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    • 专利摘要:
    A method for producing amino-tetracycloionane aminoproducts of the general formula T: V. x A-NHz R. where Kd is a hydrogen atom or C -C-alkl l, A - 1,2 is an ethylene group or a group of the formula -CH-R2, where Rj is a hydrogen atom , C-C-alkyl, diclohexyl, phenyl-C-C-alkyl, 4-C-C-alkyl alkyl, 4-Ci-C (. -Alkoxyphenyl or 4 chlorophenyl, and with an A-CH-R value of at least one is Rz and Rj is not a hydrogen atom or their salts, characterized in that the primer of tetracyclononane of the general formula II: where R has the indicated value, is a methylene group or a simple bond, X is a cyano group, a carbamoyl group or a group of general formula III: O) RrCl-NR where R2 has the indicated value Rg is a hydrogen atom, hydroxy group or a group of the formula Mg-Y, where Y is a bromine or iodine atom, moreover, if B0 is 1, the methylene group is R2 or O) hydrogen atom and, at value B, a simple bond with at least one of R and R2 is not a hydrogen atom, is subjected to reduction with sodium borohydride in the presence of cobalt chloride or nickel chloride, or with hydrogen in the presence of rhodium on alumina; b, X is a group of the indicated formula (ill), where R is methyl and Rj is an oxy group , or lithium aluminum hydride with a subsequent allocation of the target product in free form or in the form of a salt.
    公开号:SU1156591A3
    申请号:SU782699554
    申请日:1978-12-22
    公开日:1985-05-15
    发明作者:Линтин Своллоу Дуглас
    申请人:Империал Кемикал Индастриз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new chemical compounds - amino derivatives of tetracyclononane of the general formula: V. where R is a hydrogen atom or C-Cd-alA - 1,2 - ethylene group or a group of the formula - CH-R, where Rj is a hydrogen atom, C-C-alkyl, cyclohexyl, phenyl-C.-Cp-alkyl, ( -alkyl-phenyl, 4-C., -C-alkoxyphenyl or 4-chlorophenyl, and with A being CH-R, at least one of R and Rj is not a hydrogen atom, or their salts, possessing an antiviral effect. tetracyclononane, for example, 8-aminotetracyclo (4,3,0,) nonane, has a pronounced anti-viral effect 1. However, this compound does not have sufficiently high functional activity at low concentrations Acid preparations, for example, the compound did not have an antiviral effect at a concentration of 50 µg / ml. A known reduction reaction of oximes of ketones with sodium borohydride by heating in an inert organic solvent with the formation of the corresponding amine C2J as well as the reduction of oximes, amides or nitriles using lithium aluminum hydride or hydrogen in the presence of ro d on alumina when heated in an inert organic solvent such as lower alcohol zT. The purpose of the invention is to develop a process for the preparation of new amino derivatives of tetracyclononane, having an above 1m antiviral effect. This goal is achieved by new chemical compounds - amino derivatives of tetracyclononane of the general formula (1) or their salts,. I have antiviral action. These compounds are obtained by using a method based on known recipes and conclude with the fact that Tetracyclononane is a general derivative of the formula: Bn Ki where R has the indicated value; In a methylene group or a simple bond, a cyano group, a carbamoyl group or a group of the general formula: where R has the indicated value, R is a hydrogen atom, an hydroxy group or a group of the formula No. YY, where Y is a bromine or iodine atom, and R2 is a hydrogen atom, and when B is a simple bond, at least one of R and Rj is not a hydrogen atom, is subjected to reduction with sodium borohydride in the presence of cobalt chloride or nickel chloride or hydrogen in the presence of rhodium on alumina and B is simple Bind, X group of formula (III), where R2 is methyl and RJ is a hydroxy group, or lithium aluminum hydride, followed by isolation of the desired product in free form or as a salt. Example 1. 8- (2-aminoethyl) tetrai-cyclo (4.3.0.,) Nonane hydrochloride. From magnesium (12.0 g) and methyl iodide (71.0 g) in ether (400 mp) a solution of methylmagnesium iodide is obtained. The ether was distilled off and replaced with dry toluene (300 ml). To the toluene solution was added 8-cyantetracyclo (4.3.0,. 02 |,) nonane (58.0 g), which, according to gas-liquid chromatography, is a mixture of exr- and endoisomers in a ratio of 3.6: 1. The mixture is heated to reflux until all the nitrile has reacted (about 6 hours). This solution is cooled; the suspension is added to room temperature and a suspension is added slowly for a while while stirring.
