• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Certain 3-substituted octahydropyridoindolobenzazepines and their addition salts with pharmaceutically acceptable acids produce a marked central nervous system depressant activity in warm-blooded animals. These compounds are stereoisomers of prior art 3-substituted octahydropyridoindolobenzazepines which have a central nervous system antidepressant activity.
    公开号:SU741798A3
    申请号:SU741990060
    申请日:1974-01-21
    公开日:1980-06-15
    发明作者:Девитт Адамс Чарльз；Джильберт Бергер Джоел
    申请人:Эндо Лабораториз Инк. (Фирма)；
    IPC主号:
    专利说明:

    7 14a have a trans configuration in relation to each other. According to the invention, the proposed procedure for the preparation of octagsphiopyridoindolyl benzazepines of general formula 1 or their salts consists in the fact that hexahydropyridoyldolylbenzazepine is total pvtylyly II where Rj is RI or -CO-P3, where RE is phenyl, chlorophenyl, methylphenyl, Ih; substituted by chlorine, bromine or methoxy, 2-furyl, 2-thiesh, hydrogen, Ci-C4-alkyl, C2 C4-alkenyl, styryl, styryl, substituted by chlorine, bromine or methoxy group € 3-07 - cycloalkyl, methyl cycloprochem , GS- € 7-cycloalkenyl, Cj- € 7- cycloalkadienyl, 23-dimethylcyclo prop-2-ene-1SH1, exo-7-norkarsh1, 4-metsh1bitsiklo 2.2. -1-Sh1, bicyclo 2.2.1 hept-2-yl, Fmethylbicyclo 2.2.2 octene-1-yl, bicyclo 2.2.1 -hept-2-en-5-nl Ladadmal or 2-adamanth 1, is subjected to reduction by the complex hydride compound boron and tetrahydrofuran followed by treatment of the reaction mass with a mineral acid, for example, hydrochloric acid and separation of the target product in free form or in the form of a salt. Reduction of hexahydro derivatives of general formula II to octahydro compounds proceeds best of all with a four- or five-fold excess of the complex of boratetrahydrofuran hydride at such a low temperature as О С, or as high as the boiling point of tetrahydrofuran under reflux. The reducing ability of boron – tetrahydrofsfane hydride reagent can be further enhanced by dilution with high boiling ether, for example diglyme, which makes it possible to carry out the reaction at a higher temperature, usually not higher than 100110 ° С. Then the reaction mixture is acidified with about 4-10 M hydrochloric acid, heated to 100 ° C, the reaction mixture is cooled and neutralized with caustic soda. The product can be isolated in the usual way, including extraction, evaporation, followed by extraction by salt conversion, etc. Examples of pharmaceutically acceptable acids that can be used to obtain the salts according to the invention are hydrochloric, sulfuric. 84 sulfamic, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic acid, tetra, nitro, methanol, methanesulfonic acid, 1,2 tisulfonic acid, acetone, propionic wine, salicylic acid, gluconic acid, lactic acid, acetone, propionic wine, salicylic acid, gluconic acid, glucose, lactic acid, acetone, propionic wine, salicylic acid, gluconic acid, glucose, milk sulfide, acetone, propionic wine, salicylic acid, gluconic acid, glucose, milk glucose, acetic acid, nitric acid, nitric acid itaconic, glycolic, para-aminobenzoic, glutamic acid and p-toluenesulfonic acid. All compounds of the formula i have at least two asymmetric centers as a result of the restoration of the double bond at position 4a, 14a to the transcondensed system. The invention includes the racemate as well as individual enantomers. In addition, if the substituent in the 3-position includes a group capable of existing in stereoisomeric form, then all diastereisomers obtained are also covered by the invention. Example 1. / + / - trans-1,2,3,4,4a, 8,9,14a-Octagidro-3-methyl-pyrido (43: 23) -indole (1,7-ab) / 1 / benzaseshsh . A solution of 4.76 g of 1, 2, 3, 4, 8, 9-hexahydro-3-methylpyridine 4, 2.3 indole, 1.7-aB 1 benzazepine in 50 ml of tetrahydrofuran is added dropwise while moving to 1N. a solution of boron hydride in tetrahydrofuran (42 ml) under a nitrogen atmosphere. The resulting mixture was heated under reflux in a nitrogen atmosphere for 5 hours, then cooled with ice and shifted from 20 ml of 6N. hydrochloric acid. This mixture is transferred, replaced by dioxane from time to time. Then the mixture is heated under reflux at 91 C for 1 h with an additional