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    • 专利摘要:

    公开号:SU845777A3
    申请号:SU782669395
    申请日:1978-10-03
    公开日:1981-07-07
    发明作者:Майкл Зиммерман Деннис
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    hydride, namely 4a-aryltetrahydro-2,6-dioxocyclopenta (c) pyran with ammonia according to the scheme, followed by reduction of the obtained cyclic imide at 1 and 3-oxo groups. The analgesic activity of the target products is assessed by the cramps in the mice and, in startling, the tail in rats. For example, with subcutaneous administration of 4- (3-methoxyphenyl -2-methyl-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine as a hydrochloride salt at a dosage of 20 mg / kg 100% suppression was observed in the living weight of the carcass which then caused painful crusts, and 96% suppression of the painful cramps was observed with subcutaneous administration at the O mg / kg dosage. pain suppression to Erchey was provided at a dosage of 20 mg / kg of live weight; 98% pain cramp suppression was achieved at a dosage of 10 mg / Except It has been found that naloxone completely prevents the inhibitory effect of such a compound when given subcutaneously at a dosage of 5 mg / kg, thus indicating that this compound is a narcotic type analgesic. When tested in rats with a flinching tail, this compound caused a significant an increase in reaction time at a dosage of 80 mg / kg, both with subcutaneous injection and oral administration, and showed the same effect when administered orally at a dosage of 20 mg / k, with all the properties defined whether over a period of 0.5 and 2 hours after administration in the indicated dosages. 4a (3-hydroxyphenyl) -2-methyl-2,3,4, 4a, 5 6,7,7a-octahydro-1H-2-pyrindine was subjected to similar tests. When injected subcutaneously at a dosage of 0.5 mg / kg of such a compound, a 75% reduction in pain cramps in experimental animals is achieved. When administered orally at a dosage of 10 mg / kg of such a compound, 98% suppression of pain writhing was observed 0.5 hours after the administration of this substance. Naloxone completely prevented the inhibitory effect of the said compound upon subcutaneous injection at a dosage of 0.5 mg / kg. Tests on rats with flinching tails showed that this compound caused a significant increase in reaction time with subcutaneous injection and oral administration at a dosage of 20 mg / kg. 4a-phenyl-2-methyl-2, X4.4a, 5j6,7,7a-octahydro-1H-2-pyrindinium bromide exhibits a 70% ability to suppress cramps in a group of experimental animals at a dosage of 100 mg / kg 0.5 hours after compound administration. At a dosage of 20 mg / kg, this substance caused a 58% inhibition after 1.5 hours after administration, and this effect was completely prevented in the presence of napoxone. Tests on rats with startling tail showed that the proposed compound provides only a moderate increase in reaction time at a dosage of 80 mg / kg. During testing in mice with painful cramps and in rats with a shudder tail for the compounds of formula D, the following results were obtained (the dosage at which the number of painful cramps is reduced by 50% compared with the control experiments) (see table). 3Hydrobromide 1.0 1.0 4Hydro1O1Orid-Swipe Over 80 to 20 Starting Materials PRI me R A. A solution of 130 g of 2-phenyl-2-ethoxycarbonylmethylcyclohexanone in 2000 ml of diethyl ether containing 56 g of ethyl formate and 11.5 g sodium metal, stirred at 25 ° C for 48 hours. The reaction mixture was then poured into 1000 ml of ice-water and the ether layer was separated. The aqueous layer was acidified to pH 6.5 by the addition of 1 n. hydrochloric acid solution and then extracted with fresh portions of diethyl ether. The ether extracts were combined, washed with water and dried. As a result of evaporation of the solvent under reflux pressure, 98 g of 2-phenyl-2.-Ethoxycarbonylmethyl-6-formylcyclohexanone were obtained in the form of an oil-like product with a boiling point. 