    3
    aluminohydrate (7.6 g) in anhydrous ether (200 ml).
    The mixture is heated for 6 hours, cooled to room temperature, and the excess lithium aluminum hydride is decomposed by carefully adding water drops with vigorous stirring. A dilute solution of caustic soda (15 ml of pacTieopa 18.6 g of sodium hydroxide in 50 ml of water) is then added to decompose the Grignard complex. The precipitate is then filtered and washed thoroughly with ether. The combined liquids and washes are dried over anhydrous potassium carbonate, filtered, and treated with excess 914
    lump of gaseous x-porous hydrogen. In this way, a precipitate of 8- (2-aminoethyl) tetracyclo- (4 ,,, OO nonane hydrochloride, which is filtered off, washed with ether, dried and recrystallized from isopropyl alcohol is obtained. The product has mp. 265.5--266 C. Obtain 33.4 g of the desired product (yield
    41.8%)
    Example 2. Under the conditions described in example 1, using a corresponding alkyl halide, aryl alkyl halide or haloaryl, the following compounds are obtained (see table 1).
    Table 1
    CH-ZNg-HX R
    СНгСНзХлор Iodide ethyl СН2СН2СНз Benzoate Propyl bromide L-propyl bromide 191klog hexyl hexyl phenylpropyl bromide phenylpropyl | ; h-chlorobromobenzene O / Jl
    p-bromoanisole- / QN Q j Benzoate188-19126,5
    P-bromo toluene {OU-CH, Benzoate 217-21918,5
    Example 3. Exo-8- (1-amino-Exo-8- (1-oximinoethyl) | tetracyclo
    ethyl) tetracyclo (4,3,0,02. +, 0z.t) ion- (4,3,0,02,, 0 .-) nonan (3,0 g) solution on hydrochloride. are in dry ether ( 20 ml) at room-benzoate benzoate benzoate benzoate 229-231 185-187 175-178 114-116 148-150 158-160 198–201 temperature and added with stirring to the refluxing suspension of aluminum lithium hydride ( 1.0 g) in dry ether (50 ml). When the addition is complete, the mixture is heated for another 16 hours, cooled, and water is carefully added dropwise to decompose excess lithium aluminum hydride. The precipitate is filtered off from the organic phase and carefully mixed with ether. The organic phase and the washing are combined, dried using anhydrous potash, filtered and treated with an excess of dry hydrogen chloride in the ether. In this way, a precipitate is obtained (31H3O-8 - (1 -aminoethyl) tetracyclo (4.3.0, 0.). Non-hydrochloride hydrochloride, which is then recrystallized from isopropyl alcohol. The recrystallized product has a melting point of 254-255 ° C 1.1 g of the desired product is obtained (yield 32.5%). Exo-8- (1-oximinoethyl) tetracyclo (jSjOjO.O / O noian, used as a starting material, is obtained as follows. 8-cyanotetracyclo (4 , 3.0,,) nonane (29 g) is treated with methylmagnesium iodide, obtained from magnesium (6.0 F) and methyl iodide (35.5 g). This solution is cooled below 5C in an ice bath and a cold solution of glacial acetic acid (25 ml) in water (25 ml) is added dropwise with stirring and cooling. The temperature is not maintained above. Water (150 ml) is added to the thick suspension and stirring is continued until the solid elements dissolve. the phase is separated, washed three times with water (50 # 1), dried using magnesium sulfate and filtered. The toluene is evaporated on a rotary evaporator and the remaining Mac is distilled under vacuum. A mixture of exo-and zdo-B-acetyltetracyclo (3,4,3,0,021% 0zl) nonane is obtained, bp. 66 € / 0.5 mm. The specified analytical derivative (16.2 g) was dissolved in ethanol (60 ml), hydroxylamine chlorohydrate (7.6 g), anhydrous sodium acetate (T2.3 g) was added to the solution. The mixture is heated under reflux and water is added in small portions until the solids are completely dissolved. The boiling is continued for 21 hours, and then the solution is cooled in an ice bath. A white crystalline solid is filtered off. Recrystallization from a mixture of ethanol and water (70:30) gives exo-8- (1-oximinoethyl) tetraxlo (4, 3.0.0i, Oz) nonane, m.p. 103-104 S. EXAMPLE 4: 8-1 C. tetracyclo (4.3.0, 0, Ononan is prepared by the method of Holaa (1960). It is a mixture of exo- and endo-isomers, as shown by gas-liquid chromatography. Isomers separated by gas-liquid chromatography, a pure sample of the exo-isomer is obtained. However, the endo-isomer is obtained with only 80% purity. Separate reduction in ether using lithium aluminum hydride gives