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    • 专利摘要:
    The invention relates to new hydroxyamino-eburnane derivatives of the general formula (I), <IMAGE> (I) wherein R1 and R2 each stand for a C1-6 alkyl group, as well as to pharmaceutically acceptable acid addition salts and optically active isomers of these compounds. These new compounds can be applied as peripheral vasodilatating agents or can be converted into other compounds, e.g. vincamine and apovincamine derivatives of valuable therapeutical effects. The compounds of the general formula (I) are prepared according to the invention by reacting a hexahydro-indoloquinolisinium derivative of the general formula (II), <IMAGE> (II) wherein R2 is as defined above and X stands for an acid residue, with a methylenemalonic acid diester derivative of the general formula (III), <IMAGE> (III) wherein R1 is as defined above, subjecting the resulting product to catalytic hydrogenation, treating the resulting product with an alkali, and reacting the resulting octahydroindoloquinolisine monoester derivative with a nitrosating agent in an acidic medium.
    公开号:SU927116A3
    申请号:SU802927202
    申请日:1980-05-30
    公开日:1982-05-07
    发明作者:Сантаи Чаба；Сабо Лайош；Калауш Дьердь；Шапи Янош；Данчи Лайош；Кеве Тибор；Газдаг Мария
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    M1indoloquinolizinate ester of the general form IVe and / or IVb, li-CR2 COOB where R, R and X have the indicated meanings, the octahydroindoloquinolizine derivatives of the general formulas Va and / or Vb obtained are catalytically hydrogenated.  C-CH, Biooc / i B OOS VOOB where -R and R have the indicated meanings, are treated with an inorganic base in ethanol and water, and in the case of an ester of formula (Vb), the treatment is repeated and the octahydroindoloquinolysin monoester of total VI is obtained R and R have the indicated meanings, are reacted with alkali metal nitrite in an acetic acid medium and the whole products are isolated, and during the process, bases, compounds of formula 1, are separated from compounds of the formula ((Va) and (IV)) ), (Vb), (VI) and target products are allocated in the form of salts and / or section l them on optical isomers.  At the same time, triztanolamine or a catalytic amount of tert. -butyl potassium.  Also described is a process for the preparation of octahydroindolequinolysis monoester derivatives of general formula VI or their salts or optically active isomers, where in and R have the indicated meanings, the compound hexahydroindoquinolysin of the general formula (II), where R has the indicated values, and X is an acid residue subjected to interaction with the dimer methylene acids of general formula (N1), where R has the indicated meanings, in an environment of an inert solvent in the presence of a basic catalyst, the resulting hexahydroindoloquinolysine esters of the general form l (IVa) and / or (IVb), where R and R have the indicated meanings, are catalytically hydrogenated and the octahydroindoloquinolizine esters obtained in this way with the general formulas (Va) and / or (VB), where R and R have the indicated meanings, are subjected to alkaline treatment using an inorganic base in ethanol and.  water, followed by isolation of the desired product in free form, in the form of salts or in the form of optically active isomers, and, if desired, bases, compounds of the general formulas (Va) and (Vb), are obtained from the compounds of formulas (IVa) and (IVb) if desired. ) is isolated in the form of salts and / or divided into optical antipodes by known techniques.  Example.  (±) -1a-Etsh1-1 / - (2, 2-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12 a-octahydro-indolo (2,3-a) quinolysin and (±) -1 "-ethyl-l / J- (2, 2, 4, 4-tetraethoxycarbonyl-butyl) 1, 2,3,4,6,7,12,12 a-octahydro-indolo (2,3 -a) chi, nolizin.  A suspension of 10.00 g (28.4 mmol) of 1-ztil, 2,3,4,6,7-hexahydro-12H-indolo (2,3-a) quinolizin-5-ium-perchlorate in 60 ml of dichloromethane and 3.6 ml (2.60 g; 25.7 mmol) of triethylamine are mixed with stirring with a solution of 8.0 ml (8.4 g; 48.8 mmol) of methylenemalonic acid diethyl ester in 10 ml of dichloromethane.  