• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Compounds of formula I <IMAGE> in which n=0 or 1; R1 is C1- alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, cycloalkylalkyl or optionally substituted phenyl when n=0 or R1 is H or C1-3 alkyl when n=1, R2 is H or C1-3 alkyl, R3 and/or R4 are H, formyl, C1-3 alkyl, C3-6 alkenyl, C3-6 alkynyl, C3-7 cycloalkyl or R3 and R4 together with the nitrogen atom form a heterocyclic ring system; R5 and/or R6 are H, halo, CF3, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio or R5 and R6 together with the carbon atoms to which they are attached form a second benzene ring and R7 and/or R8 are H or C1-3 alkyl show therapeutic activity in the treatment of depression. Pharmaceutical compositions and processes for preparing compounds of formula I are disclosed.
    公开号:SU1461372A3
    申请号:SU853834158
    申请日:1985-01-09
    公开日:1989-02-23
    发明作者:Эдвард Джеффри Джеймс；Козлик Антонин；Чарльз Вилмшерст Эрик
    申请人:Дзе Бутс Компани, П.Л.С. (Фирма)；
    IPC主号:
    专利说明:

    one ;
    This invention relates to a process for the preparation of new compounds of (1-arsh1-cyclobutyl) -alkylamines possessing antidepressant activity of the general formula
    R ,, CHRi (CHR2.) NNHo
    Ofa
    R

    s
    where n o or 1, and when n o
    R is C-C-alkyl, C-cycloalkyl or phenyl; when n is 1, R is hydrogen;
    RI and R together with the phenyl ring form 4-chlorophensh1, 3-chloro-5-methylphenyl, 3, A-dichlorophenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 4-bromofvnil, Z-chloro- 4-methylphenyl, 2-naphthyl, 4-fluorofensh1 or 4-biphenyl;
    Rj - with, -C-alkyl, and also covers the pharmacologically acceptable salts of these compounds.
    The aim of the invention is to develop a method for producing new (1-α-aromatic cyclobutyl) -alkylamines, about benefits that provide antidepressant activity and at the same time do not possess tyramine inhibitory activity.
    Example 1. A solution of chlorobenzyl cyanide (10 g) and 1,3-dibromopropane (7.5 ml) in dry dimetip sulfoxide (12 ml) is added dropwise under nitrogen to water (60 ml) and water layer is extruded with toluene. The tsuluol bases are washed with water, dried and evaporated to give a residue, which is dissolved in methanol (50 ml). Add: 6N hydrochloric acid (5 ml), the solution is filtered and ground. Rubbing with anhydrous acetone gives
    10 hydrochloric acid o (-1- (4-chlorophenyl) cyclobutyp benzylamine (mp 277-279 ° C).
    Example 2. A solution of tilmagnesium bromide is crawled by adding 15 isobutyl bromide (99 g), in ether (150 ml) under nitrogen, to a stirred mixture consisting of magnesium chips (18 g) and ether for 1 h 45 min. Otecb
    20 is heated for 30 minutes with reverse linen; the ether is replaced by toluene (300 mi) and a solution of 1- (4-chlorofensh1) -1-cyclobutanecarbonitrile (97.2 g, prepared as in
    Sewing a mixture of sodium hydride (3.6 g), 25 Example 1) in water (60 ml) is added in toluene (60 ml) and the aqueous layer is extracted with toluene. The tsuluol bases are washed with water, dried and evaporated to give a residue, which is dissolved in methanol (50 ml). Add: 6N hydrochloric acid (5 ml), the solution is filtered and ground. Rubbing with anhydrous acetone gives
    hydrochloric acid o (- 1- (4-chlorophenyl) -cyclobutyp benzylamine (mp. 277-279 ° С).
