2- (Luctoyl-amino) thiazole was obtained. M.p. 212-216 ° C (recrystallized from ethyl acetate). and o2 | 5 -5 (concentration 0.1 mol / l, dimethylformamide).
    EXAMPLE 40 To a suspension of (3-indolyl) piperidinomethyl -2- (2-acetoxyacetylamino) thiazole (0.9 g) in 20 ml of ethanol was added 1N. an aqueous solution of sodium hydroxide (3 ml). After 1 hour of stirring, the reaction mixture is concentrated, the resulting precipitate is collected by filtration and it is recrystallized from a mixture of water and ethanol to obtain 0.28 g of (3-indolyl) piperidinomethyl -2-glycoloylaminothiazole. M.p. 185-188 ° C.
    IR (Nujol), 3250: 1680; 1530.
    NMR spectrum (deuterodimethylsulfoxide) d: 1.4-3.4 (9H. Multiplet); 3.51 (2H, singlet); 4.10 (2H, singlet); 6.8-7.2 (2H, multiplet); 6.96 (1H, singlet), 7.0 (1H, doublet, J 2.0 Hz); 7.35 (1 H, dw. Doublet, J 2.0 and 7.0 Hz); 7.58 (1 N, dw. Doublet, J 2.0 and 7.0 Hz); 10.65 (1H, broad singlet).
    Mass spectrum (m / e): 370 (M4).
    Calculated,%: C 60.86; H 6.05: N 14.94.
    CigH22№02S
    Found,%: C 60,56; H 5.90; N 14.59.
    Example 41. To (3-indolyl) piperidinomethyl -2- (3-acetoxypropionylamino) thiazole (1.1 g) was added 20 ml of ethanol and 1N. an aqueous solution of sodium hydroxide (2.6 ml), and the mixture was stirred at room temperature for 3.5 hours. To the mixture was added 2.6 ml of 1N. hydrochloric acid and ethanol are evaporated. The residue is extracted with a mixture of chloroform and methanol (10: 1 by volume), the extract is dried over magnesium sulfate and concentrated. The residue is purified on a chromatography column with silica gel, which is eluted with a mixture of chloroform and methanol (10: 1 by volume). 290 mg of (3-indolyl) piperidinomethyl-2- (3-hydroxypropionylamino) thiazole are obtained. M.p. 212-218 ° C (decomposed), recrystallized from aqueous ethanol.
    Mass spectrum (m / e): 384 (M4); 366; 266: 199.
    Calculated,%: C, 62.48; H 6.29; N 14.57.
    Found,%: C 62.79; H 6.33; N 14.68.
    C20H24 N402S
    EXAMPLE 42. In hot ethanol (80 ml), 0.5 g of 4- {2-4- (3-indolyl) piperidino ethyl} -2-mesylaminog.1azole is dissolved. After cooling the solution to room temperature, 3 ml of a 15% aqueous solution of hydrogen chloride in ethanol is added, and then cooled to 5 ° C. The resulting precipitate 5 is collected by filtration and washed with ethanol. This precipitate is recrystallized from water (50 ml) to obtain 0.42 g4- {2-4 (3-indolyl) -piperidino ethyl} -2-mesylaminothiazole hydrochloride 0 a. Mp 200-203 ° C (decomposed).
    IR Spectrum (Nujol), 3450; 1525; 1280; 1130; 970; 900; 760.
    Calculated,%: C 51.75: H 5.71; N 12.70.