158-175 C at a residual pressure of 0.5 mm Hg Calculated,%: C, 70.81; H 6.99. Found,%: C 70.85; H 6.77. Example B. The process described in Example A was repeated with the reaction of 2- (3-methoxyphenyl} -2-ethoxycarbonylmethylcyclohexanoc with ethyl formate in the presence of metallic sodium, resulting in 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-6 α-formylcyclohexanone Example B. A solution of 87.0 g of 2-phenylcyclohexanone in 100 ml of benzene was added dropwise to a stirred solution of 28.0 g of sodium amide in 400 ml of benzene at a boiling point over 1 hour. The reaction mixture was kept at a boiling point temperature. for another 2.5 hours and then cooled , to an ice bath. To the cold reaction mixture was added 1 portion of a solution of 83.5 g of allyl iodide in 100 ml of benzene. The reaction mixture was further held at reflux temperature for 0.5 h and then cooled to 250 s. and drank in 400 g of ice. The organic benzene layer was separated, washed with water and run out. As a result of solvent injection, 50 g of the 2-phenyl-2- (2-propenyl) cyclone of the sanone were obtained with a boil 114-120 C at the residue nominal pressure of 0.1 mm Hg Example D. A solution of 30 g of 2-phenyl-2- (2-propenyl} -cyclohexanone in 600 ml of diethyl ether, containing 3.4 g of metallic sodium and 11.8 g of ethyl formate, was stirred for 48 hours at. Then into the reaction The mixture was added with water and the organic layer was separated. The aqueous layer was acidified to a pH of 2.5 by adding an aqueous solution of hydrochloric acid. The aqueous acid layer was extracted with fresh portions of diethyl ether. The ether extracts were combined, washed with water, dried and removed from them. dissolving by evaporation at a pony pressure to obtain m product in the form of oily mass. The oily product obtained in this way was distilled and 14.6 g of 2-fesh1l-2- (2-propenyl) -6-formylcyclohexlone were obtained on a batch of 125–130 ° C with a residual pressure of 0, 1 mm Hg. Example D. A solution of 50.0 g of 2-phenyl-2-ethoxycarbonylmethyl-6-f) rmylcyclohexanone in 500 ml of diethyl ether was stirred while temporarily adding a solution of 24 diethyllate in 100 ml of diethyl ether dropwise during 30 min. After stirring the reaction mixture for 2 hours at 25 ° C, the cooling solution was added, and then a solution of 33, i g of p-toluenesulfonylaide in 50 ml of diethyl ether, was added dropwise over 45 minutes. The reaction was heated to room temperature for an additional 5 hours. After the reaction, the mixture was washed with water and dried. I, by evaporation of the solvent under reduced pressure, obtained 43.0 2-phenyl-2-ethoxycarbonylmethyl-6-; Dimaslopod: reazocyclohexanone as an iioro product. IR spectrogram: 2080 cm, diazogroup. Examples E and G. In accordance with the depiction: in Example D, the conversion of 2-СЗ-methoxy (1enyl) -2-ethoxycarbonylmethyl-6-formylcyclohexanone to 2- (3-methoxyphenip) -2-ethoxycarbonylmetnp-6- diazocyclohexanone and the conversion of 2-phenyl-2- (2-propenyl) -6-formylcyclohexa it into 2-phenyl-2- (2-propenyl} -6-diazocyclohexanone. II p and me r I. Solution 57 g 2 ns1- 2-ethoxycarboxymethyl-6-diazo | cyclohexanone in 50 ml of anhydrous methanol was stirred at 25 ° C with passing nitrogen gas through the reaction mixture. The solution was irradiated for 40 h to Then, the solvent was removed under reduced pressure and the product was obtained as an oil, which was dissolved in 500 ml of diethyl ether. The ether solution was tested with an aqueous solution of sodium bicarbonate, water and evaporated. solvent under reduced pressure yielded 27.4 g of 2 Fensch-1-2-ethoxycarbonylmethyl-1-N etoxycarbonylcyclopentane as an N-product. It was additionally 78 purified by distillation, b.p.160-190 ° C (0.02 mm Hg). Calculated,%: C, 70.32 H, 7.64. And Found,%: C 70.30; H 7.36. Example K. In the same manner as described in Example II, 2- (3-methoxyphenyl) -ethoxycar6onylmethyl-6-diazo1-cyclohexanone was subjected to photolysis by irradiation with light at 3000 A, resulting in 2- (3-methoxy