pure exo-8-aminomethyltetracyclo (4.3.0.0.) nonane, mp 270-271C hydrochloride and 80% purity endo-isomer, mp 274-276 hydrochloride 0. Example 5. Exo-8-aminomethyl-endo-8-me Iltetracyclo (4,3,0, Oz, 7) nonane hydrochloride. Exo-8-cyano-endo-8-methyltetracyclo (4.3,0,0,05) nonane (2.0 g) slow:; lithium aluminum hydride (0.6 g) in d ethyl ether (25 ml) is heated to reflux for 16 h. Excess of reducing agent is destroyed by careful addition of water. The residue is filtered off, washed well with ether, the rinses and the filtrate are combined They are dried, using anhydrous potash, and treated with an excess of hydrogen chloride dissolved in ether. One gets exo-8-amine.methyl-endo-8-methyltetracyclo (A, 3.0, O.) nonane hydrochloride, which, after recrystallization from isopropanol / ethyl acetate 425: 75 v / v), has a melting point of 245-24 b . Obtain 0.7 g of the target product (yield 26.9%). Exo-8-cyano-endo-8-metilte ratsiklo (4,3,0,02 |% 0) nonane, use (life as a starting material, can be obtained by the method of Schrauzer and R. Glockner. To obtain a clean material is necessary intensive purification by capillary chromatography, Gas-liquid chromatography showed 95% exo-nitrite, 5% endo-nitride. Example 6. Endo-8-aminomethyl-exo-8-met11ltetracyclo (A, 3.0, O ") nonane hydrochloride. Endo- 8-cyano-exo-8-methyltetracyclo (4.3.0.02., 0310nonane (80% endo-cyano-isomer, 500 mg) is reduced with lithium aluminum hydride (0.5 g) as in Example 5. An endo 8th Nomethyl-exo-8-metsh1Tetracyclo- (4,3,0 ,,) nonan hydrochloride (80% endoaminomethyl, 20% exo-aminomethyl), mp 222 ° C, Obtain 0.2 g of the desired product, (yield 31 , 9%). The endo-nitrile isomer used as a starting material was obtained in the following way. Butyl lithium (15.4 ml of a 1.43-10 G solution in tetrahydrofuran of 0.022 M) is slowly added to a solution of diisopropylamine (2.22 g, 0.22 m) in dry tetrahydrofuran (10 ml) under nitrogen at 5-10 sec and stirred for 15 min. This solution is cooled to and added to it is 8-diano-tetracyclo (4.3.0.0% 05) nonane (3.045 g 0.022 M) dissolved in hexamethanol (4.5 g). The mixture is stirred for 1 h. A solution of methyl iodide (3.55 g, 0.025 m) in dry tetrahydrofuran (5 ml) is added dropwise as well, the mixture is stirred for 1.5 hours at this temperature and then for 16 hours at room temperature. Water (20 ml) is added, the tetrahydrofuran is evaporated, and the remaining mixture is extracted with chloroform (3-15 mp). The extract is dried using anhydrous magnesium sulphate, filtered, the solvent is distilled off Kug. Chromate residue is scaled on silica gel with toluene as eluent. Endo-8-cyano-exo-8-methyltetracyclb is obtained (4.3.0.02.03.3 nonane (80% endocyano-isomer, 20% exo-cyano-isomer according to g of liquid chromatography), mp 118-120 C / 18 mm Example 7. 8- (2-aminostil) tetracyclo (4.3.0 ,,) nonana hydrochloride 8-cyanomete tetracyclo (4.3.0, ) nonane (0.5 g) is reduced with lithium aluminum hydride (0.5 g) under the conditions described in Example 5. 8- (2-aminoethyl) tetracyclo (4.3.0.0., O |) onana hydrochloride is obtained , mp 252254 C. 0.35 g of the expected product is obtained (yield 55.8%). 8-cyanomethyltetrac Clo (4.3.0.0, O) onan, using as a starting material, the following was obtained. To a solution of 8-1 bar tetracyclo (4.3, 0,, 0) nonane (87 g) in carbon tetrachloride (600 ml), phosphorus chloride (168 g) is added. The mixture is heated under reflux for 60 hours, cooled and poured into a mixture of crushed ice and water (1 l). The mixture is stirred for 30 minutes and the organic layer is separated. It is washed with a 10% aqueous solution of sodium carbonate (200 ml), an saturated saline solution (UOKP), and then dried using anhydrous potassium carbonate. The filtrate is then dried to remove the solvent, and h, then distilled to obtain 8-cyano-8-chlorotetracyclo (4, 3.02,% 03O nonane, bp 136140 ° C / 20 mm, yield 83%. The resulting chloronitrile (13.45 g) was dissolved in ethanol (60 mp), cooled, made to ice, and a solution of sodium hydroxide (2.4 g) in water (20 ml) was slowly added with stirring and cooling. Hydrogen peroxide ( 2 7 MP (29% w / v solution in water) are added dropwise and a dense belp4 precipitate is obtained. This mixture is stirred for 3 hours at 0 ° C and then 2 hours at room