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    • 专利摘要:
    Aminopropanol derivs. of formula (I) and their physiologically acceptable salts are new. In (I), R1 and R2 are H, lower alkyl (opt. substd. by OH or alkanoyloxy), or COZ; X is OH, alkoxy or NR6R7; R6 and R7 are H or lower alkyl or hydroxyalkyl; R3 is H or OR8; R8 is H, lower alkanoyl or aroyl opt. substd. by halo lower alkyl or alkoxy, alkoxycarbonyl, OH, alkylthio, CN, NO2 or CF3; R4 and R5 are H, halo, OH, lower alkyl, alkoxy or alkylthio, COOH, benzyloxy, benzyloxycarbonyl or alkoxycarbonyl; X and Y are N or -C(R9)=; R9 is H, lower alkyl opt. substd. by OR8, or COZ. (I) are vasodilators (hypotensives) and inhibitors of beta-adrenergic receptors. In an example, 4- 2-hydroxy-3-(4-phenoxymethylpiperidino)propoxy indole was prepd. from 4-(2,3-epoxypropoxy)indole and 4-phenoxymethyl-piperidine.
    公开号:SU1041033A3
    申请号:SU772541695
    申请日:1977-11-11
    公开日:1983-09-07
    发明作者:Кампе Вольфганг；Фрибе Вальтер-Гунар；Видеманн Фритц；Шпонер Гисберт；Барч Вольфганг；Дитманн Карл
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    interfacing a compound of the general formula
    0- (JH2-X- JH2-Y
    with a compound of the formula Z-Rj, where R and R have the indicated meanings, one of Y and Z is an amino group, and the other is a reactive residue, X or CHt-A, where A is a hydroxy group.
    The aim of the invention is the expansion of the range of products acting on the living environment.
    The goal is achieved by the method of obtaining compounds of the formula, in which the compound of the general formula
    M. (Ii)
    oCH-A-CHg-B;
    where X, y, R ,, and R, j have the specified
    B value - halogen or sulphonate residue; A - group SNL or
    CH-E, where E is the group -O-Rfo, or
    together with B can mean oxygen and is hydrogen or a protective group G, for example benzyl, acetyl, benzoyl or tetrahydropyranyl residue,
    is reacted with a compound of the general formula
    ) - 2®-Ov y
    where R4 and% have the indicated values
    The desired product is isolated in a known manner in free form or as a salt. The process is usually carried out in an inert solvent, for example toluene or dioxane, in the presence of an acid-binding agent. For the preparation of pharmacologically acceptable salts, hydrochloric acid, hydrobromic, phosphoric, sulfuric acetic, citric, maleic or benzoic acid are used.
    Example. 4- 2-Oxy-3- (4-phenoxymethylpipovidino) -propoxy-tindole.
    A solution of 6.0 g of 4- (2,3-epoxypropoxy) -indole and 6.0 g of 4-phenoxymethylpiperidine in 50 ml of and -butanol can be used for 4-6 hours. Then the solvent is evaporated in vacuo. The residue is dissolved in about 300-400 ml 0.5 n. hydrochloric acid and solution shaken with ether. The ether phase is discarded and the aqueous phase is alkalinized with potassium carbonate solution. The extracted oil is repeatedly extracted with a mixture of ether and ethyl acetate (1: 1). The organic phase is dried, processed with active charcoal and the solution is evaporated in vacuo. The residue is dissolved in a mixture of 60 ml of ether and 25 ml of AC. sulfuric acid, Fira and the solution are mixed with 3.0 g of acetic acid; crystallized overnight and then sucked off. After recrystallization from isopropanol, 8.0 g (.57% of theory) of 4-2-hydroxy-3 (4-phenoxymethylpiperidino) -propoxan of indole are obtained in the form of an acetate with m.p. 127129 ° C. Getting benzoate. 7.3 g of 4- 2-hydroxy-3- (4-phenoxymethyl piperidino) -propoxy-indole are dissolved in 25 ml of ethyl acetate. To the resulting solution was added a solution of 2.3 g of benzoic acid in 25 ml of ethyl acetate. The precipitate formed is filtered off with suction and recrystallized from approximately 50 ml of isopropanol. 4.4 g of 4- 2-hydroxy-3- (4-phenoxy methylpiperidino) -propoxy} -indole are obtained in the form of a benzoate with m.p. 146-147 €. When using 0.94 g of S-4- (2, epoxypropoxy) -indole and 0.95 g of 4phenoxymethylpiperidine by refluxing in 50 ml of butanol by concentration, dissolving in ethyl acetate and mixing with 0/44 ml of acetic acid acids give 0.56 g of S / - / - 4- 2-hydroxy-3- (4 phenoxymethylpiperidino) -propoxy indole as acetate (26% of theory) with m.p. 121-124 ° C; totl (1.5% solution in methanol). Example2. Analogously to Example 1, the compounds shown in Table 1 are obtained. 