phenyl) -2-ethoxycarbonylmethyl-1 - carbonylcyclopentane labels with. 190-210% calculated: C H 7.55. F Found,%: 67.61; H 7.37. ; Similarly, 2-fensh1-2- (2-propenyl) -b-diazocyclohexanone was irradiated with ultraviolet rays of 3000 A using a quartz lamp in the presence of methanol, resulting in 2-phenyl-2 - {2-propenyl) - - 1-methoxycarbanylcyclo pentane with bp. 113-115 ° C. (0.1 mm Hg). Calculated,%: C 78.65; H 8.25. Found,%: -C 78.80; H 7.99. Example L. A solution of 2- {3-methoxyphenyl) -2-ethoxycarbonyl1 Methyl-1; -methoxycarbonylcyclopentane in 650 ml of I, 4-dioxane containing 500 ml of a 5% aqueous solution of potassium hydroxide was stirred and kept at boiling point for 12 After cooling the reaction mixture to room temperature, 500 ml of water was added to it. The reaction mixture was acidified by adding 2 n. hydrochloric acid and the aqueous acidified mixture were extracted several times with equal volumes of diethyl ether. The ether extracts were combined, washed with water and dried. By evaporation of the solvent under reduced pressure, 38 g of 2- (3-methoxyphenyl) -2-0 xylic of arbonylmethyl-1-o xy carbonyl-dicdlopentane were obtained in the form of a crystalline solid with T.Sh1. 175-180 ES: ... Examples of Min. As described in Example L, 2-feiyl-2-ethoxycarbonylmethyl-I-methoxycarbonylcyclopentane was hydrolyzed to give 2-phenyl-2 oxycarb nylmethyl-1-oxbene-carbonopopentane, m.p. which amounted to 205-208 C. It is calculated,%: C 67.73; H 6i50. CwH "P 7 Found,%: C 67.70; H 6.32. 2-Phenyl-2- (2-propenyl) -I-methoxycarbonylcyclopentane was hydrolyzed by reaction with an aqueous solution of potassium hydroxide to give 2-FeHN1-2- (2-propenyl) -1-hydroxycarbonylcyclopentane. Example 0. A solution of 25 g of 2-phenyl-2-hydroxycarbonylmethyl / -1-hydroxycarbonylcyclopentane in 150 ml of acetyl chloride was stirred and kept at boiling point for 4 hours. After cooling the reaction mixture: to room temperature, the excess solvent was removed under reduced pressure, with creeping 26 g of tetrahydro-4-phenyl-2, 6-dioxocyclopent / c / pyran as an oil. This product was then further purified by distillation, b.p. the final product was 205-2071 0 (0.25 mm Hg). Calculated,%: C 73.03; H 6.13. Found,%: C 73.30; H 6.37. Perimer P. B according to the example described in Example O 2- (3-methoxyphenyl) -2-hydroxycarbonyl-1-hydroxycarbonylcyclopentane was subjected to dehydration and cyclization by reacting with acetyl chloride, resulting in tvtrahydro-4- (3-methoxyphensh1) -2 6-dioxocyclopenta / c / pyran with bp. 200-220 0. Example P. To a stirred solution of 6.2 g of 2-phenyl-2- (2-propenyl) -1-hydroxycarbonyl-1 cyclopentane in 100 ml of chloroform was added dropwise 30 g of thionstchloride over 30 minutes. Then, the reaction mixture is held at boiling point with stirring for 15 hours. After cooling the reaction mixture, the solvent was removed under reduced pressure. The yield of 7.4 g of 2-phenyl-2- (2-propenyl) -1-chlorocarbonylcyclopentane. Example 0.-A solution of 10.7 g of benzylamine in 100 ml of toluene was stirred at while simultaneously adding dropwise a solution of tetrag.hydro-4- (3-methoxyphenyl) -2,6-dioxocyclopent / s / pyran to it in 1 hour in 300 ml of toluene. After complete addition of the pyran derivative, the reaction mixture was stirred and aged at a boiling point for 3 days in a flask equipped with a Dean-Stark trap to remove water. After soaking at the boiling point with reverse
    cooler, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure, whereby the product was obtained as an oil. This oil was dissolved in 400 ml of 1N. the sodium hydroxide solution and the mixture was heated to 15 minutes, then extracted with several portions of diethyl ether and the ether portions were combined, washed with water and dried, the solvent was evaporated under reduced pressure to give the product as a solid residue. Recrystallization of the solid from diethyl ether gave 4- (3-methoxyphenyl) -2-benzyl-2,3,4, 4a, 5,6, 7, 7a-octahydro-1,3-dioxo-H-2-pyrindine. from m.p. 75-71 C.