temperature. The linen is filtered off and preserve. The filtrate is evaporated to remove ethanol and the aqueous residue is extracted with chloroform (100 mp). The organic phase is dried, filtered and evaporated to a white solid. This solid and white precipitate are combined, recrystallized from ethanol and 8-chloro are obtained - 8-carbamoyl tetra-cyclo (4.3.0.0.0 g), nonane, mp 124-126 C. This chapramide (19.75 g) is heated under reflux under nitrogen in a mixture of potassium hydroxide (16.8 d) and h-propanol (200 ml) for 40 minutes. Propanol is boiled out and the residue is partitioned between ether (100 mp) and water (100 ml). The organic phase is washed with a brine solution (50 ml), dried using anhydrous potash, filtered, and the solvent is evaporated. The residual oil is distilled under a vacuum to obtain 8-oxotetracyclo, 4.3.0,, 0) nonane, since ip. 12I130 ° C / 29 mm. 911 Sodium hydride (2.4 g, washed from oil) is treated with dimethyl sulfoxide (100 ml) and heated under nitrogen to Ultrasonic-C for 35 minutes. The mixture is then cooled to room temperature and a solution of diethyl cyanomethyl phosphonate (17.7 g) in dry tetrahydrofuran is added dropwise. The mixture is stirred for 30 minutes. A solution of the indicated ketone (13.4 g) in a mixture of dimethylsulfoxide (100 ml) and tetrahydrofuran (100 ml), is then added dropwise and stirred in: For 16 hours at room temperature. The product is drunk in water (1000 ml and the mixture is extracted with ether (5-100 ml). The combined extracts are washed with a valuable brine, dried with. Using potassium carbonate, filtered and evaporated. Distillation under vacuum gives b-200 g of methane-tetracyclo (4.3.0 , 02, Oz. O nonan, bp G38-140 ° C / / 18 mm. This non-saturated nitrile (6.17 g) is reduced in hydrogen atmosphere at room temperature and pressure in the presence of 5 wt.% / Weight palladium. on coal (1.7 g) in ethanol solution (200 ml). When hydrogen is no longer absorbed, the product is filtered the solvent is evaporated to obtain 8-Shch1-anomethyltetracyclo (4.3.0,,) nonane, which is analyzed by mass / spectrum, infrared spectrum and NMR spectrum, this product is then used without further purification. Example 8. Endo-8- (1 -aminoethyl) tetracyclo (4.3.0,, 0) nonane hydrochloride ... To a solution of endo-8- (1-oximinoethyl-tetracyclo (4.3.0, 03) nonane (1.0) in ethanol ( 50 ml) 5% w / w rhodium on alumina (0.3 g) is added. The mixtures are hydrogenated in an autoclave at 60-65 ° C for 24 hours at a pressure of 50 atm of hydrogen, filtering the product, followed by careful evaporation l gives the endo-8- (1-s Noetus) tetracyclo (,, 4,3,0) nonane as a pale yellow masla.Hlorgid rat, m.p. 265-266.5C, upon recrystallization from isopropanol, is obtained by adding an ethereal solution of hydrogen chloride to the ethereal solution of the free base. Endo-8- (1-hydroxyminoethyl) tetracyclo (4, 3.0,, 0) nonane, using 1 as the starting material, was obtained by continuous synthesis. After obtaining exo-8- (1-hydroxyminoethyl) tetracyclo (4, 3.0.0-., 00 nonane analogously to example 3), reactionary tissues remain, which contain both exo- and endo-oxy-isomers. SUBSTANCE: samples of this material (2.0 g each) were fed for dry capillary chromatography on 1.0 kg of silica gel (kieselgel 60.0; 0.630, 2 mm particle size) using a mixture of toluene and ethyl acetate 9: 1 (w / w). The position of the separated materials on the column determined by sampling, followed by thin layer chromatography. Column zones containing pure exo- and pure endo-isomers were cut and washed separately with ethyl acetate. Evaporation of the eluates gave a total yield of pure isomers of approximately 1.2 g, but the actual exo-isomer was em from 0.8-0.2 g, and endo-0.4-1.0 g, depending on the ratio of the isomers of the sample supplied in. After separation by the above method, the exo-isomer has so pl. 103 UZ C, and the endo-isomer - 80-83 ° C. . Example 9. Exo-8- (1-aminoethyl) tetracyclo- (4.3.0,., 0) nonane hydrochloride prepared in Example 3 is a mixture of two diastereoisomes, each of which in turn is a mixture of two optical isomers. The same applies to the endo-isomer of Example 8. These diastereoisomers are defined as separate spots on thin-layer chromatography on silica gel plates using any of the two solvent systems. The spot can be seen in the solvent system 1 either by using an iodine boil or by spraying a solution of cerium ammonium nitrate in sulfuric acid, followed by heating, or in system 2 by using 1% w / v ninhydride in butanol. System 1: toluene / ethanol / ethyl acetate 7a 1miac (beats. 