1., Table. 4-3-hydroxy-3g- (4-phenoxymethylpiperidino) -propoxy-2-ethoxycarbonylindol from 4- (2.3 epoxy-propoxy) -2-ethoxycarbonylindole and 4-phenoxymethylpiperidine (I-PROPanol). Continuation of table 1 -3- (4-phenoxymethylpiperidino) -propoxyZ-2carbamoylindole from 4- (2,3-epoxypropoxy) -2-carbamoylindole and 4-phenoxymethylpiperidine59 (ethyl acetate) 4- 2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy 3 -2-dimethylaminocarbonylindole from 4- (2,3-epoxypropoxy) 2-dimethylaminocarbonylindole "4-phenoxymethylpiperidine93 (Isopropanol) 4- 2-Oxy-3- (4-phenoxymethylpiperid Eno) propoxy-6-methoxycarbonylindol from 4- (2,3-epoxypropoxy) 6-methoxy-carbonylindole and 4-phenoxymethylpipene139-140 ridine87 (Acetic 4-2-Oxy-3- (4-phenoxymethylpiperidine-β-preproct -c-o-β-c- -pro- c -pro-β -c-ko-p- o-pi-3-(4-phenoxymethylpiperidine-α-4-phenoxymethyl) - (2,3epoksipropoksi) and 4--6metilindola fe122-123 nokyimetilpiporidina 39 (Acetic I: 2-ethoxycarbonyl-4- 2oksi-3- (4-phenoxymethylpiperidine) propoxy 6-metilindolbenzoat of 2-ethoxycarbonyl-4- (2, 3 epoxypropoxy) -6-methylindole and 4-phenoxy-methylpiperidine 44 (Isopropanol) 4- 2-Oxy-3- (4- / 2-chloropheno-methyloxy / piperidino) -propoxyZ-indole-isoate from 4t (2,3-epoxypropoxy) -ind la and 4- (2-chlorophenoxime140-142 thyl) piperidine (Acetic 4- 2-Oxy-3- (4- / 3-chlorophenoxymethyl) iperidino) -propoxy 3-indole benzoate from 4- (2,3-epoxyproxy) -indole and 4 - (3-chlorophenoxymethyl) -piperidine 149-15L (UksusNII ether)
    . Continued table. 1 4- 2-hydroxy-3- (4-chlorophenoxymethylpiperidyl propoxy-indolbene from 4- (2,3-epoxypropi si) indole and 4- (4-chloro phenoxymethyl) -piperidine 4-, 2-hydroxy-3- ( 4- / 2methoxyphenoxymethyl / piperidino) -propoxy 3 - Indolbenzoate of 4- (2 epoxypropoxy) -indo and 4- (2-methoxyphenoxy methyl) -piperidine 4 - 2-Oxy-3- (4- / 2me type-nyox oxy / piperidine) -propoxy1 - indole benzoate from 4- (2,3-epoxypropi si) indole and 4- (2methylphenoxymethyl) piperidine 4-2-Oxy-3- (4- / 3methylphenoxymethyl / piperidino) propoxy indolbenzoate from 4- (2 epoxypropoxy) -indoyl and 4- (3-methylphene methyl) -piperidine 4- 2-Oxy-3- (4- / 2methylmer ptophenoxy methyl (-piperidino) nponoKcnJ-indole from 4- (2,3-epoxypropox I indole and 4- (2-methylm captofenoxymethyl) piperidine 4-2-Oxy-3- (4-phdrphenoxymethylpiperidino) -propoxy D-bmethylindole (2,3 epoxypropoxy) -6methylindole and 4- (4fluorophenoxymethyl) pipridine 4- 2-Oxy-3- (4- / 3-methylphenylacetate / y-piperidino) -propoxy b-methylindol benzoate from 4- (2, 3-. epoxypropoxy) -6-methylindole and 4- {3-methylphenoxymethyl) -piperidine
    Continued table 2T
    1 4- 2-Oxy-3 .- (4- (2-benzyloxyphenoxymethyl) -piperidino) propoxy-indole and 4- (2,3-epoxypropoxy) -indole and 4- (2-benzyloxyphenoxymethyl) -piperidine 90 (Oil) 4- 2- Hydroxy-3- (4- / 4-benzyl-oxifenoxymethyl / -piperidino) ) -propoxy -2 pivaloyloxymethylindole from 4- (2,3epoxypropoxy) -2pivaloyloxymethylindole and 4- (phenoxy 22 130-132 methyl) -piperidine (Acetic ester) 4- 2-Oxy-3- (4- / 2methoxyphenoxymethyl / piperidino) -propoxy 2 -methylindole from 4- (2,3 epoxyprop hydroxy) -2-methylindole and 4- (2-methoxyphenoxymethyl) 38 137-138 piperidine (Acetic ester) 4- -Oxy-3- (4- / 2chlorophenoxymethyl / piperidino) -propoxy 2-methyliidol from 4- (2.3 epoxypropoxy ) -2methylindole and 4- (2chlorophenoxymethyl) piperidine 4-2-hydroxy-3- (2,5-dimethylpheioxymethylpiperidino) -propoxy-indole from 4- (2,3-epoxypropoxy) -indole and 4- (2,5-dimethylphenoxymethyl ) -piperi44 153-156 dyne (Acetic ester) 5-2-OXI-3- (4-phenoxymethylpiperidino) propoxy-indole from 5- (2,3-epoxypropoxy) indole and 4-phenoxyme59 121-123 tons and lp ip eri d and na forez. (4-Phenoxymethylpiperidino) -propoxy - indole. A mixture of 4.0 g of 4- (3-bromopropoxy indole, 3.4 g of 4-phenoxymethylpiperidium with 50 ml of isopropanol and 2.4 g of N-ethyldiisopropylamine was heated