The reaction mixture was allowed to stand at room temperature for 2 days. .  The solvent is distilled off in vacuo and the orange colored oil remaining after evaporation is triturated with 30 ml of ether and three times with 30 ml of petroleum ether.  Thus, a mixture of 1-ethyl-1- (2,2-diethoxycarbonyl-ethyl) -1,2,3,4,6,7-hexahydro-12H-indolo (2,3-a) chiolysis is obtained in the form of an oil -5-imum-perchlorate and 1-ethyl-1,2 (2,2, 4,4-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7-hectare sagidro-12H-indolo (2,3 -a) quinolysin-5-ium) - perchlorate, which can be used without purification in the subsequent stages of the reaction. .  IR (in EHF), 3260 (indole-NH); 1735, 1715 (CO); 1615; 1520 (C-N).  18 g of the oily mixture is dissolved in a mixture of 200 ml of ethanol and 50 ml of dichloromethane and hydrogenated in the presence of 8 g of pre-hydrogenated 10% palladium on carbon as a catalyst.  After absorbing the theoretical amount of hydrogen, the catalyst is filtered off and washed first three times with ethanol in 3 ml portions.  then three times with dichloromethane in 30 ml portions.  The filtrate is combined with the washing liquid and evaporated to dryness in vacuo.  The residue after evaporation is crystallized in 50 ml of ethanol.  The product is washed with ethanol and then dried.  In this way, 9.0 g (±) -1a-ethyl-1 | 3- (2,2,4,4-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,7,12b a- are obtained. octa hydro-indolo (2,3-a) quinolizin-perchlorate, which corresponds to a yield of 45.3%, based on 1-eth1-1,2,3,4,6,7-hexahydro-12H-indolo (2,3 -a) quinolysin-5-ium-perchlorate.  T.  square  216-218 ° C (ethanol).  Elemental analysis.   SzzN4bM2O8 HCfD4 (Mol. at.  699. 18).  Found,%: C 57.00; H, 6.55; N 4,10.  Calculated,%: C 56.68; H 6.63; N 4.01.  The hydrochloride compound is melted at 211212 ° C (ethanol).  Mass spectrum, (m / e,%): 426 (M 172; 6); 425 (3. ); 411 (0.3); 397 (0.3); 381 (2); 353 (I); 267 (100); 253 (3); 197 (8); 185 (6); 184 (6); 170 (10); 169 (10); 156 (6) 144 (5); 127 (10); 99 (10) (±) -1-a-Ethyl-1p- (2,2,4,4-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,1,1,1,12 La-octahydro-indolo ( The 2,3-a) quinolizium base is prepared by dissolving perchlorate or hydrochloride in dichloromethane, the solution is shaken with 5% sodium carbonate solution, the organic phase is separated, dried over solid magnesium sulphate and evaporated in vacuo H- PMR (COC, 5): 7.86 (1H, indole-NH); 4.30 - 3.85 (8H, O-CHj); 1.45 - 1.0 (15H.  CHj - SNS).  From ethanol mother liquor (±) -1 a-ethyl-1 p- (2,2,4,4-tetraethoxycarbonyl-butyl) -1. 2 3,4, 6,7,12,12 а a-octahydro-indolo (2,3-a) -quinolysi-perchlorate distilled ethyl alcohol.  The residue after distillation is dissolved in 30 ml of dichloromethane.  The solution is shaken with 20 ml of a 5% aqueous solution of sodium carbonate, the organic phase is separated, dried over solid magnesium sulphate and then evaporated in vacuo.  The residue is dissolved in 10 ml of ethyl alcohol, the solution is acidified with this hydrochloric acid solution to pH 5, and then the hydrochloride is precipitated by adding 10 ml of ether.  The product is filtered, washed with ether and then dried.  4 g (±) -1 a-ethyl-1 J- (2 2-diethoxycarbonyl-ethyl (1, 2, 3, 4) are obtained. 6,7,12,12b o-octahydro-indolo (2,3-a) -quinolizin-hydrochloride, which corresponds to a yield of 30.4%.  Schtgga on 1-ethyl-1, 2,3,4,6,7-hexahydro-12H-indolo (2,3-a) -quinolizin-5-ium-perchlorate.  Tsl 202-204 ° С (ether).  IR (EHF), cm-: 3300 (indole NH), 1720 (CO).  Mass spectrum (m / e,%), 426 (M + 15): 425 (12); 411 (1); 397 (1); 381 (8); 365 (0.5); 353 (2); 307 (0.6); 267 (100); 253 (2); 237 (4); 197 (12); 185 (8); 184 (7); 170 (10); 169 (12); 156 (5); 145 (0.6); 44 (5); 143 (3); 127 (1); 124 (3).  (±) -1 "-Etil-1 | 3- (2 2-diethoxycarbonyl-ethyl) -l, 2,3,4,6,7,12,12b a-octahydro-and-10 (2,3-a) quinolizin the base is obtained by dissolving the hydrochloride in dichloromethane, the solution is shaken with 5 f-HbiM aqueous sodium carbonate solution, the organic phase is separated, dried over magnesium sulfate, filtered and then evaporated to dryness.  1H-PMR (CDCt, - 5); 7.82 (1I, indole-NH); 7.2-6.85 (4I, arom. ); 3.90 (4H, g 3 7.3 sf S, O-CHj), 1. 2-0.8 (9H, -CH3).  Obtained in the described way (±) -1 a-ethyl-1 (3- (2,2-diethoxycarbonyl-ethyl) -1,2,3, 4,6,7,12. 12b a-octahydro-indolo (2,3-a) quinolizine base is treated by thin layer chromatography (KG 60.  PF 254-366, benzene: methanol 14; 3), elute with acetone.  After elution and evaporation of the elution liquid, the residue after evaporation is recrystallized from ethanol.  A product with a high refraction Rf is (±) -1 sc-ethyl-1 ethyl-1 / 3- (2,2-diethoxycarbonyl-ethyl) -1,2, 3. four. 6 7,12,12 a-octahydro-indolo (2. 3-a) quinolysin.  The yield is 0.25 g.  t. e.  2%.  counting on 1-ethyl-1. 2 3 four. 6,7-hexahydro-12H-NDDOLO (2,3-a) quinolizin-5-ium-perchlorate.  T.  square  127-128 ° C (ethanol).  IR (VHF) cm-: 3280 (indole-NH); 1730, 1705 (CO).   Mass spectrum (m / e. %): 426 (m 18); 425 (7.1): 4P (0. eight); 397 (0. eight); 381 (4. 2); 366 (0. 9); 353 (1.8); 337 (0.8); 335 (0.5); 307 (0.6); 267 (100).  EXAMPLE 2, (±) -1a-Ethyl-1 | 3- (2 2-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,1,12b a-octahydro-ivdo ( 2,3-a) -quinolizin and (±) -1 sc-ethyl -1 p (2,2,4,4-tetraethoxycarbonyl-butyl) -1,2, 3,4,6,7,1,1,12BA- Octagvdro-Indolo (2,3-a) quinolisc.  5.00 g (14.2-mol) of 1-ethyl-1,2,3,4,6,7-hexa-hydro-12H-INDOLO- (2,3-a) -quinolizin-ium-perchlorate are suspended in a mixture consisting of 30 ml of dichloromethane and 0.080 g (0.715 mmol) of potassium t-butylate.  To the suspension, while stirring, a solution of 0.03 ml (3.12 g; 18.4 mmol) of methyl methylanonic acid diethyl ester in 5 ml of dichloromethane is added.  The reaction mixture was allowed to stand at room temperature for one day.  The solvent is then distilled off in vacuo and the organic oil remaining after evaporation is triturated three times with 5 ml of petroleum ether.  9 g of a mixture consisting of 1-ethyl-1- (2,2-diethoxycarbonyl-ethyl) -1,2,3, 4,6,7-hexahydro-12H-indolo- (2,3-a) quinolizin are obtained -5-imum-perchlorate and 1-ethyl-1- (2,2,4,4-tetraethoxycarbonylbutyl) -1,2,3,4,6,7-hexahydro. -12N-INDOLO (2,3-a) quinolizin-5-ium-perchlorate as an oil.  It can be used without further purification in the subsequent reaction step.  IR (UHF), CM-3260 (indole-NH); 1735; 1715 (CO); 1615; 1520 (C-N).  9 g of the resulting oil are dissolved in a mixture of 10 g of ethanol and 25 ml of dichloromethane and hydrogenated in the presence of 6 g of pre-hydrogenated 10% palladium on carbon.  After the desired amount of hydrogen is absorbed, the catalyst is filtered out of the solution and washed first three times with ethanol in portions of 3 each.  ml, then three times with dichloromethane in 10 ml portions.  The filtrate is combined with the washing liquid, evaporated in vacuo to dry and the residue after evaporation is crystallized from 30 ml of ethanol.  The product is filtered, washed with ethanol and then dried.  In this way, a mixture (8 g) of (±) -1 a-ethyl-1 (2,2,4; 6-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,7,12b a- is obtained. Octahydro-indolo- (2,3-a) quinolizin-perchlorate and (±) -1 a-ethyl-1 p- (2,2-diethoxycarbonyl-etch1) -1,2,3,4,6,7, 12 , 12Ba-octahydro-indol6 (2,3-a) quinolysin-perchlorate, which melts at 181-185 ° C. The mixture of salts without isolation and separation can be used in the subsequent reaction stage as a solution obtained after separation of the catalyst.  To determine the composition of the perchlorate mixture, 0.8 g of the mixture is dissolved in 6 ml of dichloromethane and shaken the solution with 4 ml of a 5% aqueous solution of sodium carbonate.  The organic phase is separated, dried over solid magnesium sulphate, filtered and the filtrate is evaporated to dryness in vacuo.  