    Example 2 A solution of tilmagnesium bromide is crawled by adding isobutyl bromide (99 g), in ether (150 ml) under nitrogen, to a stirred mixture of magnesium chips (18 g) and ether for 1 h 45 min. Otecb
    The mixture is heated for 30 minutes with reverse canvas; the ether is replaced by toluene (300 mi) and a solution of 1- (4-chlorofensh1) -1-cyclobutanecarbonitrile (97.2 g, prepared as in
    example 1) in toluene (60 ml) add
    dispersed in mineral oil (3.6 g) and dimethyl sulfoxide (70 ml) at a temperature of 30–35 ° C. Oiecb is stirred at room temperature for 2 hours and then propan-2-ol (10 ml) is added dropwise and water (150 ml). The mixture is filtered through solid diatomaceous earth celite; and then the solid residue is flushed:
    thirty
    they are added to the isobutylmagine tribromide solution prepared as indicated. The reaction mixture is heated to a temperature of about 90 seconds for 19 hours and then cooled. A suspension of sodium borohydride (30 g) in ethanol (750 ml) is added dropwise over 1 hour and 45 minutes. Reaction mixture
    The reaction is carried out at 70 ° C. for 2 hours and then with ether. The resulting extract-: ethanol (580 ml) filtrate is removed by evaporation with ether, and the ether extracts are blended, washed with water, dried and evaporated. 1- (A-chlorophenyl) -1-cyclobutanecarbonitrile (m.p. 116 -;; 120 C at 0.6 mm Hg) is obtained, separated by distillation.
    FacTBOp bromobenzene (15.7 g) in ether (50 ml) is added dropwise with cooling to magnesium chips (2.4;) under nitrogen atmosphere to form a solution of phenylmagnesium bromide-1, a solution of 1- ( 4-chlorophenyl) -1- -cyclobutanecarbonitripe (19.1 g), obtained in the same way as .; described to obtain | 1- (3,4-dichloro-: phenyl) -cyclobutanecarbonntril, and the ester is replaced with anhydrous toluene; (130 ml). The reaction mixture is heated on the steam bath for 1 hour. A sample (20 ml) of the solution obtained is added to a solution of sodium borohydride (1 g) in diethyl stylenoldimethyl ether (60 ml) and the mixture is stirred for 1 , 5 h. Slowly drbav-t40
    eat. Water (70 ml) is added, and then after 16 hours, concentrated hydrochloric acid (200 ml) is added dropwise. The toluene layer of the reaction mixture is dried and the solvent is removed, resulting in a residue that is mixed with from ether and petroleum ether (m. bale. 40-60 s) and 16-aqueous growth; 45 thief sodium hydroxide. The organic layer is washed, dried and evaporated with; the resulting (4-chloro; phenyl) cyclobutip; 1 -3-methylbutylamine (bp 124-128 C at 0.2 mm Hg
    The primary amine (102.7 g) and 98% formic acid (310 ml) are mixed with ice cooling and a 37-40% aqueous solution of aldehyde forms (123 ml) is added. Laugh .. warm up
    55 to 90-100 seconds for 16 hours, then cooled and poured into a mixture of ice (500 g) and 16 N, an aqueous solution of sodium hydroxide (250 ml). The product is extracted with ether and extra
    50
    are added to a solution of isobutylmagine bromide and prepared as indicated. The reaction mixture is heated to a temperature of about 90 seconds for 19 hours and then cooled. A suspension of sodium borohydride (30 g) in ethanol (750 ml) is added dropwise over 1 hour and 45 minutes. Reaction mixture down
    is kept at 70 ° C for 2 hours and then: ethanol (580 ml) is removed by evaporation.