under reflux for 6 hours, the residue was concentrated in chloroform and washed. diluted with NaOH solution and water. After concentrating the organic phase, it is recrystallized from ethyl acetate to obtain 2.0 g (4-phenoxymethylpiperidino) -propoxy-indole (34% of theory) with mp 118-119 ° C. e p 4. Analogously to Example 1, the compounds shown in Table 2.t Table 2 (4-phenoxymethylpiperidino) -propoxy indole from 5- ( 3-chloropropoxy) -indole and 4-phenoxymethylpiperi 107-108 dyin47 (Acetic acid (4-phenoxymethylpiperidino) -propoxy | indole from 6- (3-chloropropoxy) -indole and 4-phenoxymethylpipene123-124 ridine36 (isopro1 polyol) -indole and 4-phenoxymethylpipene123-124 ridine36 (isoprophol) indol) -Oxy-3- (4phenoxymethylpiperidino) -propoxy 2-metolindol. A mixture of 5.9 g of 4- 2-oxy-3- (4-pheno-symtilp-iperidino) -proc sy J2 hydroxymethylindole, 114 ml of acetic anhydride and 55 ml of pyridine 4 hours at room temperature and concentrate in vacuo. The residue is dissolved in ethyl acetate, taken up in water and concentrated. The resulting compound (8.0 g) is dissolved in 100 ml of methanol and hydrogenated over 2.0 g of 10% palladium on carbon at a hydrogen pressure of 1 bar. After the calculated amount of hydrogen is taken up, it is filtered, concentrated by half, adjusted to pH 9 with 2 n. The sodium methoxide solution is heated under reflux for 10 minutes, poured into water and extracted with chloroform. After concentrating the extract, the residue is dissolved in ethyl acetate, 0.01 mol of benzoic acid is added and the liberated benzoate is recrystallized from 25 ml of isopropanol. 1.6 g of 4- {2-hydroxy-3- (4-phenoxymethylpiperidino) -product of 2-methyl-ethyl benzene (28% of theory) are obtained, m.p. 145-148c. Example 6; 4- 2-Oxy-3- (4-phenoxymethylpiperidino) -propoxy -2-hydroxymethylindole. To a suspension of 0.95 g of lithium aluminum hydride in 45 ml of absolute tetrahydrofuran, a solution of 4.5 g of 4-2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-2-ethoxycarbonylindole in 25 ml of absolute tetrahydrofuran is added dropwise, then stirred for 1 hour at room temperature temperature, decomposed by cooling with a solution of NaCl, filtered, washed with tetrahydrofuran and the combined filtrates are mixed with 0.01 mol of benzoic acid. After recrystallization of benzoate from 25 ml of ethyl acetate, 2.5 g of 4-2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-2-hydroxymethylindol benzoate (47% of theory) are obtained. 146-14bs. Example 7. Analogously to Example 5, the compounds listed in Table 2 are obtained. 3 T a b i c a 3 4- 2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy-6-hydroxymethylindole benzoate from 4-2-hydroxy-three- (4-phenoxymethylpiperidino) -propoxy-6-methoxycarJ.53- 155 bonilindola (Acetic 4- 2-Oxy-3- (4-phenoxymethylpiperidino) -propoxy-6-hydroxymethyl-5-methylindole from 4-2-hydroxy-3- (4.-phenoxymethylpiperidino) -propoxy-6-labels of sicarbonyl- 5-methylindole, PRI mme p 871 - 2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-inol-2-carboxylic acid. Suspension 2.0 g 4-2-hydroxy-3- (4-oxymethylpiperidino a) -propoxy -2-ethoxycarbonylindole in 50 ml of dioxane is added a solution of 0.5 g of hydroxy in 25 ml of water, stirred for 16 h at 50 ° C, concentrated.
    dissolved in water and neutralized with dilute sulfuric acid.
    1.8 g of 4-2-hydroxy-3- (4phenoxymethylpiperidino) -propoxy indole-2-carboxylic acid (96% of theory) were isolated with a mp. 218-220 ° C (with decomposition).
    PRI me R 9. 4- 2-Pivaloyloxy3- (4-phenoxymethylpiperidine) -propoxyT-indole.
    The mixture of and 4.4 g of 5-2-hydroxy-3- (4phenoxymethylpiperidino) -propoxy} indole acetate, 10.2 g of pivalic acid and 2.0 g of pivalic anhydride is stirred until the formation of a solution and then left to stand at room temperature within 2 days. The mixture is poured onto ice, the pH is adjusted to 9 with an ammonia water, extracted with S {methylene chloride, the extract is concentrated and the residue is triturated with ether. 3.2 g of 4- 2-pavaloyloxy-3- (4-phenoxymethylpiperidino) -propox- d-indole (69% of theory) with T.PL. lOS-lOS C.