The residue after evaporation is separated by thin layer chromatography (alumina type T, flowing liquid dichloromethane: benzene in a ratio of 20: 1, eluting liquid dichloromethane: methanol 20: 1) into its component parts.  The compound with a high refraction value Rf is dissolved in 1.2 ml of ethyl alcohol and the solution is acidified with an alcoholic solution (ethanolic) hydrochloric acid to pH 5.  The hydrochloride is precipitated by adding 1.2 ml of ether, filtered off, washed with ether and then dried.  0.46 g (±) -1 a-ethyl- - (2,2-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12, 12L a-octahydro-indolo (2,3- a) quinolysin hydrochloride, which melts at 202-204 ° C (ethyl alcohol, ether).  Yield 20.5%.  From a compound with a lower Rf refraction, perchlorate is obtained with 70% aqueous perchloric acid and then recrystallized from ethanol.  0.26 E- (26%) (±) -1 a-ethyl-1 (2,2,4,4-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,7,12b is obtained. octagidro-indolo (2,3-a) quinolysin-perchlorate, which melts at 216-218 ° C (ethyl alcohol).  Froze  (±) -1a-Ethyl-1 | 3- (2,2-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12b a-Octagvidro-indolo (2,3-a) quinolizin .  600 ml (1 mmol) prepared according to examples Gu 2 (±) -1a-ethyl-1 - (2,2,4,4-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,1,1,12 a-octahydro-indolo (2,3-a) quinolysin is dissolved in 8 ml of ethanol.  To the solution was added a solution of 120 mg of potassium hydroxide in a mixture of 1 ml of ethanol.  The reaction is carried out using thin-layer chromatography (alumina type T, current dichloromethane liquid: benzene 3: 1, Rf is the value of the diethoxycarbonylethyl derivative greater than that of the tetraethoxycarbonylbutyl derivative) and carried out for 20 minutes.  The reaction mixture is acidified with acetic acid to pH 6 and the solvent is distilled off in vacuo.  The residue after evaporation is dissolved in 8 ml of water, the solution is alkalinized with 5% aqueous soda solution to pH 9 and then extracted three times with 5 ml of dichloromethane.  The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and the solvent is removed in vacuo from the solution.  The oil obtained as an evaporation residue is dissolved in. 3 ml of ethanol and the solution are mixed with ethanol hydrochloride.  The resulting hydrochloride is precipitated with ether.  Obtain 0.25 g (53%) (±) - a-ethyl-1 j8- (2. 2 diets: SicarboNyl-ethyl) -1,2,3,4. 6.7. 12, 12b a-octahydro-indolo (2,3-a) quinolizine hydrochloride, which melts at 201-204 ° C.  IR (KVH),.  3300 (indole-NH), 1720 (CO).  PRI me R 4.  (±) -1 a-Ethyl-1 {2-carboxy-2-ethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12 a-octahydro-ivdo (2,3-a) quinolysin.  0.46 g (1.08 mmol) obtained in Examples 1 Ю1И 2 (±) -1 a-ethyl-1 (2,2-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,1,12 , 12 a-octahydro-indolo (2,3-a) quinolizine is dissolved in 3 ml of ethanol and a solution of 0.067 g (1) 2 mmol of potassium hydroxide in a mixture of 0.3 ml of water and 0 is added to the solution. , 9 ml of ethanol.  The reaction mixture is boiled for 90 minutes in a water bath.  Then the solvent is filtered off.  The residual oil was dissolved in 3 ml of water and the solution was extracted twice with 2 ml of ether.  The aqueous phase is acidified with acetic acid to pH 6.  The precipitated white crystals are filtered, washed with water (5 ml) and then dried.  Obtain 0.23 g (74%) (±) -1 a-ethyl-1 jЗ- (2-carboxy-2-ethoxycarbonyl-ethyl) -l, 2,3,4,6. 7, 12, -12b a-octahydro-indolo (2,3-a) xcnolysin, which melts at IZ-E5 ° C (from Dy).  The refraction value of Rf (±) -1 a-ethyl-1 jЗ- (2 -diethoxycarbonyl-ethyl) -l, 2,3,4,6,7,12Л2ba-octagidro-indolo (23-a) quinolysin is greater than y ( ±) -1 o-ethyl-1 j3- (2-carboxy-2-ethoxycarbonyl-ethyl) -1,2,3,4,6,7,12Л 2Ь a-octahydro-indolo (2,3-a) xHHojyi3HHa (on silica gel G benzene: methanol: concentrated ammonia 15 ml: 5 ml: 2 drops).  IR (KWH), cm-3360 (indole-NH); 1715 (CO); 1600 (carboxylate).  Mass spectrum (m / e,%); 354 (N1 + 44.58); 353 (58); 339 (8); 325 (8.3); 309 (12); 281 (2 267 (100) 44 (1000).  PRI me R 5.  (±) -1 a-Ethyl-1 (3- (2-carb-2-ethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12 Ь a-ca tahydro-indolo (2,3 a) quinolysin.  0.428 g (0.715 mmol) prepared according to Examples 1 or 2 (±) -1 a-ethyl- / 3 - (, 4 4-tetraethoxycarbonyl-butshl) -1,2,3,4,6,7,12,12Ь a-octahydro-indolo (2,3-a) xlolux is dissolved in 3 ml of ethanol.  . A solution of 0.092 g (1.64 mmol) of KALIUM hydroxide in a mixture of 0.3 ml of water and 0.9 ml of ethanol is added to the solution.  The reaction mixture is boiled for 45 minutes in a water bath, then the solvent is distilled off in vacuo.  Received, c.  As a residue, the oil was dissolved in 3 ml of water and the solution was extracted twice with 2 ml of ether.  The aqueous phase is acidified with acetic acid to a pH value of 6.  The precipitated crystals are filtered off, washed with 5 ml of water and then dried.  0.24 g (74%) (±) -1 sg-ethyl-1 p- (2-carboxy-2-ethoxycarbonyl-ethyl) -l are obtained, 2,3,4,6,7,12, 12b a- octahydro-indolo (2,3-a) -quinolizina, which melts at 112-114 ° C.  Example 6  (±) -1 a-Ethyl-1E- (2-carbox-2-ethoxycarbonyl-ethyl) -I, 2,3,4. 6,7,12,12b “-octagidro-indolo (2,3-a) quinolizin.  Starting from the filtrate, which is prepared in Example 2, after filtering off the catalyst.  This filtrate contains dissolved in a mixture of ethanol and dichloroethane (±) -1 a-ethyl-1 / 3- (2,2-diethoxycarbonyl-ethyl) -1,2,3,4,6,7, 12,2bog-octahydro indolo (2,3-a) quinolizin-psrchlorate and (±) -1 a-ethyl-1 (- (, 4-tetraethoxycarbonyl-butyl) - 1,2,3,4,6,7,7,12,12 a - Octahydro-indolo (2,3-a) quinolysin-perchlorate in an approximately weight ratio of 3: 1.  From the filtrate, the solvent is distilled off in vacuo.  As a residue, a mixture of perchlorates of oily consistency is obtained.  It is dissolved in 50 ml of dichloromethane, the solution is shaken with 30 IWH of a 5% dilute solution of sodium carbonate, then the organic phase is separated, dried over solid magnesium sulfate, filtered and the filtrate is evaporated in vacuo.  Obtained as an oil residue (1.54 g.  2.34 mmol of diethoxy and 0.90 mmol of tetraethoxy base (only 3.24 mmol) are dissolved in 16 ml of ethanol.  0 is added to the solution. 24 g (4.28 mmol) of potassium hydroxide in 2 ml of water.  The reaction mixture is boiled over. 5 h in a water bath.  Then. the solvent is evaporated in vacuo, the residue is dissolved in 10 ml of water and the silk solution is extracted three times with 10 ml of ether.  The organic phase is dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated.  The oily residue in the amount of 0.4 g is mainly a mixture of the starting compounds. . .  The pH of the aqueous phase extracted with ether by adding acetic acid is set to 6 and the precipitated organic matter is extracted four times with 15 ml of dichloromethane.  The combined organic phases are dried over anhydrous magnesium sulphate and, after filtration, evaporated in vacuo.  The residue remaining as residue was triturated with 10 ml of ether, the precipitated substance was filtered off, washed with 5 ml of ether and then dried.  0.76 g (59%) (±) -1a-eth1-1-1 j3- (2-carboxy-2-ethoxycarbonyl-ethyl) -1 is obtained. 2 3.4. 6.7, 12g12b a-octahydro-indolo (2,3-a) quinolysin, which melts at 108-C1 ° C with decomposition.  Example.  (±) -Cis-14-Ethoxycarbonyl-14-oxyaminoeburnan (ZaH, 16aEt).  0.75 (1.885 mmol) obtained according to example 6 (±) -1 a-ethyl-1 (2-carboxy-2-ethoxycarbonyl-ethyl) -1,2,3,4,6,7,1,12b a- Octagonal-indolo (2,3-a) quinolysin is dissolved in 15 ml of glacial acetic acid.  A solution of 0.39 g (5.65 mmol) of sodium nitrite in 5 ml of water is added to the solution.  The reaction proceeds at room temperature for 1 hour.  Then the reaction mixture with very intensive cooling (ice) is made alkaline with 30% aqueous sodium hydroxide solution to pH 11 ij and the organic matter is extracted four times with 40 ml of dichloromethane.  The combined organic phases are shaken with 10 ml of water, dried over anhydrous magnesium sulphate.  neither and filtered.  The solvent is distilled off from the filtrate under vacuum.  