0.880) 6: 4: 2: 0.25 v / v. System 2: acetone / ammonia (special weight, O, 880) 40:: 0.5 v / v (see table 2). 11 g and b lc of a 4 diastereomer can also be determined by the resonance spectra of the chiral side chain atom, while the determination of the relative content of each isomer can be determined by the height of the peak. The chemical indices of the shift of each diastreomer vary depending on the concentration and type of salt, but the mixture of basic chlorohydrates obtained in Example 4 has the following indicators, see Table 3). T a b l and tg a 3 Chemical Indicators shift from tetramethylsilane mil.doli The separation of exo-diastereomers is achieved as follows. To a solution of exo-8 -. (1-aminoethyl) -tetracyclo (4.3.0.0),) conan (32.2 g) in dry ether (250 ml) is added a solution of L - () tartaric acid ( 7.16 g, €, 25 mol) in a mixture of this (100 ml) and dry ether (300 ml). The precipitate of the tartaric salt is filtered off and dried with dry ether and subjected to 9112 fractions of recrystallization from ethanol five times. The final product was pure upper exo-tartrate (9.0 g), which was converted through the base into chloro-hydrochlorine (4.3 g), m.p. which is 257-259C. Although it was not misleading that this method could be used to separate one of the optically active isomers of the deastereomer, the product indicated showed a zero rotation when tested in the polarimeter, and the NMR spectrum using an optically active reagent showed that this mixture had equal amounts of optical isomers. Adding a further portion of b (+) - tartaric acid (7.15 g, 0.25 mol) to the liquid from the first ossilane results in a sticky precipitate, which, after two fractional recrystallization from ethanol and subsequent conversion to hydrochloride, gives the pure exogenous material. spot. Recrystallization of this chlorine hydrochloride from ethanol gives a very thin yield of the first fraction (0.12 g) and the residue (1.74 g). The first fraction turned out to be optically active (oi) ° + 22 °, and according to the NMR spectrum with an optically active reagent it is a pure optical isomer. The separation of the lower exo-spot is achieved by transferring the liquid to the base from all liquids, fractional recrystallization (13.3 g in total), dissolving in dry ether (100 mp) and adding the D - (-) - mandelic acid solution (6.2 jr , 0.25 mol) in a mixture of ethanol (10 ml) and dry ether (50 mgg). The precipitated salt (14.6 g) was fractionally crystallized twice from ethyl acetate, converted into the hydrochloride and recrystallized from ethanol to obtain pure hydrochloride of the lower exo-spot (3.0 g), i.e. 266-268C. This product has zero rotation and is, according to NMR using an optically active reagent, a mixture of optical isomers. An analogue separation method was applied using the endo-amine base (10.8 g) obtained in Example 8. L - (+) - tartrate was fractionally crystallized five times from isopropanol to obtain pure top spot monohydrate tartrate
    (1.16 g), m.p. 195-205С. Residues are transferred back to the base. D - (-) mandelate is prepared in ether containing some alcohol. Three fractions were obtained. Fraction 1 is fractionally crystallized 3 times from ethyl acetate to obtain pure upper endpoint mandelate, i.e. 191192 C (0.38 g), while fractions 2 and 3 are combined and recrystallized 4 times from ethyl acetate to obtain pure lower end-spot mandelate (1.1 g), m.p. 166-167 ° C. Example 10. A solution of exo-8- (1-oximinoethyl) tetracyclo (4.3.0.0.) Nonane, obtained as in the last part of example 3, in a mixture of pyridine (35 ml) and acetic anhydride (30 ml) is heated with reflux for 48 hours. The solvent is removed under vacuum and the black precipitate is shaken with ether (portions 3-50 ml). The black solid is removed by filtration, and the filtrate is extracted with aqueous 1 (5% w / v sodium bicarbonate solution (3-20 ml). The organic phase is dried and evaporated to give a brown oil (4.3 g), which is then