    PRI m e r10. Analogously to Example 8, the compounds listed in Table 2 are obtained. four .". Table4 4- 2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy} -5-methylindole from 4-2-hydroxy-3- (4phenoxymethylpiperidino) -propoxy-b-hydroxy122-123 methylindole 23 (ethyl acetate) 4- 2- Hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-5, 6-dimethylindole from 4-2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-6-hydroxymethyl-5methylindol. PM and Mme r 11. 4- 2-Oxy-3- (4- (oxyphenoxymethyl) -piperidino) -propey -indole. 13.8 g of 4- 2-hydroxy-3- (4/2-benzyloxyphenoxymethyl / -piperidio) -propoxy-indole are hydrogenated in 250 ml of methanol at room temperature and 1 bar of hydrogen is used while using scientific research institute 3 g of 5% palladium (carbon), o filter, concentrate and crystallize from ethyl acetate. A get 4.7 g of 4-2-hydroxy-3- (4-U2-oxyphenoxy methyl / -piperidino) -propoxy-indole (42% of theory) from m.p. 119-12lc.
    Example 12, 4- 2-Pivaloyloxy3-, (4-phenoxymethylpiperidino) -propoxy-benzimidazole.
    3.8 g of 4-2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-benzimidazole and 1.3 g of pivaloyl chloride in 25 ml of pyridine are refluxed for 2 hours. After removing the solvent, the residue is dissolved in 100 ml of chloroform . The resulting solution is washed thoroughly, dried over. sodium sulfate and mixed with 50 ml of ethereal hydrochloric acid. After concentration of ethanol, 4- 2-pivaloyloxy-3- (4-phenoxymethylpiperidino) -propoxy-benzimidazole hydrochloride crystallizes with mp. 132-134 C.
    P r e e p13. Analogously to Example 10, the compounds listed in Table 2 are obtained. five. ... . .
     ..
    Table 5 5 4- 2-Pivaloyloxy-3- / 4 (2-methoxyphenoxymethyl) piperidino / -propoxy indole from 4- 2-OXI-3- / 4 (2-methoxyphenoxymethyl) piperidino / -propoxy indole and 107 anhydride of pivalic acid 66 (ether) 4- 2-pivaloyloxy-3 (4-phenoxymethylpiperidino) -propoxy-6methyl endoL from 4-2oxy-3- (4-phenoxymethylpiperidino) -propoxy-6-methylindole and pivinic acid anhydride (isalivol acid) (isalic acid anhydride (isoxymethylpiperidino) and 6-phenoxymethylpiperidino-propoxy; ) 4- 2-Pivaloyloxy-3- (4phenoxymethylpiperidino) -propoxy-6-pivaloyloxymethylindol from 4-2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-b-hydroxymethyl 76-78 dol and pivaloyl chloride (Hep tanester) 4- 2-Benzoi 1toxy-3-} (4-phenoxymethylpiperidino) -propoxy indole from 4- | 2-hydroxy-3-phenoxymethylpiperidino) -propoxy-indole and 108-110. and benzoic anhydride 40. (Ether) Continuation of Table T1 1 4- 2-Pivaloyloxy-2 (4-phenoxymethylpiperidino) -propoxy-2 pivaloyloxymethylindole from 4-2-hydroxy-3- (4phenoxymethylpiperidino) pro .poxy - 2-pivaloylo- / xymethylindole and pivalic anhydride24 93-95 acid (Hepf, 4- 2-Pivaloyloxy-3- / 4 (2-methylphenoxymethyl) piperidino / -propoxy-12-methylindole from 4-2oxy-3- / 4 (2-methylphenoxymethyl) -piperidino / -propoxy-2-methylindole and anhydride of pivalic acid, P. and meur 14. 4- 2-Pivalo 3- (4-phenoxymethylpiperidino) -prop cI-benzotriazole Mixture of 5.1 g of 4-2-hydroxy-3 - (4phenoxymethylpip ridino-propoxy benzotriazole hydrochloride, 6.7 g of pivalic anhydride and 33.3 g of molten pivalic acid are stirred for 3 at room temperature, poured onto ice, neutralized with ammonia water and extracted with methylene chloride, after concentrating the extract the oily residue in methanol and weakly acidified with dilute hydrochloric acid. After evaporation of the solvent, 2.53 g of 4-2-pivaloyloxy-3- {4-phene simethylpiperidino) -propoxy-benzene triazole hydrochloride is obtained (38% of theory with m.p. 131-133 ° C. PRI m e p15. Similarly, at rue 12, the compounds shown in Table 2 are obtained. 