0.60 g of solid residue crawls, which is triturated with 5 ml of dichloromethane.  The precipitating substance is filtered off, washed with 3 ml of dichloromethane and then dried.  0.52 (72%) (±) -cis-14-ethoxycarbonyl-14-oxyaminoeburnan (ZoH, 16aEt) is obtained, which melts at 156-158 ° C (dichloromethane) The refraction Rf value of this compound is higher than that of (±) -1 a-ethyl-1 / - (2-carc pxy-2-ethoxycarbonyl-etchl) -G, 2, 3, 4, 6, 7, 12, l2b o-octahydro-indolo (2,3- a) quinolysin (silica gel G, benzene: methanol 14: 3).  The proposed compound thus obtained does not give a melting point depression compound with the known compound.  IR (KWH), cm-3400 (NH, OH), 1700 (CO). . -.   1H-PMR (CDCfj 6): 8j3 (IH, NH); 4.0 (2H 5, M - 7.3 cpS, СООСНг - СНз); 1.18 ppm (3N, t, 3 7.3, cpS, СООСНгСНз).  .  Mass Spectrum (m / e;%): 383 (M + 98) ;.  382 (58); 366 (100); 354 (10); 338 (7.7); 310 (31); . 292 (29); 278 (8.5); 267 (40); 253 (92); 237 (15); 211 (18).  PRI me R 8.  (±) -3aS, 16a5-14-ethoxncarbonyl-14-eburnan.  This compound is obtained if obtained analogously to example 7 (±) -cis-14-ethoxycarbonyl-14-eburnan (ZoH, 16aEt) by digibenzoyl tartaric acid, it is decomposed into its optical antipodes.  The compound recrystallized from dichloromethane melts at 169-171 ° C.  a - 56.1 ° C (c 1.05 dimethylformamide) PRI me R 9.  (±) -1-14-Methoxycarbonsh-I-hydroxyhms-eburnan (3cdl, 16ftEt).  Similarly, example)} 2, 6, and 7, however, it does not come from methylenemalonic acid diethyl ester, but from equivalent amounts of methylenemalonic acid dimethyl ester. . The resulting compound melts at 179 ° C (from methanol).  IR (UHF), 3420 (NH, OH); ) 710 (CO, SNZ).  N-PMR (SOSGs, 5): 8, O ppm (1H, NH); 7.6 - 7.0 (4H, M, arom, protons); 3.5 (ЗН, М,), 1.1 (ЗН, t, СНгСНз).  Mass spectrum, m / e: 70 eV, M 369.  Found,%: C 68.58; H 7.29; N 11.28.  Calculated,%: C 68.27; H 7.36; N 11.38; Elemental analysis.  Cji At 7 N303 (C 369.44).  PRI me R 10.  (±) -Cis-14-Ethoxycarbonyl-14-hydroxyamino-eburnan (ZaH, 16aEt).  8 g of the mixture obtained analogously to example 2, consisting of (±) -1 a-eth1-1 - (2,2-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,7,12,1a: octahydro α-indolo (2,3-a) quinolysin and (±) -1 a-ethyl-1 / 3- (2,2,4,4-tetraethoxycarbonyl-butyl) -1,2,3, 4,6,7, 12,12 a-octahydro-indolo (2,3-a) quinolizine, dissolved in 80 ml of dichloromethane.  The solution is shaken with 40 ml of a 5% aqueous solution of sodium carbonate, the organic phase is separated, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated to dryness in vacuo.  The remaining oil was dissolved in 80 ml, a solution of 1.00 g of potassium hydroxide in 4 ml of water was added to the solution, and the reaction mixture was left to stand at room temperature for 3.5 hours.  The solvent is then distilled off in vacuo, the oil obtained as a residue is dissolved in 16 ml of water and extracted twice with 8 ml of benzene.  32 ml of glacial acetic acid are added to the aqueous phase, and then with cooling from the outside with ice for 10 minutes, 2.00 g of sodium nitrite in 4 ml of water is added dropwise.  The mixture is left to stand at room temperature for one hour and then, under intensive external ice-cooling, is alkalinized with 30% sodium hydroxide solution to pH 9.  The mixture is extracted three times with 50 ml of ethyl acetate.  The combined organic phases are shaken in 20 ml of water, then separated, dried over solid magnesium sulphate, filtered and the solvent is distilled off from the filtrate.  The remaining solid amount of 4 g is recrystallized from 20 ml of dichloromethane.  3.44 g of product is obtained, which by its chemical and physical properties coincides with the product obtained by analogy with Example 7.  Calculation of the starting compound, which is 5.00 g of 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo (2,3-a) quinolizin-5-ium-perchlorate (Example 2 ), the yield is 65%.  Compounds of general formula (1) have a vasodilating effect, especially sucking
    expansion effect on the vessels of the extremities.