chromatographed on Si lycagepe using the toluene / ether system (9i1 v / v) as eluent. Fractions containing the spot material, 36 on thin-layer silica gel plates, which show up in the toluene / ethyl acetate system (9: 1 v / v) , combined and evaporated, the remaining oil is crystallized from petroleum ether, so kip. 40-60 0. So a rough solid is obtained (0.618 g), which is then sublimated to form the E-isomer-8- (1-diacetylamino) ethylene ethanethylethyclo (4.3.0.02,) nonane (0.60 g) (configuration interpreted with evaporation of petroleum ether from the mother liquor gives a colorless oil, iJoTOpoe is distilled under vacuum to obtain a z-isomer of 8- (1-diacetylamino) ethyldetrat1lo (4,3,0 ,,) nonane, t.bz- Ultrasound C (0,) (concentration, interpreted by NMR).
    The E-isomer (377 mg) is hydrogenated in the presence of platinum oxide (100 mg) in ethanol (15 ml) at room temperature and pressure. When the theoretical amount of hydrogen is absorbed, the reaction mixture is filtered and the solvent is evaporated, leaving a colorless gum. Extracting it with boiling petroleum ether (bp 60Z C) and cooling the extracts gives an amorphous white solid, mp 112-128 0, which is 8- (1-acetylaminoyl) tetracyclo (4,3,0, , 0) nonan.
    This product is subjected to hydrolysis with concentrated alcoholic caustic; w with cooling for 36 hours. After evaporation of ethanol, dilution with water, extraction with ether, drying and precipitation with ethereal hydrogen chloride solution, 8- (1-: α-amino-ethyl) tetracyclo (4, 3 , 0,, 0) h, nonana hydrochloride. This product, according to thin layer chromatography, is a mixture of a diastereomer of the lower exo-spot and a diastereomer of the lower e-spot. 0.05 g of the expected product is obtained (yield 1.1%).
    This product, obtained by cis-hydrogenation of a double bond with a known stereochemistry, allows interpretation of the absolute configuration of these two diastereoisomers. This in turn allows the interpretation of the absolute configuration of the diastereoisomer of the upper exo-spot and the upper end-spot. These interpretations are presented in table 4.
    Table 4
    sh
    Ssns
    NH,
    Absolute con4 1GuraDiastereood isomer
    8 S, 10 S and 8 R, 10 R
    8 S, 10 R and 8 R, 10 S
    8 R 10 R and 8 S, to S
    8 R 10 R and 8 S, 10 R P p and, m e p 11. Exo-8- (1-amino-ethnl) tetracyclo (, 3.02.02., 03-) nonana hydrochloride. A solution of 1.77 g of exo-8- (1-oximinoethyl) -tetradiclo (4.3, 0.02-, 0) -nonane and 4.76 g of hexahydrate-cobalt chloride in 100 ml of ethanol is treated at room temperature 3, 8 g of sodium borohydride in small portions, with stirring and cooling, to keep the temperature below 20 ° C4. After the addition is complete, the mixture is stirred at room temperature for 2 hours, then heated under reflux for 2 hours. The black slurry was filtered through diatomaceous earth and the colorless filtrate was evaporated in vacuo to leave a sticky solid. It is partitioned between ether and 2N sodium hydroxide solution. The organic phase is washed with essential brine, dried over anhydrous potassium carbonate, filtered and treated with an excess of ethereal hydrogen chloride solution. The obtained linen precipitate of exo-8- (1-amino-ethyl) -tetracyclo (4,3,0,, -non hydrochloric acid) is filtered off, washed with ether and dried. According to thin-layer chromatography, it is pure and has Rf values for two ex-diatreoisomers 6. Polutage 1.59 g of the desired product (yield 79.0%). Example 12. Exo-8- (1-aminoethyl) tetracyclo (4.3.0.0.0) nonane hydrochloride The procedure and loading of Example 7 is used with the exception that the cobalt chloride hexahydrate is replaced with nickel chloride hexahydrate and the whole reaction is carried out for 20 hours. and room temperature. The initial hydrochloric acid product shows traces of impurities that are removed by crystallization from isopropanol. This final product is pure by thin layer chromatography and has a temperature of 26 (5-267 ° C. Antiviral effect of the proposed compounds are studied as follows .. A 3-month ferret's trachea is opened using aseptic techniques and cut across into cold tissue. Get 30-40 rings from one trachea. Each ring is placed in a sterile glass test tube 1 9116 (9-1 cm) immersed in 0.5 m of sterile support medium containing an appropriate concentration of the test compound. The final concentrations of the compound are 45, 9, 1.8, 0.4, 0.08 µg / ml and zero. Three tubes are used for each concentration. The tubes are pulled out during the day at 37 ° C in a support that is gently rotated in order to immerse each tracheal ring in the nutrient medium. On the next morning, each ring is examined under a microscope to determine approximately how many cilia on the inner lumen of the ring still fluctuate. The result is the following: 1. 