amount of 6 n. hydrochloric acid, cooled to 70 ° C, alkalinized with sodium hydroxide and evaporated in vacuo. The semi-solid residue is treated with water and chloroform, and the chloroform layer is additionally treated to obtain 1.50 g of solid product with m.p. 128-131. In addition, some amount of product with m. Pl. 129.5-130.5 ° C. After crystallization from zfir t. PL. increased to 132-134C; UV spectrum: L max 279.5 im / log 6 4.13 / (in methanol). With the reduction of 1, 2, 3, 4, 8, 9-hexahydro-3-metsch1pyrid 4, 3: 23 indole (1.7-aH 1 benzazepine sodium in liquid ammonia, get the well-known / + / - cis-octahydro compound with t. Sh1 120-122 ° С; Lmax 287 nm / 1od6 4.08 / (in methanol) / ± / -trans-1, 2, 4, 4a, 8, 9, Ma-Octagidro3-methyl-pyridoMZ 23 indol 1, 7-ab 1 benzazepine can also be obtained by following with the reductive cleavage of 3-methoxymethylhexahydro-compound: A. A mixture of 2.74 g (0.0} mol) of 1, 2, 3, 4, 8, 9-hexahydropyrid 4, 3: 2.3 Indole 1.7-ab 1 5, 741 | benzazepine and 65 ml of anhydrous benzene are boiled until solution forms. To a warm solution. trietstamine (10.5 ml, 0.075 mol) is added, and then 2.0 ml (0.026 mol) of chloromethyl methyl ether is added dropwise. The resulting mixture is heated under reflux for 15 minutes, cooled, cooled to room temperature and filtered. After evaporation filtrate half-dry 3.05 g of a yellow oil, which, as shown by infrared spectroscopy, does not contain the NH group .. B. The product of the previous stage (3.0 g, 0.01 mol) in 50 ml of freshly purified tetrahydrofuran is added dropwise while stirring, add to 75 ml of a 1 M solution of boron hydride in tetrahydrofuran under nitrogen. The resulting mixture is heated under reflux for 26 h, then cooled on ice and carefully decomposed 50 ml of 5.5 n. hydrochloric acid. During the distillation, approximately 30 ml of liquid was removed and 50 ml of glacial acetic acid was added to dissolve the precipitate formed. The solution is heated under reflux for 1 h, cooled to 55-50 ° C and alkalinized with 50% sodium hydroxide solution. The product is isolated2 upon extraction with ether, evaporating the solvent
    and chromatography of its solution in benzene on a basic alumina column of activity 1. The pure product melts at 136138 ° C and is identical with the product prepared by the first method of this example.
    Example 2. / + / - trans-3- (Cycloproshsh Methyl) -, 2, 3, 4, 4a, 8, 9, 14-oxahydropyrido 4, 3: 2.3 indole 1,7-ab) 1 benzazepine.
    A. A mixture of 24.6 g of N -amino-iminobenzyl-5-.amino-10, 11-dihydro-5H-dibenz b, T azepine and 14.8 g of 4-piperidine hydrochloride in 250 ml of ethano.p. is heated on a steam bath for 15 minutes, and then cooled and a solution of 20 g of concentrated sulfuric acid in 250 ml of ethanol is added. The resulting mixture is again heated on the steam bath for 40 minutes, the resulting solution is cooled, made basic with ammonia and diluted with 1 liter of water. The separated crude semi-solid is taken up in ether and the aqueous mother liquor is extracted with additional ether pores. The combined ether extracts are concentrated to 500 ml and treated under nitrogen with vigorous stirring 50 ml of 5N. hydrochloric acid. The precipitate is filtered off, washed with ether and I. n. hydrochloric acid and dried in vacuum at 100 ° C. Hydrochloride is obtained 1, 2, 3, 4, 8, 9-hexahydropyrid 4, 3: 2.3 indole (1.7-aB {benzazepine with mp 309 ° C; this salt is very slightly soluble in water. After dissolving this salt in aqueous acetic acid and underchealing with ammonia is filtered off the crude product, from which, after recrystallization
    After separation of the inorganic salts by filtration, the filtrate is dried with anhydrous sodium carbonate and evaporated in vacuo. The residue is dissolved in a mixture of 1: 1 ethyl acetate and benzene and chromatographed on a 14x2.2 cm column of basic alumina oxide, activity 1. The eluate is evaporated to dryness and the residual oil is dissolved in absolute alcohol, the solution is saturated with ethanolic hydrogen chloride solution. and again, evaporated to dryness. After recrystallization of the residue from acetone, 3-cyclopropylmethyl-1, 2, 3, 4, 8, 9-hexahydropyrido 4: 3: 2.3 indole 1,7-ab 1 benzazepine is obtained, m.p. 267 ° C.