    eat. Water (70 ml) is added, and then after 16 h, concentrated hydrochloric acid (200 ml) is added dropwise. The toluene layer of the reaction mixture is washed, dried and the solvent is removed from the floor; as a result of the residue, which is mixed with a mixture of ether and petroleum ether (m.p. 40-60 s) and 16-water plant; Sodium hydroxide thief. The organic layer is washed, dried and evaporated with; the resulting (4-chloro; phenyl) cyclobutyl; 1 -3-methylbutylamine (kip. 124-128 C at 0.2 mm Hg),
    The primary amine (102.7 g) and 98% formic acid (310 ml) are mixed; sew under ice cooling and add a 37-40% aqueous formaldehyde solution (123 ml). Laugh .. warm up
    to 90-100 seconds for 16 hours, then cooled and poured into a mixture of ice (500 g) and 16 N, an aqueous solution of sodium hydroxide (250 ml). The product is extracted with ether and extra
    Kty washed, dried by evaporation to obtain as a result of N, N-flHMeTmi--1-C1- (A-chlorophenyl) -cyclobutyl-3- -methyl butylamine (t. 53-55 0. Example 3. Solution 1- (3 - gchlor-5-metsh1fensh1) -1-cyclebutane-. carbonitrile (8.0 g), obtained as in example 1, in ether (40 ml) is added to a solution of bromopropipmagnesium, obtained by the reaction of 1-bromopropane ( 6.7 g) and magnesium (1.3 g) in ether (80 ml), and the mixture is heated under reflux for 2.5 hours
    Two thirds of the ether is evaporated, and then after cooling to 30 seconds, a solution of sodium borohydride (3.5 g) in ethanol (150 mp) is added. The mixture was stirred for 1 hour, and then water (50 ml) was added and then 5 K. hydrochloric acid (50 ml) was added. The ether layer is separated, dried and evaporated to give a solid, which is recrystallized from propan-2-aol, to give the hydrochloride
    1-U (3-chloro-5-methylphenyl) -cyclobutylZbutylamine (mp 145-14b s). ; The hydrochloric salt, obtained as indicated, is shaken with efit rum and with a 5N solution of sodium hydroxide, then the ether layer is discharged, crawling the primary amine, which is converted to hydrochloric. : N, N-dimethyl-1-G1- (3-chloro-5-methylfe-: nyl) -cyclobutyl butylamine (m.p.,: 148 C) as in Example 2.
    Example 4. A solution of methyl-: bromide (173 g) in ether (800 ml) is added to: stir to a mixture consisting of magnesium chips (45 g) in anhydrous ether under a nitrogen atmosphere. Oiecb is stirred without external heating for 30 minutes and then a nitrogen solution consisting of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile is added under nitrogen atmosphere;
    XJ40 g) in ether (400 ml). ;. The Ckecb is heated under reflux: for a period of 20 hours, the precipitate is formed, which is then separated by filtration, washed and dried. The solid precipitate is mixed with ethanol; (1000 ml) and sodium borohydride
    (70.6 rj, which is added in portions under nitrogen for 1 hour,
    The resulting mixture was stirred for 2 hours and then acidified by the addition of concentrated hydrochloric acid while cooling with ice. Volume of
    si is reduced by about half by evaporation and then successively
    add 12 N hydroxide solution
    sodium (50 ml), water and ether. The resulting mixture is then filtered and the ether layer is separated, which is washed and dried. After removal of the solvent, an oil is obtained which is purified by distillation (134-138 s at 0.8 mm Hg), to obtain (3,4-dichlorophenyl) -cyclobutyl -e-typeamine. Example 5. A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane (153 ml) in dry dimethyl sulfoxide (150 ml) is added dropwise in a nitrogen atmosphere, to the stirred mixture, consisting sodium hydride (7.5 g) dispersed in mineral oil (7.5 g) and dimethyl sulfoxide (200 ml) at 30-35 ° C. The mixture is stirred at room temperature for 2 hours and then added dropwise propan-2-ol (0.8 ml) and then water (ml ml). Oiecb is filtered through solid diatomaceous earth like celite and the resulting solid residue is washed with ether. Solve the ether, rinse with water, dry and dry. 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitg is semitched; Ril t. Kip. 108-120 ° C at 015 mm ryl (m.p. 108 - at 0.15 mm Hg), which is separated by distillation.