    Found,%: C 51.76; H 5.43; N 12.67. 5 Ci8H24NM02S27HCI
    The results of pharmacological tests of some representatives of the compounds of formula (I):
    A: 2-acetylamino-4 4- (3-indolyl) pipo-0-ridinomethyl thiazole;
    B: (3-Indolyl) piperidinomethyl -2-mesylaminothiases;
    C: 4- {2- 4- (3-indolyl) piperidino ethyl} - 2-mesylaminothiazole;
    5D: (3-Indolyl) piperidinomethyl -2-propionylaminothiazole;
    E: (3-Indolyl) piperidinomethyl -2-isobutyrylaminothiazole;
    F. 4- {3- 4- (3-indolyl) piperidino propyl} -2-aminothiazole;
    G: 4-3-4 (3-indolyl) piperidine propyl-2-mesylaminothiazole;
    H: (3-Indolyl) piperidinomethyl -2-butyrylaminothiazole;
    5I: (3-Indolyl) piperidinomethyl -2cyclopropylcarbonylaminothiazole;
    J: (5-nitro-3-indolyl) piperidino-methyl -2-ethoxycarbonylaminothiazole;
    K: (5-nitro-3-indolyl) piperidino-0 methyl -2-propionylaminothiazole.
     Test 1. Antagonistic effect on anaphylactic asthma in guinea pigs.
    Male Hartley guinea pigs weighing 305-5,400 g were used in the experiment. These animals were sensitized by intravenous injection of 0.5 ml / animal of rabbit antiserum on egg albumin (RCA antibody titer 4000). After 24 hours, the animals were placed in 0 separate plastic chambers with a volume of 5.3 l. Using a commercially available nebulizer, a 5% solution of egg albumin albumin was sprayed into each chamber for 2 minutes at a rate of 0.16 5 ml / min. 30 min before spraying the solution of albumin of the egg protein, the test compound was administered to the animals in various concentrations through the mouth. Each group consisted of 5 animals. The preventive effect on anaphylaxis was expressed in
    values of a 50% effective dose of EDO, determined on the basis of the number of guinea pigs that survived at least 2 hours after spraying the antigen for each concentration of the test compound administered.
    The values obtained are presented in Table 1.
    Test 2. Activity against anaphylaxis slow-reacting substance (SRS-A).
    The peritoneal exudate cells were collected from standard rats injected with glycogen, and adjusted to a concentration of 1,107 cells / ml with Tyrode solution. 1 ml of the cell suspension was grown with indomethacin (10 MCH / ml) and each with different concentrations of the test compound for 10 minutes, and then further grown with Ca4-ionophore (A23187, 1 µg / ml) for 10 minutes. The supernatant was collected by centrifugation and the activity against anaphylaxis slowly reacting was determined by the ability to contract the isolated ileum of guinea pigs in the presence of mepyramine and metizergid
    The results are presented in terms of the inhibitory concentration of l / lKso, which suppresses by 50% the synthesis of the slow-reacting substance anaphylaxis or secretion from cells of peritoneal cancer.
    The research results are given in table 2.
    Biological test data.
    Antagonistic effect on anaphylactic asthma in guinea pigs. This test was carried out according to the test method 1 described above. The test compound is 4- {2- 4- (3-iidolyl) piperidino ethyl} -2-methylsulfonylaminothiazole hydrochloride (a). Test results: EDso 0.02 ml / kg.
    Anti-SRS-A activity. This test was performed according to test method 2 described above. Test compounds:
    b) (3-indolyl) piperidinomethyl -2- (3-methylurechdo) -thiazole;
    c) (3-indolyl) piperidinomethyl -2-crotonoylaminothiazole;
    d) (3-indolyl) piperidinomethyl -2- (0-lactoylamino) -thiazole;
    e) (3-indolyl) piperidine methyl -2- (1-lactoyl amino) thiazole;
    f) (3-indolyl) piperidinomethyl -2- (3-methoxypropionylamino) thiazole;
    e) (1-methyl-3-indolyl) piperidino-methyl -2-cethylam notiazole;






    p) (5-amino-3-indo-yl) piperidino-methyl -2-propionylaminothiazole;
    I) (5-acetylamino-3-indolyl) piperidinomethyl -2-propionylaminothiazole;
    J) M- {2- 4- (3-Indolyl) piperidino ethyl} benzimidazole is a known compound (Table 3).