    B. A solution of 9.25 g of the free base of the above hexahydro compound in 75 ml of tetrahydrofuran is reduced to 100 mp 1 M solution of boron hydride in tetrahydrofuran,
    5: as described in Example 1. The target product weighs 4.43 g and has an mp. 1 $ 2.5-155 ° C; UV spectrum: L max / 1 € 4 10 / (in methanol). The hydrochloride salt melts at 273. 276 ° C.
    In the reduction of 3- (cyclopropylmethyl) -1, 2, 3, 4, 8, 9-hexahydropyrido 4, 3: 2.3 1 Sdol 11.7-aB 1 benzazepine sodium in liquid ammonia is obtained / -1 - / - sh1C-product , whose hydrochloride has so pl. 2.41-243 ° C: UV spectrum
    Lmax 285 nm / 1od 4.10 / (in methanol).
    It has been established that the two indicators above the octahedral compounds have a rat magnitude of Rf in
    to the system. chromatograph1 and in a thin layer with an admixture of benzene, free 1, 2, 3, 4, 8.9 hexahydropyrvdo up to 3 3:23 indol is obtained (1.7-aB 1 benzazepine. B. K rastvorU 16.4 g 1, 2, 3, 4, 8, 9-hexahydropyrido 4, G: 2.3 indole t1,7-abj 1} beisazepine in 500 ml of dichloromethane, 7.3 g of cyclopropanecarbonyl chloride is added, and then 10 ml of triethylamine are added dropwise. the reaction is stirred at room temperature overnight, then the mixture is rinsed with 1N hydrochloric acid and water and dried with anhydrous sodium carbonate. Raw 3 (cyclopropylcarbonyl) -, 2, 3, 4, 8, 9-hexahydropyrvodo 4, 3: 2.3 indole 11,7-ab 1 benzazepine as a vitreous product is obtained dry. After recrystallization from ethanol, the pure product melts at 154- 156 ° C. A solution of 8.6 g of this product in 120 ml of tetrahydrofuran is added dropwise to a suspension of 2.3 g of lithium aluminum hydride in 180 ml of tetrahydrofuran. This mixture is first heated under reflux for 1 hour and then stirred at room temperature for nights, after which they decompose in the usual way. the use of chloroform: butanol :: 28% aqueous ammonia as a solvent, 96: 10: 5 by volume, respectively. Example 3. / + / - transC-3- (Csh: lopropyl methyl) -, 2, 3, 4, 4a, 8, 9, 14a-octahydroxy-4, 3: 2.3 indol 11.7- a b (Zbenzazepine (recovery in one stage). A solution of 100 g of 3- (acciopropyl1sarbot1l) -1, 2, 3, 4, 8, 9-hexahydro.pyrido 4, W: 231 indo 1,7-aB 1 benzazepine in 500. ml of tetrahydrofuran is added over a period of about 30 m to 946 ml of a 1 M solution of boron in tetrahydrofuran.The resulting solution is kept for 72 h, and then a solution of 50 ml of concentrated hydrochloric acid in 100 ml of water is added to it and the mixture is distilled until the temperature in the percussion flask reaches 100 ° C. The IC product was cooled and diluted with 200 ml of water and 75 m of a 50% aqueous solution of sodium hydroxide sodium.The product was extracted with methylene chloride and the crystals obtained after stripping with acetone were isolated in the form of crystals after distilling methylene chloride. Yield 50.3 g, m.p. 146-151. After recrystallization from a mixture of methanol and chloroform 9: 1 by volume, the melting point rises to 153-155 ° C. A sample of this product is converted to an ointment (methanesulfonate) with an mp. 227-232 ° C. Example 4. / ± / -trans-3 - Ethyl-1, 2, 3, 4 4a, 8, 9, 14a-octahydroharido 4, H: 23 indole 1,7-abi1 benzazepine. To a mixture of 9.0 g of N-nitrosoimindibenzyl, 12.4 g of 1-acetyl-4-piperidone and 13.0 g of zinc dust in 75 ml