    A solution of 1- (3,4-dichlorofensh1) -1-cyclobutanecarbonitrile (70 g) in manufactured methylated alcohol (200 ml) is stirred with a solution of sodium hydroxide (3.7 g) in water (5 ml) and added dropwise 30% hydrogen peroxide solution. The mixture is heated to 1 h, and then stirred with 10% palladium applied on activated gamma. Vanilla coal (0.5 g) is filtered for 1 h. and quenched to dryness to obtain 1- (3,4-dichlorophenyl) -1-cyclobutanecarboxamide.
    1- (3,4-Dichlorfensh1) g of 1-cyclobutane-arboxamide is dissolved in dioxane (500 ml), concentrated hydrochloric acid (100 ml) is added dropwise and then a solution of nitrite (35 g) in water (80 ml) The mixture is heated to 85 - 95 seconds for 16 hours and then poured into water. The mixture is structured with ether and the obtained extract is re-extracted with an aqueous solution of potassium carbonate. The basic extract is washed with ether and acidified with concentrated hydrochloric acid to give 1- (3, A-dichlorophenyl) -1-cyclobutanecarboxylic acid (t pp. 120-121 c).
    A solution of 1- (3,4-dichlorophenyl) -1-Gdblicobutanecarboxylic acid (64 g) in tetrahydrofuran (780 ml) is added dropwise under nitrogen to a mixed suspension consisting of lithium aluminum hydride (5%) and tetrahydrofuran (95%). The mixture is filtered through celite diatomaceous earth and the product is extracted in ether. After washing with water and drying, the ether is distilled off to obtain 1-C 1- (3,4-dichlorophenyl) cyclo type J-methyl alcohol (t. pl. 60-62 C). A solution of 1-G1- (3,4-dichlorophenyl) -. . -cyclobutyl methyl alcohol (64 g) in pyridine (47 ml) was added dropwise to a solution of para-toluenesulfonyl chloride (54.4 g) in pyridipum (91 g) while cooling with ice. As a result of the reaction, the temperature will rise to room temperature and remain at that level for 18 hours. By pouring the reaction mixture into a mixture consisting of ice and concentrated hydrochloric acid, 1-fl- (3,4-dichlorophenyl a) for another 2 hours. Filtering the methyl 1-1- (3,4-dichlorophenyl) -cyclobutyl-2-butanimine-magnesium bromide and a sample of the solid (about 1 g) is added to a solution of sodium borohydride (3 g ) in diethylene glycol-di-ethyl ether (30 ml). The mixture is moved at 45
    10 within 90 min. The reaction mixture is extracted with 5N hydrochloric acid. The aqueous phase is alkalinized with aqueous solution of sodium hydroxide and extracted with ether, the ether extract with
    15 hrsht and gaseous hydrogen chloride are passed into it to precipitate hydrochloric 1- {G1- (3,4-dichlorophenyl) -cyclobutyl methyl-propyl amine (mp 223-224 C).
    20 Approx. Using a similar procedure, except for the fact that the reduction with sodium boro greennd was carried out in methanol, 2-and- (4-chloro-3-three
    25 fluoromethyl) -cyclobutyl -1-methylethamyl-w-hydrochloride having m.p. 178-182 C.
    Example 7. A solution of 1- (3,4-β-dichlorophenyl) -1-cyclobutanecarbonite 30 roil (21.1 g) of the obtained in accordance with the procedure analogous to example 5 in ether (50 ml) is added to a solution of propyl magnesium MFA obtained by adding
    -cyclobutyl methyl-para-toluene sulfo-5 solution of propyl bromide (17.6 g) in
    nat with so pl. 99-100 C.