25% i. OcNfOTp indicates whether the compound is toxic to the ciliary epithelium. The tube is then contaminated by adding a standardized amount of influenza virus and held for 2 hours at. During this time, the virus is adsorbed on the cells and penetrates into the cells of each ring and infection begins. After 2 hours, the fluid containing the virus is drained, the rings are gently washed with fresh medium, and then 0.5 ml of the medium containing the compound is added. Then they are kept at, as well as those that are before, until the next morning, when the second inspection of the ciliated epithelium occurs. The results of the inspection of the non-female part show the toxicity of the preparation, the results of the inspection of the infected part without the preparation show the degree of damage caused by the virus, and the results of the inspection of the treatment with the preparation show the degree of protection. The medium is removed from each tube and combined with the medium from the double-sided tubes of identical preparation concentration. Combined samples are treated with 0.3 ml of sterile plasma albumin, frozen at room temperature - and stored for further titration of the virus. A fresh solution of the drug is added to each set of three tubes and the aging is continued. This process is repeated three more times so that only four portions of the medium are obtained from each reparate solution and control parts. 171 Samples of the frozen medium are thawed and the virus they contain is titrated into primary calf renal cells using the already known quantitative method of hemoadsorption by IB Fintsr. Therefore, it is possible to compare both visually and quantitatively the effect of the test compound on the growth of the influenza virus in pieces of the tracheal rheumatic epithelium. All compounds described in the examples are active in this text against influenza viruses A and A,; and some compounds are also active against the influenza A virus. Thus, all compounds are active in this test against influenza A NA at a concentration of 5 µg / lb or lower and have a toxicity ratio (activity from 9 to more than 550). The known compound 8-aminotetracyclo (4.3.0, 0., 0- |) ionane is not active against the influenza virus at a concentration of 50 µg / ml (see Table 1). The test of mouse flu in mice was carried out as follows. Two groups of 10 pathogen-free male white mice weighing 2022 g each, a tested compound was optically administered, one group of 125 mg / kg (2.5 mg / mouse) and the other group 50 mg / kg (1.0 mg / mouse). A third group of 10 mice is not treated with the compound and is used as a control group. After
    K-CH-NHz
    .0.36 SNL
    R-CH-NHz
    I3
    0.36
    CHj
    44
    and about
    44
    7110 118 two hours mice are placed individually in an aerosol chamber and subjected to aerosolization by the influenza virus for 0.5 h. An hour later after infection, and then 4 hours later after infection, mice in the first groups receive a stomatologic dose of the test. substances. The next day, the same mice receive the compound at 9 o'clock in the morning, at 13 o'clock and at 17 o'clock. 8 hours after the infection, we are killed, and the lungs are lost. The lungs from each separate group are combined into two groups of five, and after inspecting damage on the surface of the lungs, each of the 6 groups is homogenized in a mixer with a sterile saline solution Khanka a. Goms genates are centrifuged to remove scraps of tissue, and the lumps are placed in a bottle and diluted with 9 parts of bovine Guo albumin plasma. The diluted portions are then stored at a temperature until the virus concentration can be determined. The quantitative hemoadsorption method described above is measured. Thus, the growth in the virus in light animal animals treated with the preparation is compared with the growth of virus I in Mbouax not treated with the preparation. Those who receive the compounds described have no obvious signs of toxicity. The therapeutic properties of the proposed compounds are presented in table.5. Table 5