of absolute alcohol, 24 ml of glacial acetic acid are added dropwise with continuous stirring and periodically cooling, maintaining a constant temperature of 20–25 ° C. After 6 hours, unreacted zinc is filtered off and the mother liquor is evaporated almost to dryness. After the residue was extracted with benzene, the extract was washed with a saturated solution of sodium chloride, dried with sodium sulfate and the solvent was removed by distillation. A yellowish-brown residue is dissolved in 50 ml of ethanol, treated. Wash with a solution of 8 ml of concentrated sulfuric acid in 50 ml of ethanol and heat it with a steam bath for about 10 minutes. When the reaction mixture is poured into cold water, resin is released. After decantation of the BODE, the resin is dissolved in ethyl acetate, the solution is washed with a saturated solution of sodium chloride and dried with sodium sulfate. After evaporation of the solvent, a solid is obtained; yellowish-white color, from which, after crystallization from acetone, 3-acetyl-1, 2, 3, 4, 8, 9-hexahydropyrido 4, 3: 23J 7 88 indole 1,7-ab is obtained Zbenzazepin in the form of a white solid with mp 193-196 ° C. This 3-acetyl compound is reduced by boron hydride in tetrahydrofuran, as described in Example 3. The target compound is isolated in 36% yield as its hydrochloride salt from mp. I1. 258-260 ° C (decomposition); UV spectrum: / 1odb4,11 / (in methanol). The same compound can be obtained by reducing the 3-acetyl compound under more severe conditions in the following way. A warm solution of 3-acetyl compound (11.53 g of 0.0365 mol) in 300 ml of diglyme is quickly added dropwise to a mixture of 250 ml of diglyme and 150 ml of a 1 M solution of boron hydride in tetrapadrofuran. This mixture is heated with stirring for 12 hours at 100 ° C. under a nitrogen atmosphere. Then it is cooled to 20 ° C, decompose 75 ml Yun. hydrochloric acid and heat-. Kug with reflux 1 h at. After cooling to 60 ° C, the mixture is made alkaline with 100 ml of a 50% potassium hydroxide solution, concentrated in vacuo, and extracted with chloroform. From the extract, 3-ethyl compound is obtained with a yield of 67%. Example 5. / + / - trans-1, 2, 3, 4, 4a, 8, 9, 14a-octahydro-3-isobutylpyrido 4, 3: 2.3 indole 1,7-ab 1 benzazepine. 1, 2, 3, 4, 8, 9-Hexahydro-3-isobut1Pirido 4, 3: 231 indole 1,7-aB 1 benzazepine with t. Pl. 122-124 ° C is obtained by reacting U: 2, 3, 4, 8, 9-hexahydropyrido 4, 3: 23 1 indole 1,7-aY 11 benzazepine with isobutyrol chloride. This amide is reduced with a boron-tetrahydrofuran hydride complex in diglyme, as described above, as another method of reducing 3-acetyl compound to obtain 3-ethyl-compound of Example 3. The desired compound is prepared in the form of the hydrochloride with m.p. 286-289 ° C (decomposition) .., Example 6. / + / - trans-3-Benzyl-1, 2, 3, 4, 4a, 8, 9, 14a-octahydropyrido 4 3: 23} indole 1.7 - aa 1 benzazepine. By condensation of N-nitrosoimide benzine with 1-benzyl-4-sh1peridone under the conditions described in example 4 for the condensation of 1-acetyl-4-sh1peridane, 3-benzyl-1, 2, 3, 4, 8, 9-hexa-adadiridone is obtained 4, W: 2.3 indole 1,7-ab1 Zbenzazepin hydroeiurid, so pl. 200 ° C. When the free base is reduced with a boron-tetrahydrofuran hydride complex in diglyme under the conditions of the second method described in Example 4 to