    Calculated,%: C 75.62; H 6.63; N 4.01.
    Found,%: € 75.40; H 6.58;
    N 3.78.
    Example T. A tetrahydro-4-fench1-2,6-dioxocyclopenta / c / pyran was reacted with benzylamine as described in Example C, resulting in 4a-phenyl-2-benzch1-2, 3,4,4a, 5,6,7,7a-octahydro-1, 3-dioxo-1H-2-pyrindine with so pl. 77-79 C.
    Calculated,%: C 78.97; H 6.63; N 4.39.
    C2, H2,
    Found,%: C 78.73; H - 6.65; N 4.26.
    Example U. A solution of 18 g of 4a-fensh1-2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1, 3-dioxo-1H-2-pyridine, dissolved in 200 ml of tetrahydrofuran in over 90 minutes, 5.8 g of lithium aluminum hydride in 150 ml was added dropwise to the stirred suspension. tetrahydrofuran. After the addition was complete, the reaction mixture was boiled for 10 hours. Maintaining the temperature of the reaction mixture at a lower level for 15 minutes, 50 ml of ethyl acetate was added dropwise. by the following addition of 100 ppm of an aqueous solution of ammonium chloride. Then, additional tetrahydrofuran was added to the aqueous reaction mixture to separate the organic layer from the aqueous layer. The organic layer is decanted and concentrated under reduced pressure to give the product as an oil, which is then dissolved in 500 ml of diethyl ether. The ether solution is washed with water, dried and the solvent is removed by evaporation under reduced pressure to give 15 g of 4a-phenyl-2-benzyl-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine. M / e 291 (maximum of the mass spectrum corresponding to non-dissociation of one molecule), 213 (-77, phenyl) and 20 (-91, benzyl).
    Example F. In accordance with the foregoing, Example 4a (3-methoxphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1, 3-dioxo-1H-2- Pirdind was reduced by reaction with lithium aluminum hydride to give 4a- (3-MeTOKc: iphenyl) -2-benz1-1,3,4,4a, 5,6, 7 .i7a-octahydro-IH-2-pyridine.
    Example X. A solution of 21 g of 4a-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine in 172 ml of ethanol was stirred with the addition of 7 g in one portion 5% papladi applied to coal. This reaction mixture was stirred in a hydrogen gas atmosphere at a pressure of 4.13 atm and held at bO-C for 3 hours. The reaction mixture was cooled to room temperature, filtered and the solvent was removed under reduced pressure. the addition of 13.3 g of oil, which surply to obtain 4a-phenyl-2,3,4,4a, 5,6,7 7 a-octahydro-1H-2-pyridine.
    Example C. 4- (3-Methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-oxahydro-1H-2-pyrindine was hydrogenated in the presence of palladium deposited on charcoal in in accordance with the foregoing in Example F with the use of 4- (3-methoxyphenyl) -2,3,4,4 a, 15.6,7,7a-octahydro-1H-2-pyridine with a bp. 145-160 ° C (0.05 mm Hg).