6 ,. . ,,. . T a b l i c a 4- 2-Oxy-3- (4- / 4-OXYphenoxymethyl / -piperidino) -propoxy Zgindol from U- 2-Oxy-3- (4- / 4-bisyloxyphenoxymethyl / 1piperidino) -propoxy ; inola39 167 (From 4- 2-Oxy-3- (4- / 2-pano-carboxyphenoxymethyl / piperidino) -propoxy indole from 4-2-hydroxy-3 (4-; / 2-benzyloxycarbonylphenoxymethyl / piperidine) -propoxy } Indole. Example 16, (4-Phenoxymethylpiperidine) -propoxy-indazole; 4.4 g. 2 benzyl-4- 3- (p-toluenesulfonyloxy) -propoxy) -indazole and 3.8 g of 4- (phenoxymethyl) -piperidine in 20 ml of 1,2-dimethoxyethane is heated at 6010 ° C with stirring for 15 hours. The mixture is diluted with 30 ml ether, sucked off and the filtrate concentrated in vacuo. Treatment of the residue on the filter 40 ml. 2 and. HC1 results in crystalline hydrochloride. It is dissolved in methanol and, after addition of palladium (on carbon), is hydrogenated at normal pressure. After the catalyst was aspirated and the filtrate was concentrated in vacuo, it was mixed with 2N. NaOH and dissolved in methylene chloride. It is dried over sodium sulfate, the solvent is removed in vacuo, the crystalline residue is stirred with ligroin and recrystallized from methanol. 2.1 g are obtained (57.7% of theory) of colorless leaves, mp 160161 ° C. The 2-enzyl-4- (3-p-toluenesulfonyloxypropoxy) -indazole used as the starting material was prepared as follows. 2-Benzyl-4-hydroxyindazole. The benzylation of 4-nitroindazole using 1-benzyl-4-nitroindazole and 2-bennyl-4-nitroindazole using benzylation is reduced by hydrazine and Rene nickel in methanol and then heated with an excess amount of sodium bisulfite in water. This leaves undissolved 1-benzyl-4-amino-indazole (mp. 73-75 s). 2-benzyl-4-hydroxyindazole (colorless crystals), m.p. 172-174 ° C. 2-Benzyl-4- (3-hydroxypropoxy) -indazole. A mixture of 24 g of 2-benzyl-4-hydroxyindazole, 10.4 ml of 3-bromopropanol (1) and 16 g of potassium carbonate in 100 ml of dimethylformamide is stirred at 70 ° C for 30 hours. After dilution with methylene chloride, it is sucked off, the filtrate is concentrated and the residue is purified by chromatography on silica gel (solvent: a mixture of methylene chloride and ethyl acetate 9: 1); and get the oil. 2-Benzyl-4- (3-P-toluenesulfonyloxypropoxy) -indazole. To a solution of 7.3 g of 2-benzyl-4- (3-oxypropoxy) -indazole, 3.6 ml of triethylamine and 50 ml of toluene, 4.9 g of P-toluenesulfonic acid chloride, dissolved in 20 ml of toluene, are added and stirred for about 100 hours at room temperature. The triethylamine hydrochloride formed is filtered off with suction, the filtrate is carefully concentrated in vacuo and the residue is purified by silica gel column chromatography (solvent: a mixture of methylene chloride and ethyl acetate 9: 1). Colorless crystals are obtained by trituration of the initially obtained oil with ether, mp. 99-100 ° C. Example 17. Similarly to Example 14, the compound given in Table 2 is obtained. 7. T and b. L and c a (3,4,5-trimethoxybeneoyloxy) 3- (4- / 2-chlorophenoxymethyl | -piperidino) -propoxy-benimide Aeol from 4-2-hydroxy-3- (4-y2- chlorphenoxymethyl) -piperidino) -propsi-benzimidazole and 3,4,5-trimethoxy158-16 benzoyl chloride (Etano
    Example 18. In a similar manner to Example 16, the compounds shown in Table 2 are prepared. eight.