reduce the 3-acetyl derivative, a target compound is obtained in 84% yield, which is isolated in hydrochloride iide with a m.p. 210-212С (decomposition). The free base is obtained by treating hydrochloride dissolved in methanol with anhydrous ammonia. The free base melts at 146148 ° C; UV spectrum: Amax 279 im / 1 d 4,13 / (in methanol). Example 7. / i / trans-1, 2, 3, 4, 5a, 8, 9, 14a-Octagidro-3- (exo-7 norkarylmethyl) pyrido 4, 3: 23 nndol 1,7-ab Zbenzazepin. A solution of 7.05 g (0.0788 mol) of 1, 2, 3, 4.8.9 hexahydro-3-exo-7-norkarylcarboshsh pyrido 4, 3: 231 indole (1.7-aB 1 benazepine obtained from 1 , 2, 3, 4, 8, 9-hexahydropyrido {4, G: 231 indop 1.7-aB 1 benzazepine and (exo-7-norkaryl) -carbonyl chloride, and 100 ml of diglyme are added dropwise in a nitrogen atmosphere at stirring to a mixture of 100 ml of a 1 M solution of boron hydride in tetrahydrofuran and 400 ml of diglyme.The mixture is heated at 110 ° C for 23 h and then cooled to about 20 ° C. After the addition of 75 ml of 10 and hydrochloric acid the mixture is heated with reverse 1m refrigerator 1 at 100 ° C, then cool example about 60 ° C and alkalinized with 100 ml of 50% sodium hydroxide solution. The product is isolated and purified by several stages of extraction and recrystallization, mp 186-187 ° C. The following compounds of formula 1 can be described using the methods described above: hydrochloride / + / - trans-3-cyclohexylmethyl-1, 2, 3, 4, 4a, 8, 9, 14a-oxahydropyrido 4, W: 2.3 indole, 1.7-av 1 benzazepine, p. 180 ° C (decomposition); hydrochloride / 1 / -trans-3-cyclopentylmethyl-1, 2, 3, 4, 4a, 8, 9, 14a-octahydropyrido 4, 3: 2,3} indol 11,7-ab 1 benzazepine, t. square 263 ° C (decomposition); hydrochloride / + / - trans-3-cyclopropyl-1, 2, 3, 4, 4a, 8, 9, 14a-octahyropyrido 4, 3: 2.3 indole 1, 7-ab Zbenzazepina, t. pl. 195 ° C (decomposition). hydrochloride / + / - trans-3- (laadamantylmethyl) -1, 2, 3, 4, 4a, 8, 9, 14a-octahydropyrido 4, 3: 231indole 1,7-aB 1 benzazepina, t. pl. 195-196 ° C (decomposition); hydrochloride / 1 / -trans-3- (2-adamantnlmetsh1) -1, 2, 3, 4, 4a, 8, 9, 14a-octahydropirido 4, 3: 23 indole 1,7-ab 1 benzazepine, so pl. 169-176 ° C; hydrochloride / + / - trans-3- (cis-2,3-Dimethylcyclopropyl) -methyl 1 4, 3; 23 incol 1,7-ab 1 benzazepine; hydrochloride / ± / -trans-1 ,, 2, 3, 4, 4a, 8, 9, 14a-octagidro-3- (4-mets1 Dicyclic 2,2L oct 1-yl) methyl pyrido 4 W: 231 indole J1-7 - (b) 1 benzazepine; hydrochloride / i - / - trans- 1, 2, 3, 4, 4a, 8, 9, 14a-octahydro-3- ((1-methylcyclogophenyl) -methyl Crido, H: 23 3 IND on 11.7-aY 1 Benzazepine hydrochloride / + / - trans-3- (dicyclo 2.2.2) hept2-yl) metal-, 2, 3, 4a, 8 9, 14a-octapadirido 4, 3: 231 indole {1,7-ab; 1 benzazepia; hydrochloride / ± / -trans-3 -furfuryl-1, 2, 3, 4, i a, 8, 9, 14a-octahydropyrido (4, 3: 231nndol 1,7-aB 1 benzazepine; hydrochloride / ± / trans-3 - (4-chlorobenzyl) -1,2, 3, 4, 4a, 8, 9, 14a-octahydropirido 4.3: 2.3 ndol 1.7-aH 1 benzazepine; hydrochloride / + / - trans-3- ( 2-methoxybenzyl) 1, 2, 3, 4, 4a, 8, 9, 14a-octahydropyrido 4, 3: 23 indole 1,7-aB 1 benzazepine; hydrochloride / + / - trans-3- (2-chlorofensh1) - Proyl-, 2, 3, 4, 4a, 8, 9, 14a-octagndropirvdo 4, 2.3 shadol 1.7-aH 1 benzasesh; hydrochloroporid / + / - trans-3- 3- (4-bromophenyl) -propyl -1, 2, 3, 4, 4a, 8, 9, Ia-octahydropirido 4, C: 2.3, indole, 