    Pharmacological studies were conducted on dogs anesthetized with urethane chloralose. Blood pressure, pulse, blood supply to the artery of the artery femora Ms and After ia caret is niterna, as well as the state of the vessels of both vein areas (condition: blood pressure is separated by the blood flow of the vessel). Substances that are near 16
    13
    The test was administered intravenously as an aqueous solution at a dose of 1 mg / kg.
    In tab. 1 shows the effect of 1 mg / kg (±) -cis-14-methoxycarbonyl-14-oxyaminoeburnan (ZoH, 16aEt; example 9) on blood circulation (average number and average value), where MAVR is arterial mean pressure, HR is number pulse rate, CBF - blood flow A. carotis nitema, CYR state of vessels A. carotis FBF - blood flow femoralis, FYR - state feVnoralis. Table
    In tab. 2 shows the maximum effect in percent (±) -cis-14-methoxy-carbonyl-14I
     The average value of P 0.05 is statistically significant. -oxiaminoeburnan (ZoN, 16aEt) in separate experiments. Table 2 i
    15
    From tab. 1, it can be seen that a compound administered intravenously at a dose of 1 MV / KI temporarily slightly decreases blood pressure, the number of pulse beats slightly increases. A more significant effect is on the amount of blood flowing in the studied areas. First of all, the blood supply to the extremities is greatly enhanced (71%); it returns to normal as a result of approximately 45% vascular dilution. In the area of the caronal vessels, the expansion is approximately 25%, which increases the blood supply by 20%.
    权利要求:
    Claims (3)
    [1]
    1. The method of obtaining the derivatives of hydroxyaminoabinaria formula 1
    where R and R, Ci-Q - alkyl. or their salts, or their optically active isomers, characterized in that the coupling of hexahydroindoloquinolizine of general formula II
    where R has the indicated meanings;
    X is the acid residue,
    subject to interaction i; methylenemalonic acid diester of the general formula III
    COOR
    (1H2 (
    Sooe
    where R has the indicated meanings. In an inert solvent in the presence of a basic catalyst, the resulting hexahyd is rockndoloquinolizine ester of the general formulas IVa and / wm IVb
    . and
    I
    . € N
    WH (;
    92711616
    where R, R and X have the indicated meanings, catalytically hydrogenate and the resulting octahydroindoloquinolizine esters of the general formula Va and / or Vb
    (v
    V
    (N)
    f: soob
    where in and R have the indicated meanings.
    treated with an inorganic base in ethanol and water; in the case of an ester of formula (Vb), the treatment is repeated and the resulting octahydroindoloquinolysine monoester of the general formula VI
    Noos
    ROOC / I Kg
    where R and P have the indicated meanings, react with alkali metal nitrite in an acetic acid medium, and target products are isolated, and, if desired, during the process, bases, compounds of formulas (Va), ( Vb), (VI) and the desired products are isolated as salts and / or are divided into optical isomers.
    [2]
    2. A method according to claim 1, characterized in that triethylamine or a catalytic amount of potassium t-butylate is used as the main catalyst.
    [3]
    3. Method for preparing derivatives of octahydroindo-quinolizine monoester of general formula VI
    or their salts or optically active isomers,
    where R and R have the indicated meanings. characterized in that it combines. . 17 92 hexahydroindoquinolysine of the general formula (II), where R has the indicated values, and X acid residue, is reacted with methylenemalonic acid diester of the general formula (III), where R has the specified values, in an inert solvent in the presence of a basic catalyst, obtained hexahydro-ivolynolysine esters general formulas (IVa) and / or (tVb), where R and in have the indicated meanings, are catalytically hydrogenated and the resulting octahydroindoloquinolizine esters of the general formulas (Ve) and / or (Vb), in which B and B have the indicated meanings, Alkaline treatment is performed using an inorganic base in Ep618 de ethanol and water, followed by separation of the target product in free form, in the form of salts or in the form of optically active isomers, moreover, during the process, from the resulting compounds of formulas (IVa) to (IVb) Bases, compounds of general formulas (Va) and (Vb) are extracted from as salts and / or divided into optical antipodes. Sources of information taken into account in the examination 1. Weigand - Hilgetag. Experimental methods. ment in organic chemistry. M., Himi, 1968, p. 393-394.