    Table B
    ... i
    4- 2- (4-Methylbenzyloxy) -3- (4- / 2-methoxy-phenoxymethyl / -piperidino) -propoxy-benzotriazole from 4-2-hydroxy-3- (4- / 2-methoxyphenoxymethyl) -perpi-propoxy-benzotriazole and 4-methylbenzoic acid anhydride in dioxane
    4- 2- (2-Chlorobenzoyloxy) g-3- (4- / 3-methylphenoxymethyl / piperidino) ".proxy 3-benzotriazole from 4-Q2-OKCH-3- (4/3 methylphenoxymethyl / piperidino) -propoxy benzotrmazole and anhydride 2 chlorobenzene acid in dioxane
    4- 2-Oxy-3- (4- | 2chlorophenoxymethyl / -piperidine) -propoxy indazole from 4- (2.3epoxypropoxy) -indazole and 4- (2-chloro5 phenoxymethyl) -pead 154
    45 read
    (Isopropanol)
    4-J 2-OKCH-3- (4- / 20 methylphenoxymethyl) -piperidino) -propoxy indazole from 4- (2.3epoxyprop (xi) -indazole and 4- {2-methylpheno1. Simethyl) -piperidine 38
    127-129
    4- 2-OKCJJ-3- (4- / 3-methylphenyl-xymethyl / pyridino) -propoxy indazole from 4- (2.3 epoxy-propoxy) -indazole and 4- (3-methylphenoxymethyl) -piperidine
    4- 2-Oxy-3- (4- / 2methoxyphenoxymethyl / piperidino) -propoxy indazole from 4- (2,3, epoxypropoxy) -indazole and 4- (2-methoxyphenoxymethyl) -piperidine Example 15. 4- 2-Oxn-3- (4phenoxymethylpiperidino) propoxyZindazole. A mixture of 5.6 g of 4- (2,3-epoxypropoxy) -indazole, 11.2 g of 4-feyoxymethylpiperidine and 11 ml of dimethoxyethane is heated for 20 hours, mixed with 40 ml of ether, filtered and the precipitate is recrystallized from isopropanol. Obtain 4.6 g of 4- 2-hydroxy. 3- (4-phenoxymethylpiperidino) -propoxy-indazole (41% of theory) with so pl. 142-143 s. Using an ethereal HC1 solution, the hydrochloride is obtained with a mp. 22022200. Example20. Analogously to Example 18, the compounds are given in Table. 9. Table9 Continuation of the table. E 4- 2-Oxy-3- (4-phenoxymethylpiperidino). Propoxy-5-methyl 1 -indazole from 4- (2,3-epoxypropoxy) -5methylindal) la and 4phenoxymethyl156-157 piperidine (Isopro-Panol) 4-2-Oxy-3- (4-phenoxymethylpiperidino) -. Propoxy-6-methylindazole from 4- (2,3, -epok1 (Cipropoxn) -6-methyl indazole and 4-phenoxy152-153 methylpiperidine 54 (Isopropanol) Example 21. 4-; 2-Oxy-3- (4poluximethylpiperidine) - Propoxy indazole. 127 g of 4-phenoxymethylpiperidine is added at 36.8 g of 1-acetyl4 (2,3.-epoxypropoxy) -idazole, stirred for 2 hours, 400 ml of ether are added and the precipitate is recrystallized from isopropanol. 3 g of 4- 2oxy-3- (4-phenoxymethylpiperidino) propoxy-indazole (57% of theory) mp 141-142s. Example 22. 3-Acetoxymethyl4-2-OXY-H- (4-phenoxymethylpiperidino) -propoxy -indazolhydrochloride, a mixture of 4.7 g W-ace toxymethyl-4 (2, Zuepoxypropoxy) -indazole, 3.8 4-phenoxymethylpiperidine and 35 ml of 1,2-dimethoxyethane are heated for 20 hours at, concentrated in vacuo, the residue is dissolved in ether and the hydrochloride is precipitated with ethanolic HCl solution. 2.6 g of 3-acetoxymethyl-4-2-hydroxy-3- (4-phenox methylpiperidino) -propoxy-indazole hydrochloride (30% of theory) with mp 203-204 ° С (from ethanol). Used as starting substance 3-acetoxymethyl-4- (2,3epoxypropoxy) -indazole can be obtained as follows. 2- (2-Hydroxyethyl) -3-nitrufeylbeneyl ether. Prepared by reacting 2-methyl-3-nitrophenyl benzyl ether with para-formaldehyde and potassium tpeT-6yTHnaite in dimethylformamide as a yellow oil. 2- (2-Hydroxyethyl) -3-aminophenyl ether. It is obtained from the previous one by reduction using hydroxide razinehydrate and Rene nickel in metaiol in the form of a greenish oil. 2- (2-Acetoxyethyl) -3 m acetamidophenylbenzyl ester. Formed by acetylation of the precursor with acetic anhydride in toluene: colorless crystals, m.p. Ib-IE. C. 1-Acetyl-3-letotoxymethyl-4-phenylbenzyloxy-sindazole. Obtained by nitrosation and subsequent ring closure (cyclization) by treating the previous compound with isoamyl nitrite, sodium acetate and acetic anhydride in toluene with colorless crystals, mp. 99-100 C. 1-Acetyl-3-acetoxymethyl-4-hydroxyindazole. Prepared by hydrogenolysis of the previous compound using 10% palladium (on charcoal) in tetrahydrofuran: colorless crystals, m.p. 178-179 p. .3-acetoccimethyl-4- (2, 3 epoxypropoxy) -indazole. Prepared by reacting the previous compound with epibromohydrin and potassium carbonate in dimethyl phosphate with colorless crystals, m.p. 127-129 s. 3-Acetoxymethyl-4- (2,3-epoxypropoxy) -indazole. Formed by partial aminolysis of the previous product in liquid ammonia for -5 hours, so pl. 119120С. Example 23. 4- 2-Oxy-3- (4phenoxymethylpiperidino) -propoxy-Zoxymethylindazole dihydrochloride. H-acetoxymethyl-4-2-oxy-3 (4-phenoxymethylpiperidino) - indazole is affected by an excess amount of HC1 solution, precipitated with ether, and the precipitate is recrystallized from ethanol. Allocated with 4c%. 4- 2-OXY-3- (4-phenoxymethylpiperidino) -propoxy-3-oximetic indazole dihydrochloride c. the form of crystals, painted in a slightly yellow color, with so pl. 183 C (decomposition). Test No. 24. 4-2-Oxy-3- (4phenoxymethylpiperidino) -propoxy 3-7t methyldazole. A mixture of 4.0 g of 4- (2,3-epoxypropoxy) -2-benzyl-7-methylindazole, .2.4 g of 4-phenoxymethylpiperidine and 10 ml of 1,2-dimethoxyethane is heated for 20 hours at, concentrated, the residue dissolved in 150 ml of methanol and hydrogenated with 1 g of 10% palladium (on carbon) in the presence of 20 ml of concentrated HCl. After filtration, it is concentrated / dissolved in dilute sodium hydroxide solution, extracted with methylene chloride and concentrated. 3.9 g of 4- 2-hydroxy-3- (4-phenoxymethylpiperidine) -propoxy} -7-methylindazole (73% of theory) with m.p. 132-135 ° C (from isopropanol).