    19 Example, Compound Minimum active concentration 191I, MKr / tm
    0.36
    0.36
    0.36
    0.36
    6
    0.36
    7
    No activity at 50 µg / mp
    1156591
    20 Continued table. 5 Current
    110
    63
    63
    63 63
    No toxicity at 50 µg / ml Toxicity Activity Minimum concentration, µg / mp
    权利要求:
    Claims (1)
    [1]
    A method for producing amino derivatives of tetracyclononan of the general formula I:
    where R, is a hydrogen atom or C 1 ~ C } -alkyl,
    A — 1,2 — an ethylene group or a group of the formula —CH — R 2 , where R 2 is a hydrogen atom, CyCu — alkyl, cyclohexyl, phenyl — C, —C alkyl, 4 —C., —C t- alkylphenyl, 4 -C, -Sualkoxyphenyl or 4-chlorophenyl, moreover, with A-CH-R 2 , at least one of R and R 2 is not a hydrogen atom or their salts, characterized in that the tetracyclononane derivative of the general formula II :
    where R, has the indicated value,
    B is a methylene group or a single bond,
    X is a cyano group, a carbamoyl group or a group of the general formula III:
    B. g - CNR, where R 2 has the indicated meaning;
    R 3 is a hydrogen atom, an oxy group or a group of the formula Mg-Y, where Y is a bromine or iodine atom, with a methylene group at a value of B, a hydrogen atom at R 2 , and at least one of a single bond at a value of B and R 2 - not a hydrogen atom, subjected to reduction with sodium borohydride in the presence of cobalt chloride or nickel chloride, or with hydrogen in the presence of rhodium on alumina at a value of B is a single bond, X is a group of the indicated formula (III), where R 2 is methyl and R d is an oxy group or lithium aluminum hydride followed by! m isolation of the target product in free ide or in salt form.
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    同族专利:
    公开号 | 公开日
    NO149471C|1984-04-25|
    DD140843A5|1980-04-02|
    US4454157A|1984-06-12|
    PT68974A|1979-01-01|
    DE2861796D1|1982-06-24|
    AU4224178A|1979-06-28|
    ATA913078A|1981-02-15|
    IT7852360D0|1978-12-19|
    AU517387B2|1981-07-30|
    ES476241A1|1979-04-16|
    DK150299B|1987-02-02|
    HU177222B|1981-08-28|
    EP0002896B1|1982-05-05|
    US4357352A|1982-11-02|
    JPS5490167A|1979-07-17|
    YU303778A|1983-01-21|
    NO149471B|1984-01-16|
    JPS6214539B2|1987-04-02|
    IL56167A|1982-09-30|
    DK560278A|1979-06-23|
    NO784325L|1979-07-27|
    CA1118792A|1982-02-23|
    NZ189087A|1980-11-14|
    FI783948A|1979-06-23|
    YU40544B|1986-02-28|
    CS208769B2|1981-09-15|
    FI66347C|1984-10-10|
    FI66347B|1984-06-29|
    EP0002896A1|1979-07-11|
    AT363923B|1981-09-10|
    DK150299C|1987-10-26|
    IT1110868B|1986-01-06|
    IL56167D0|1979-03-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3418368A|1965-03-24|1968-12-24|Smith Kline French Lab|Pentacyclo[6.2.0.02,6.03,10.05,9] decaneamines|
    US3456008A|1965-10-11|1969-07-15|Smithkline Corp|Aminopolycyclodecanes|
    CH472364A|1966-12-22|1969-05-15|Geigy Ag J R|Process for the preparation of a new polycyclic amine|
    US3496228A|1967-02-16|1970-02-17|Smithkline Corp|Aminotricyclononanes and the salts thereof|ZA822158B|1980-12-30|1984-10-01|
    US4668703A|1983-07-07|1987-05-26|SyntexInc.|γ-allenyl-γ-aminobutyric acids|
    JPS63188770U|1987-05-25|1988-12-05|
    US5414011A|1987-09-11|1995-05-09|SyntexInc.|Preservative system for ophthalmic formulations|
    US6150398A|1991-05-08|2000-11-21|The United States Of America As Represented By The Department Of Health And Human Services|Methods for the treatment of cancer|
    US5645988A|1991-05-08|1997-07-08|The United States Of America As Represented By The Department Of Health And Human Services|Methods of identifying drugs with selective effects against cancer cells|
    US20030225044A1|2002-06-03|2003-12-04|Bachman Stephen E.|Method to increase serum levels of vitamins in animals including humans|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB5344677|1977-12-22|
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