    As can be seen from the above data, the compounds according to the invention have a higher anti-allergic activity than the known derivative of indolopiperidine. The compounds of the invention in test doses showed no signs of toxicity and could be classified as low-toxic compounds.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of producing thiazole derivatives of the general formula
    R
    N
    ,
    Formula II
    wherein RI - lower alkanoylamino group, a lower cyclo alkenoilaminogruppag (ni- zshy) alkylcarbonylamino, a lower Al to B to carbon yl amino hydro- xi (lower) alkanoylamino, lower alkoxy (lower) alkanoylamino, lower alkanoyloxy (lower) alkanoylamino group, a lower alkylureido or lower alkylsulfonylamino;
    R2 is hydrogen or lower alkyl;
    RS is hydrogen, nitro, amino or lower alkanoylamino group;
    A is lower alkylene,
    or their acid addition salts, characterized in that. what is the connection common
    N R.
    one
    Formula II
    -
    where Rz, Ra and A have the indicated values, are reacted with an acylating agent and the target product is isolated in free form or as an additive salt thereof or a compound of formula I in the case when Ra is a nitro group, is reduced to obtain the compound of formula I, where The Ra amino group, or a compound of formula I, where the RS is an amino group, is reacted with an acylating reagent to obtain a compound, where RS is a lower alkanoyl amino group, or a compound of the formula I, where RI is a lower alkanoyl (lower) alkanoyl amino group, is subjected to pe elimination conditions for the preparation of a compound of formula I with an RI hydroxy (lower) alkanoylamino group.
    Priority featured:
    05.12.85 when RI is lower alkanoyl-amino or lower alkylsulfonylamino; R2 is a hydrogen atom, Ra is a hydrogen atom or a nitro group; A is lower alkylene.
    03.10.86 when type (A) RI is a cyclo (lower) alkylcarbonylamino group, a lower alkoxycarbonylamino group, a hydroxy (lower) alkanoylamino group, a lower alkoxy (lower) alkanoylamino group, a lower alkanoyloxy (lower) alkanoyloyl group, a lower alkoxy group, a lower alkanoyloxy (lower) alkanoyloyl group, a group and a peptide,
    R2 is hydrogen or lower alkyl; Ra is hydrogen, nitro amino or lower alkanoylamino group;
    0
    five
    A - lower alkylene:
    type (B) RI is a lower alkanolamine group or a lower alkylsulfonylamino group;
    R2 is hydrogen;
    R3 is an amino or lower alkanoyl amino group;
    A is lower alkylene;
    type (C) RI is a lower alkanoylamino group or a lower alkylsulfonyl emino group;
    R2 is lower alkyl;
    Ra is hydrogen, nitro, amino or lower alkanoylamino group;
    A is lower alkylene.
    Table 1
    Table 2
    Table3
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    同族专利:
    公开号 | 公开日
    FI87212C|1992-12-10|
    FI864879A|1987-06-06|
    EP0224919A3|1988-03-30|
    AR242574A1|1993-04-30|
    KR890003356B1|1989-09-19|
    PH23004A|1989-02-24|
    ES2040206T3|1993-10-16|
    SU1597102A3|1990-09-30|
    DE3680877D1|1991-09-19|
    NO165397C|1991-02-06|
    AU601911B2|1990-09-20|
    GR3002606T3|1993-01-25|
    KR870006039A|1987-07-08|
    IE863103L|1987-06-05|
    CA1311754C|1992-12-22|
    HUT46320A|1988-10-28|
    NO864879L|1987-06-09|
    US4742057A|1988-05-03|
    CN1017707B|1992-08-05|
    IL80729D0|1987-02-27|
    JPS63225374A|1988-09-20|
    CN86108205A|1987-06-17|
    HU207315B|1993-03-29|
    DK575386A|1987-06-06|
    AT66224T|1991-08-15|
    NO165397B|1990-10-29|
    DK575386D0|1986-11-28|
    NO864879D0|1986-12-04|
    FI864879A0|1986-12-01|
    FI87212B|1992-08-31|
    AU6581086A|1987-06-11|
    EP0224919B1|1991-08-14|
    IE59624B1|1994-03-09|
    EP0224919A2|1987-06-10|
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    法律状态:
    优先权:
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    JP23687986|1986-10-03|
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