    The 4- (2,3-epoxypropoxy 2-benzyl-7-methylindazole) used as the starting material is prepared as follows.
    2,4-Dimethyl-3-nitrophenyl benzyl ether.
    Formed by the interaction of 2,4-dimethyl-3-nitrophenol with benzyl chloride in the presence of potassium carbonate in dimethylformamide with light yellow hair, so pl. 65-b7 ° C.
    3-Amino-2,4-dimethylphenylbenzyl ester.
    Prepared by reduction of the previous compound with hydrazine and Rene nickel in methanol as a dark oil.
    3-Acetamido-2,4-dimethylphenylbenzyl ester.
    Formed during acetylation of the previous product with the HELP, of acetic anhydride in toluene: colorless crystals, m.p. 160-162 p.
    4-Benzyloxy-7-methylindazole.
    Prepared by nitrosation and subsequent cyclization of the previous compound after exposure to isoamylnirite, sodium acetate and acetic anhydride in toluene at 8 ° -90 ° C and subsequent aminolysis with isopropylamine: needles, mp. 177-178 C.
    2-Benzyl-4-benzyloxy-7-methylindazole.
    Formed by reacting the product with benzyl chloride in the presence of potassium carbonate in dimethylformamide when mixed with isomeric 1-benzyl-4-benzyloxy-7-methyl indazole (mp. 92-93 C) as a main product separated by chromatography on silica gel: colorless crystals, so pl. . 2-Benzyl-4-hydroxy-7-methyLindazole.
    Obtained by hydrogenolysis of the precursor in the presence of palladium (on charcoal): bluish crystals with m.p. 201-203 S.
    2-Benzyl-4- (2,3-epoxypropoxy) 7-methylindazole.
    Prepared by reacting jjE of the previous compound with 2,3-epoxy propyl ether P-toluenesulfonic acid. In the presence of potassium carbonate in dimethylformamide at 60-70 ° C: colorless crystals, m.p. 85-86 S.
    Note e-, p 25. 4- 2-Oxy-3- (4phenoxymethylpiperidino) -propoxy 6-tert.-butylindazole.
    4.2 g of 1-acetyl-6-tert.-butyl-4 (2,3-epoxypropoxy) -indazole and 11.2 g of 4- (phenoxymethyl) -piperidine with SO ml 1,2 dimethoxyethanone are boiled with l condense for 2 hours. Concentrate and purify the residue by silica gel chromatography (solvent: ethyl acetate: ethanol 9: 1). The oil initially obtained is triturated with 1: 1 ligroin-ether mixture to crystallize. Recrystallized (extractive) from ether. Get L, 8 g (29.% of theory) of colorless crystals, t.pl. 130-131 C.
    The 1-acetyl-6-tert.-butyl 4- (2,3-epoxypropoxy) -indazole used as the starting material can be prepared as follows.
    2-Methyl-3-nitro-5-tert.-butylphenylbenzyl ether.
    . Prepared by reacting 20 methyl-3-nitro-5-tert.-butylphenol with benzyl chloride in dimethylformamide in the presence of potassium carbonate with yellow crystals, m.p. ;
    5 2-Methyl-3-cmin-5-tert.-butylphenylbenzyl ether.
    ,
    It is formed during the restoration of the previous compound of hydrazinehydroxide and Raney nickel in methanol:. light brown oil.
    2-Methyl-3-acetamido-5-tert.-buTylphenylbenzyl ether.
    5 Obtained by acetylation of the previous compound with acetanhydride. House in toluene: colorless crystals / t. 170-172 ° C.
    1-Acetyl-4-benzyloxy-6-tert.0 butyl indazole.
    Prepared by nitrolizing and cyclizing the parent compound upon exposure to isoamyl nitride, sodium acetate and acetic anhydride in toluene at 80 ° C; colorless crystals, so pl. 7 ..;
    1-Acetyl-4-oxy-6-tert.-butylindazole. ,: Obtained by hydrogenolysis of the precursor product in the presence of palladium (on charcoal) in methanol: colorless crystals, mp. 182-184p.
    1-Acetyl-6-tert.-butyl-4- (2,3 epoxypropoxy) -indazole.