    Example III. A solution of 8.5 g of 4- (3-methoxyphenyl) -2,3,4,4a, 5,6,7, 7a-octagndro-1H-2-pyridine, dissolved in 60 ml of glacial acetic acid and 60 ml of 48% aqueous solution of hydrogen bromide, peremetili with simultaneous exposure at a temperature of 15 hours. After cooling the reaction mixture to room temperature, it was added to 100 g of ice, and then the pH of the final aqueous solution was adjusted to 10.2 1 of an aqueous solution of sodium hydroxide. Then the alkaline reaction mixture was extracted. 400 ml of a mixture of 3 parts of n-butanol with 1 part of benzene. The extract was separated, washed several times with water, dried, and the solvent was removed under reduced pressure. The resulting solid was crystallized from ethyladetate. The yield of g 4a (3-oxiphenyl) -2,3,4,4a, -5,6, 7, 7a-octahydro-1H-2-pyrivdine, i.e. which 180-181 ° C. Estimated I: C 77.38; H 8.81; N6.45. C, H, NO; Found: C77.56; H 8.84; N6.24. Similarly, 2.7 g of 4a-phenyl-2-methyl-2, 3, 3,4,4a, 5,6,7, 7a-octahydro-1H-2-pyrindinium bromide are obtained, m.p. which is 209-210 ° C (from di-isopropyl ether and isopropanol)%: C 60.81; H 7.49; Calculated N 4.73. C, 5H, BrN. C, 60.55; H 7.49; Found,%: N, 4.57. 1. 4a-Phenyl-2- (2-fe Example of nilethyl) -2, 3.4, 4a, 5.6, 7, 7a-octag1-shro-IH-2-pyrindinium bromide. In a cold (0-5c) solution, 3.0 g of 4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine in 47 ml of methanol, containing 14 ml of water and 2.6 g of potassium carbonate - added 2.6 g of phenylenedeti chloride. The reaction mixture was stirred for 30 minutes and then heated to 25 ° C and stirred for 1 hour. The reaction mixture was further concentrated under reduced pressure to obtain an oil. This oil was dissolved in 500 ml of diethyl ether and washed with dilute sodium bicarb sodium hydroxide solution and water. After drying the ethereal solution, the solvent was reduced under reduced pressure to give 4a-phenyl-2-phenylacetyl-2,3,4, 4a, 5,6,7,7a-octahydro-1H-2-pyridine obtained as a result of the described acylation reaction as oily product. This oil was dissolved in 25 ml of tetrahydrofuran, and 3.0 g of ltium aluminum hydride in 150 ml of tetrahydrofuran was added dropwise over 30 minutes to a stirred suspension. After the addition was complete, the reaction mixture was stirred at boiling point for 4 hours. After cooling the reaction mixture, 8,712 mixture was added with 60 ml of ethyl acetate and then 100 ml of saturated aqueous ammonium tartrate solution. The organic layer was separated by decantation, and the aqueous layer was extracted with diethyl ether. The organic extracts were combined and concentrated under reduced pressure, the result was an oil that was dissolved in diethyl ether, washed with water and dried, and 4a-phenyl-2- (2-phenylethyl) - was obtained by removing the solvent under reduced pressure. -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in the form of oil. This oil was dissolved in 150 ml of diethyl ether and 10 ml of 48% hydrobromic acid in 10 ml of ethanol was added to the solution. The hydrobromide salt of said pyridine precipitated out of solution, after which it was recrystallized from diisopropyl ether and isopropanol. The yield of 2.4 g of 4a-phenyl-2- (2-fensh1.atsh1) -2,3,4,4a, 5,6, 7,7a-octahydro-1H-2-pyrindinium bromide with so pl. 269-270 0 Calculated,%: C 68.39; H 7.30; N 3.63, Found,%: C 68.61; And 7.57; N 3.69. Example 2. 