1.7-aH 1 benzazepine, hydrochloride / ± / -trans-1, 2, 3, 4, 4a, 8, 9, 14a-o ktagidro-3-Z- (3-methoxyphenyl) -propyl pyrido 4, 3; 231 indole 1,7-aH 1 benzazepine; hydrochloride / 1 -, / - trans-3-1 with hlclopentylmethyl-1, 2,3, 4, 4a , 8, 9, 14a-octahydropyrido 4 C: 2.3 indole 1,7-ab I of benzazepine; / ± / -trans-1, 2, 3, 4, 4a, 8., 9, 14a-octahydro-3- fensh1-pyrvdo 4, 3 2.3 indole 1,7-ab 1 benzazepine, mp 270 ° C (decomposition); / ± / -trans-1, 2, 3, 4, 4a, 8, 9, Ia -octagndro-3- (3-phenylpropyl) -pyrido 4, 323 indole 1,7-aB 1 benzazepine; / ± / -trans- 1,2, 3, 4, 4a, 8, 9, 14a-octaguscido-3- (2-tenyl) -pyrido 4, 3: 23 indole 1,7-zb 1 benzazepine; / ± / -trans- 1,2, 3, 4, 4a, 8, 9, 14a: octahydro-3-pentylpyrido 4 G: 2.3 indole 1,7-aH 1 benzazepine; / ± / -trans-1, 2, 3, 4, 4a, 8, 9, 14a-octahydro-3-neopentshristo 4, W: 23 indole 1,7-ab 1 benzene; (L-trans-, 2, 3, 4, 4a, 8, 9, 14a-octahydro-3- (2-methyl 1-cyclopropyl) methyl pyrido 4, G: 2.3 1 Sdol 1,7-aB 1 benzazepine; Formula of the invention. The method of obtaining octahydropiridoindolylbenzazepines of the general formula where RI is a non-substituted or substituted by methyl, methoxy or chlorine and 74 chemical phenethyl, 3-phenylpropyl substituted by chlorine, bromine or methoxy group, furfuryl, substituted by chlorine, bromine or methoxy group, furfuryl, substituted by chlorine, bromine or methoxy group, furfuryl, substituted by chlorine, bromine or methoxy group, furfuryl, substituted by chlorine, bromine or methoxy group, furfuryl, substituted by chlorine, bromine or methoxy group, furfuryl, substituted by chlorine, bromine or methoxy group, furfuryl, substituted by chlorine, bromine or methoxy chain, furfuryl, 3 C4-C8BDCKalkylmethyl, (methyladclopropyl) -methyl, ek 30-7-norkarylmethyl i (4-methylbench 12.2.2 oct-1-yl) -metsh1, (bicyclo 122.1 hep7-2-yl) methyl, 1-adamantylmethyl or 2-adamatsh1metsh1; the hydrogen atoms in position 4a and 14a have a trans configuration in relation to each other; or salts thereof, characterized in that the hexahydropyridoindolylbenzazepine of the general formula where RI-RI or -CO-BH, where RH is phenyl chlorofesh methylphenyl, methoxyphenyl, benzyl, phenethyl, substituted by chlorine, bromine or methoxygroup, 2-furyl, 2-thienyl, hydrogen , C, alkyl, C 1 -C 2 alkenyl, styryl, styryl substituted by chlorine, bromine or methoxy. Se-C7-cycloalkh1, methylshch1klopr011Sh1, € 5-07 cycloalkenyl, C5-C7-cycloalkadienyl, 23-day-methylcycloprop -2-en-1-yl, 3-methyl-7-norkaryl, 4-methyl-bicyclo 12 D, 2 oct-1-yl, bi-7-norkaryl , 1 hega-2-yl, 4-metsh1bidiklo 2,2.2 octen-1-yl, bicyclo 2; 2,2-hepg-2-en-5-yl, adamantine or 2-adamantyl, is subjected to reduction with a complex compound of boron hydride and tetrahydrofuran followed by treatment of the reaction mass with a mineral acid, for example, hydrochloric acid, and isolation of the target product in a free form of salt in the form of salt. Priority by featured. 01/22/73 - when RI is benzyl, C 1 -C4-alksh1, cyc-; loprosh, phenethyl, exo-7-norkarylmethyl, € 4-C7 cycloalkylmethyl. 12/6/73 with RJ - substituted benzyl, phenethyl, 3-feshpropil, substituted Z-phenylpropyl, 2-thienyl, Cj-alkyl, Cd-cycloalkylmethyl, (methylcyclo-propyl) -methyl, szzo-7-norkarylmethyl, (4-metsibicylo 222 oct -1 -yl) -methyl, (bicyclo-t22.1 hept-2-yl) -methyl, -adamantylmethyl or 2-adamanthenylmethyl.