    Prepared by reacting the previous compound with epibromohydrin and sodium hydride in dimethylformamide at room temperature: blended oil. .
    EXAMPLE 26 4- 2-Pivaloyloxy3- (4-phenoxymethylpiperidino) -pro5 poxy-indazole. A mixture of 2.2 g of 4- 2-hydroxy-3- (4phenoxymethylpiperidino) -propoxy indazole, 1.25 g of pivalic anhydride and 10 g of pivalic acid is heated to 40 ° C, then poured into 2 and. the caustic soda solution is extracted with methylene chloride, the extract is concentrated and recrystallized from isopropanol / water. Obtain 1.3 g of 4- 2-pivaloylszhsi-3- (4-phenoxymethylpiperidino) propoxy-D-indazole (48% of theory) in the form of colorless crystals with so pl. 11b-118 ° C. 4-2-hydroxy-3- (4-phenoxymethylpiperidyl but) -propoxy -2-ethoxycarbonylindole, m.p. IGS-lTO C; (4-phenoxymethylpiperidino) -propoxy) -benzimidazole, m.p. dihydrochloride 144-14 bs a, as well as compounds shown in Table. 10. Continuation of the table. 10 4- 2-Oxy-3- (4- (2phenoxymethyl) -piperidino) -propoxy benzimidazole dihydrochloride from 2,3-diamino-1-2-hydroxy-3 (4- (2-chlorophenoxymethyl) -piperidino) propoxy) benzene trihydrochloride and 140-142 formic acid (ethanol) 4-2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-6-methylbenzimidazole dihydrochloride from 2,3-diamino-1-2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-5-methylbenzole, and 2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-5-methylbenzole, and 2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-5-methylbenzole, and 2-hydroxy-3- (4-phenoxymethylpiperidino) -propoxy-5-methylbenzole, and 2-hydroxy-3-4 and formic acid
    权利要求:
    Claims (1)
    [1]
    A method for producing aminopropanol derivatives of the general formula M n th VGO in "* wherein R (and R ^ - identical or different - hydrogen ,, lower alkyl or hydroxyalkyl, 7 (lower alkanoyl) oxyalkyl or -CO-Z, wherein Z - OH or a lower alkyloxy, or N ζ '
    TO > where R ^ and R 7 are the same or once 1 · personal — hydrogen, lower alkyl or hydroxyalkyl;
    R ^ is hydrogen or —O — Rg, where R ″ is hydrogen, lower alkanoyl or aroyl, each of which may be substituted with halogen, lower alkyl: alkyloxy, alkoxy carbonyl, hydroxy. scrap, lower alkylthio (nitrile, nitro or trifluoromethyl,
    R4 and R s are the same or different — hydrogen, halogen, hydroxyl, benzyloxy, lower alkyl, lower alkyloxy, lower alkylthio, carboxyl, benzyloxycarbonyl or lower alkyloxycarbonyl;
    Chi u - the same or different - nitrogen or C -, where R (j is hydrogen, lower-strength, which may be substituted by -O-Rg, where Rg has the indicated value, or CO — Z, where Z has the indicated value of l or their salts, characterized in that the compound of General formula
    X
    I
    Kyu where X, y, R ^ and where have the indicated value;
    B is halogen or sulfonate;
    A - ^ .CH ^ or> CH-E,
    E - -O-Rj0, or together: with B may mean: oxygen and Ic - hydrogen or a protective group G, for example, benzyl, acetyl, benzoyl or tetrahydropyranyl, are introduced into the reaction with a compound of the Formula -a where R4 and R5 have the indicated meanings, followed by isolation of the desired product in free form or in the form of a salt.
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    同族专利:
    公开号 | 公开日
    DE2651574A1|1978-05-18|
    BE860701A|1978-05-10|
    ZA776647B|1978-09-27|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2737630C2|1977-08-20|1987-11-05|Boehringer Mannheim Gmbh, 6800 Mannheim, De|
    DE2905877A1|1979-02-16|1980-08-28|Boehringer Mannheim Gmbh|NEW AMINOPROPANOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    EP0025111B1|1979-08-10|1984-07-25|Sandoz Ag|3-aminopropoxyaryl derivatives, their preparation and pharmaceutical compositions containing them|
    DE3721260A1|1987-06-27|1989-01-12|Beiersdorf Ag|NEW INDOLYL PROPANOLS, METHOD FOR THEIR PRODUCTION AND THEIR USE, AND PREPARATIONS CONTAINING THE COMPOUNDS|
    ZA9610736B|1995-12-22|1997-06-27|Warner Lambert Co|2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists|
    ZA9610738B|1995-12-22|1997-06-24|Warner Lambert Co|Subtype selective nmda receptor ligands and the use thereof|
    ZA9610745B|1995-12-22|1997-06-24|Warner Lambert Co|4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists|
    ZA9610741B|1995-12-22|1997-06-24|Warner Lambert Co|4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19762651574|DE2651574A1|1976-11-12|1976-11-12|3-Phenoxymethyl-piperidino 1-heterocyclyl-oxo-propane derivs. - useful as vasodilators and beta adrenergic receptor inhibitors|
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