4a-Phenyl-2-cyclopropylmethyl-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide. In accordance with Example 1, 4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine was acylated with cyclopropanecarboxylic acid chloride, and 4a-phenyl-2-cyclopropanecarbonyl-2 was obtained. , 3,4,4a, 5,6,7 7a-octahydro-1H-2-pyrindine. As a result of the reduction of the acylated pyrindine intermediate product by reaction with lithium aluminum hydride, the corresponding 2-alkylpyrindine was obtained, followed by a reaction of the latter with hydrobromic acid to give 4a-phenyl-2-cyclopropylmethyl-2, 3,4,4a, 5,6,7, 7a-octa.hydro-1H-2-pyrindinium bromide with i so pl. 240-2410С. Exit 63%. Calculated,%: C 64.28; H 7.79; N 4.16. %%, S-. Found,%: C 64,54; H 7.51; N 4.13. Example 3. A solution of 2.17 g of 4- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine, obtained as described in Example III, in 50 ml N, N-dimethylformamide containing 3.95 g of triethylamine was stirred at room temperature with simultaneous addition dropwise for 15 minutes 3.87 g of phenylacetate chloride. After completion of the addition operation, the reaction mixture was heated at 70 ° C for 2 hours and then poured into 200 ml of water. The aqueous reaction mixture was applied several times with distilled zfir, the ether extracts were combined, washed with sodium hydroxide, water, and dried with a saturated aqueous solution and dried. As a result of the removal of the solvent at lower pressures, 4- (3-hydroxyphenyl) -2- (2-phenyl acetyl) -2.3,4, i4a, 5.6, 7.7a-octahydro-1H-2-pyridine were obtained. This product was dissolved in 50 ml of tetrahydrofuran and stirred under the simultaneous addition of dropwise. Within 30 minutes a solution of 4.0 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. This reaction mixture was then kept at boiling point for 4 hours, followed by cooling to a temperature of approximately 25 ° C. While stirring the reaction mixture, 25 ml of ethyl acetate was added to it, followed by addition of a saturated aqueous solution of ammonium tartrate. Next, the reaction mixture was filtered and the filtrate was concentrated by evaporation of the solvent under reduced pressure. The product thus obtained was dissolved in diethyl ether, washed with water and dried. Further, as a result of the removal of the solvent, 4- (3-hydroxyphenyl) -2- (2-phenylethyl) -2.3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine was obtained as an oil. It was dissolved in 150 ml of diethyl ether and stirred with the simultaneous addition of a 50% solution of 48% hydrochloric acid in ethanol. The hydrobromide salt of the above product was crystallized and the product was collected by filtration, from which, after recrystallization from ethyl acetate, 1.3 g of 4- (3-hydroxyphenyl) -2- (2-fench1E tyl) -2.3,4,4a, 5.6 were obtained , 7,7a-octahydro-lH-2-pyrindinium bromide, T.Sh1. which was 135- | 37 C.
    Counted
    %: C 65.57; H 7.01; N 3.48.
    84
    权利要求:
    Claims (1)
    [1]
    where the values of Y. are given as above, exposed to the action of the adduct 14 Found,%: C 65.41; H 7.12; N 3.66. Example 4. 4a (3-hydroxyphenyl) -2-cyclopropylmethyl-2,3,4,4a, 5,6,7, 7a-octahydro-1H-2-pyrindine, hydrochloride, In accordance with the above and the reaction of 4- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine with chlorohydropylad c1-clopropylcarboxylic acid in the presence of potassium carbonate and 4- (3- hydroxyphenyl) -2- (cyclopropilkare oshsh) -2,3,4, A a, 5, 6, 7, 7a-octahydro-1P-2-h1iri1shchna. The indicated compound was restored by reaction with lithium SHyumyyuHydride to obtain 4- (3-hydroxyphenyl) 2-cyclopropylmethyl-2,3,4,4a, 5, 6,7,7a-octahydro-1H-2-pyrivdine; : hydrochloride salt by reaction with gaseous hydrogen chloride in diethyl ether, m.p. product was 256-258 ° C, yield 66%. Calculated,%: C, 70.22; H 8.51; N 4.55; every 11.52. Found,%: C 69.93; H 8.25; IN 4i72; All 11, 52. The invention The method of obtaining cis-4a-phenyl-2, 3,4, 4a, 5,6,7, 7a-octahydro-1H-2-1 | irindine of the general formula 7Г-Вi where K is, where T, - benzyl or cyclopropyl; (j is hydrogen or hydroxyl, or their pharmaceutically acceptable salts, characterized by the fact that a compound of the general formula
    15845777J6
    agent obtained compound restore Sources of Information
    Pour lithium aluminum hydride and take them into account when examining the left product in the free 1. Fizer L., Fizer M. Reagents in the form or in the form of a pharmaceutically acceptable organic synthesis. M., Mir, emelemoy sati. $ 1970, t, 2, p. 171.