    权利要求:
    Claims (2)
    [1]
    Claim
    A process for the preparation of oktagidropiridoindolilbenzazepinov general formula wherein Rj - unsubstituted or substituted methylene t scrap, methoxy or chlorine, benzyl, phenethyl, W-substituted fenilpropshg chlorine, bromine or metoksigrunpoy, furfuryl, 2-thenyl, Cj -C 5 alkyl, cyclopropyl, C 4 -C 8 -cycloalkylmethyl, (methylcyclopropyl) -methyl, 5 ex-7-norkarylmethyl j (4-methylbipyclo [2.2.2] oct-1-yl) -methyl, (bicyclo [22.1] hept-2-yl) - methyl, 1-adamantylmethyl or 2-adamantylmethyl; atoms. hydrogen at positions 4a and 14a have a trans configuration with respect to each other;
    or their salts, characterized in that hexahydropyridoindolylbenzazepine of the general formula where R1 — Ri or —CO — R 3 , rne R 3 is phenyl, chlorophenyl, 25 methylphenyl, methoxyphenyl, benzyl, phenethyl substituted with chlorine, bromine or methoxy group, 2-furyl , 2-thienyl, hydrogen, C t C 4 alkyl, C 2 —C 4 alkenyl, styryl, styryl, substituted with chlorine, bromine or methoxy. C 3 -C 7 -cycloalkyl, methylcyclopropyl, C 5 -C 7 cycloalkenyl, C 5 -C 7 -cycloalkadienyl, 2,3damethylcycloprop -2-en-1-yl, exo-7-norkaryl,
    4-methylbicyclo [22D] oct-1-yl, bicyclo [2.2.1] 1 hept-2-yl, 4-methylbicyclo [2.2.2] octen-1-yl, bicyclo [2.2.2] - hepg-2-en-5-yl, 1-adamantyl or
    [2]
    2-adamantyl, is subjected to reduction with a complex compound of boron hydride and tetrahydrofuran, followed by treatment of the reaction mass with a mineral acid, for example, hydrochloric acid, and isolation of the target product in free form or in the form of a salt.
    Priority by feature.
    01/22/73 - for Rj-benzyl, C. g- C 4 -alkyl, cyclo-: lopropyl, phenethyl, exo-7-norkarylmethyl, C 4 -C 7 cycloalkylmethyl.
    12/06/73 - 'with Rj - substituted benzyl, phenethyl, 3-phenylpropyl, substituted 3-phenylproduct, 2-thienyl, C 5 -alkyl, C 8 -cycloalkylmethyl, (methylcyclopropyl) methyl, exo-7-norkarylmethyl, (4 -methylbicyclo [222] oct-1-yl) methyl, (bicyclo [22.1] hept-2-yl) methyl, 1-adamantyl methyl or 2-adamantylmethyl.
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    同族专利:
    公开号 | 公开日
    US3932650A|1976-01-13|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3373168A|1964-06-02|1968-03-12|Hoffmann La Roche|Certain benzazepinoxyridoindole compounds and their preparation|CA1026331A|1973-12-06|1978-02-14|Joel G. Berger|Substituted indolobenzazepines|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US32535273A| true| 1973-01-22|1973-01-22|
    US05/422,616|US3932650A|1973-01-22|1973-12-06|Trans-octahydropyridoindolobenzazepines as central nervous system depressants|
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