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    同族专利:
    公开号 | 公开日
    FR2479828A1|1981-10-09|
    ES491992A0|1981-06-01|
    DK232080A|1980-12-01|
    NO801627L|1980-12-01|
    PT71328A|1980-06-01|
    SU1005663A3|1983-03-15|
    ES499288A0|1982-01-01|
    DD201592A5|1983-07-27|
    FI801757A|1980-12-01|
    IT1147741B|1986-11-26|
    ZA802888B|1981-07-29|
    ES8205411A1|1982-06-01|
    AT373252B|1984-01-10|
    IL60058D0|1980-07-31|
    CH646970A5|1984-12-28|
    DK153149B|1988-06-20|
    HU181495B|1983-07-28|
    IT8067826D0|1980-05-27|
    SE446003B|1986-08-04|
    IL60058A|1984-06-29|
    SE461653B|1990-03-12|
    CA1148157A|1983-06-14|
    GR68469B|1982-01-04|
    ATA287880A|1983-05-15|
    FR2457867B1|1983-07-22|
    ES8202008A1|1982-01-01|
    NL8002959A|1980-12-02|
    AU540977B2|1984-12-13|
    DE3020695C2|1991-05-16|
    FR2457867A1|1980-12-26|
    ES8202007A1|1982-01-01|
    JPS55162784A|1980-12-18|
    AU5892180A|1980-12-04|
    GB2051794A|1981-01-21|
    NZ193795A|1983-05-10|
    US4345082A|1982-08-17|
    JPH0142952B2|1989-09-18|
    ES8105731A1|1981-06-01|
    DE3020695A1|1980-12-11|
    SE8004079L|1980-12-01|
    BE883576A|1980-12-01|
    DK153149C|1988-10-31|
    NO852308L|1980-12-01|
    GB2072660A|1981-10-07|
    FR2479828B1|1983-03-04|
    ES499286A0|1982-06-01|
    YU145480A|1984-02-29|
    GB2072660B|1983-10-26|
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    SE8501069D0|1985-03-05|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    HU163143B|1971-05-07|1973-06-28|
    US4035370A|1971-11-03|1977-07-12|Richter Gedeon Vegyeszeti Gyar Rt.|Alkaloid esters|
    HU172068B|1975-06-13|1978-05-28|Richter Gedeon Vegyeszet|Process for the asymmetric synthesis of octahydro-indolo/2,3-a/quinolizidines|
    HU174502B|1976-12-30|1980-01-28|Richter Gedeon Vegyeszet|Process for preparing new octahydro-indolo/2,3-a/quinolizine derivatives|
    HU175527B|1977-03-28|1980-08-28|Richter Gedeon Vegyeszet|Totalsynthesis of esters of apovincaminic acid and homologues|
    HU180514B|1977-05-26|1983-03-28|Richter Gedeon Vegyeszet|Process for producing apovinca inic esters,or esters of vicaminic and apovincaminic acids at the same time|
    FR2398746B1|1977-07-25|1980-03-21|Roussel Uclaf|US4446139A|1979-05-31|1984-05-01|Richter Gedeon Vegyeszeti Gyar R.T.|Hexahydroindoloquinolizinium and octahydroindoloquinolizine esters, and method of increasing blood flow in an animal with hydroxyamino-eburnane derivatives|
    HU183207B|1980-09-10|1984-04-28|Richter Gedeon Vegyeszet|Process for preparing apovincaminic acid esters|
    HU183234B|1980-10-17|1984-04-28|Richter Gedeon Vegyeszet|Process for the enantioselective synthesis of optically active cys-14-oxo-e-homo-eburnan|
    HU186891B|1981-06-12|1985-10-28|Richter Gedeon Vegyeszet|Process for producing esters of apovincaminic acid|
    HU182380B|1981-09-30|1983-12-28|Richter Gedeon Vegyeszet|Process for producing esters of vincaminic acid|
    HU182411B|1981-11-03|1984-01-30|Richter Gedeon Vegyeszet|Process for preparing eburnamonine derivatives|
    HU191403B|1984-04-02|1987-02-27|Richter Gedeon Vegyeszeti Gyar Rt,Hu|Process for preparing new, raceme and optically active 14-hydroxyimino-eburnane|
    FR2648816B1|1989-06-21|1993-02-05|Richter Gedeon Vegyeszet|NOVEL DIESTER DERIVATIVES OF OCTAHYDRO-INDOLO--QUINOLIZINE AND SALTS THEREOF AND PROCESS FOR PREPARING THE SAME|
    US5122607A|1989-06-21|1992-06-16|Richter Gedeon Vegyesczeti Gyar Rt.|Racemic and optically active octahydro-indolo tetrahydropyranylquinolizine diester derivatives and process for preparing the same|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU79RI713A|HU181495B|1979-05-31|1979-05-31|Process for producing hydroxy-imino-eburnane derivatives|LV930039A| LV5256A3|1979-05-31|1993-01-18|Saturation of Oxiaminoeburnan derivatives or their derivatives or optically active isomers|
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