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    同族专利:
    公开号 | 公开日
    IL53236D0|1977-12-30|
    DK485277A|1978-05-03|
    AU3023577A|1979-05-10|
    FR2369267A1|1978-05-26|
    ATA782177A|1981-10-15|
    PL109690B1|1980-06-30|
    AR223454A1|1981-08-31|
    FR2369267B1|1980-05-16|
    GB1590155A|1981-05-28|
    RO77935A|1981-12-25|
    ES463784A1|1978-06-16|
    PL201885A1|1978-12-04|
    IE45901B1|1982-12-29|
    BE860314A|1978-04-28|
    SE8103107L|1981-05-18|
    PT67194B|1979-03-23|
    PT67194A|1977-11-01|
    DD133795A5|1979-01-24|
    PL108466B1|1980-04-30|
    ES463783A1|1979-07-16|
    DE2748466A1|1978-05-03|
    GR70053B|1982-07-26|
    SE8103106L|1981-05-18|
    PL108610B1|1980-04-30|
    IE45901L|1978-05-02|
    JPS5356669A|1978-05-23|
    RO78300A|1982-04-12|
    CS211380B2|1982-02-26|
    SU812174A3|1981-03-07|
    ZA776497B|1979-06-27|
    NL7712053A|1978-05-05|
    PH12590A|1979-06-27|
    AU513679B2|1980-12-18|
    SU913941A3|1982-03-15|
    SE7712218L|1978-05-02|
    RO72900A|1981-11-04|
    HU176231B|1981-01-28|
    CA1100136A|1981-04-28|
    NZ185539A|1979-12-11|
    ES472276A1|1979-10-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BG30927A3|1977-12-27|1981-09-15|Eli Lilly And Co.,Us|Method for obtaining of trans- 4- alpha- phenyl- octahydro- 1h- 2- pyridine|
    US4236009A|1979-06-21|1980-11-25|Eli Lilly And Company|Method of preparing 4A-arylhexahydro-1H-2-pyrindines and 4A-aryloctahydroisoquinolines|
    US4277608A|1979-06-21|1981-07-07|Eli Lilly And Company|Method of preparing 4a-arylhexahydro-1H-2-pyrindines and 4a-aryloctahydroisoquinolines|
    ZA9510829B|1994-12-23|1996-07-03|Smithkline Beecham Corp|3,3-cyclohexan-1-one monomers and related compounds|
    EP2595989B1|2010-05-06|2016-07-13|Vertex Pharmaceuticals Incorporated|Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels|
    BR112013019211A2|2011-02-02|2021-07-06|Vertex Pharma|pyrrolopyrazine spirocyclic piperidine amides as ion channel modulators|
    WO2012112743A1|2011-02-18|2012-08-23|Vertex Pharmaceuticals Incorporated|Chroman - spirocyclic piperidine amides as modulators of ion channels|
    AU2012229187B2|2011-03-14|2016-11-10|Vertex Pharmaceuticals Incorporated|Morpholine-spirocyclic piperidine amides as modulators of ion channels|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US73795876A| true| 1976-11-02|1976-11-02|
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