    ,;, j .. Solution 1-Г1- (3,4-dichlorophenyl) -. -cyclobutyl methyl p-toluenesulphonate (116.5 g) and sodium cyanide (18.2 g) in dimethylsulfoxide-SO ml) are heated on a steam bath for 18 hours. The mixture is then poured into water and
    , - ;; extracted with ether. After flushing the NIN and drying the ether by evaporating JoT with semi-ether (25 ml) to a stirred mixture consisting of magnesium chips (3,) and ether (50 ml). The mixture was heated under reflux for 30 minutes and then the ether-solvent was replaced by toluene (75 ml). The reaction mixture is then heated to 105-110 ° C for 1 hour and after cooling to
    during
    by c. the resulting solid residue, 45 to 25 seconds, is added to the reaction mixture.
    sodium borohydride suspension (8 g)
    representing 2-Cl- (3,4-dichlorophenyl) -cyclobutyl-acetonitrile. A solution of 2-Cl- (3,4-dichlorophenyl) -cyclobutyl-7-acetonitrile (23 g) in dry ether (50 mp) is added to a solution of bromoethyl magnesium obtained by adding dropwise ethyl bromide (15.83 g) in anhydrous ether ( 80 ml) to a stirred mixture of magnesium streamers (3.53 g). The mixture is heated under reflux for 30 minutes and stirred without additional heating for 16 hours and then under reflux.
    55
    ethanol (400 ml) and the mixture is stirred under reflux for 3 hours. The mixture is cooled, water is added (200 ml) and then acidified with 5N hydrochloric acid. An aqueous solution of sodium hydroxide and sodium organic solvents are added. The residue is cooled and extracted with ether. The ether extract is washed, dried, and then g is passed through it: gaseous hydrogen chloride. Next, the extract is evaporated to dryness to give a resultant
    for another 2 hours. Collect 1-1- (3,4-dichlorophenyl) -cyclobutyl-2-butanimine magnesium bromide by filtration and add a sample of solid (about 1 g) to a solution of sodium borohydride (3 g) in diethylene glycol-di-ethyl ether (30 ml). The mixture is moved at 45 ° C.
    within 90 min. The reaction mixture is extracted with 5N hydrochloric acid. The aqueous phase is made alkaline with an aqueous solution of sodium hydroxide and extracted with ether, the ether extract is dried.
    HSR and gaseous hydrogen chloride is passed into it to precipitate hydrochloric 1- {G1- (3,4-dichlorophenyl) -cyclobutyl methyl-propyl-amine (mp 223-224 C).
    Example Using a similar procedure, except that the reduction with sodium boro gndride was carried out in IU. to tanol, 2-i- (4-chloro-3-trifluoromethyl) -cyclobutyl -1-methylethipamyl-1 hydrochloride is obtained, having m.p. 178-182 C.
    Example 7. A solution of 1- (3,4-β-dichlorophenyl) -1-cyclobutanecarbonitrile (21.1 g) of the solution obtained in accordance with the procedure analogous to example 5, in ether (50 ml) is added to a solution of propylmagnesium bromide obtained by adding
    propyl bromide solution (17.6 g) in
    ether (25 ml) to a stirred mixture consisting of magnesium chips (3,) and ether (50 ml). The mixture is heated under reflux for 30 minutes and then the ether-solvent is replaced by toluene (75 ml). The reaction mixture is then heated to 105-110 ° C for 1 hour and after cooling to
    during
    25 seconds to the reaction mixture is added
    0
    five
    ethanol (400 ml), and the mixture is stirred under reflux for 3 hours. The mixture is cooled, add -. Water (200 ml) was added and then acidified with 5N hydrochloric acid. An aqueous solution of sodium padroxide is added and the organic solvents are added. The residue is cooled and the extract: simple ether. The ether extract is washed, dried, and then through non-. go g: azobrazny chlorinated hydrogen. Next, the extract is evaporated to dryness to obtain as a result 1-P- (3,4-dichlorophenyl) -CIC lo butyl butylamine hydrochloride with m.p. 200-201 €.
    Example 8. From isobutylbromide (16.44 g) and magnesium shavings. (2.88 g) in ether (55 ml) is prepared with a solution of isobutyl magnesium bromide. The ether is removed by distillation and at the same time a solution of 1- (4-methoxyphenyl) -1-cnc-lobutanecarbonitrile (15 g), prepared in accordance with a procedure similar to that described in Example 1, is added while preparing 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile, in toluene (60 ml). The mixture is heated on a steam bath for 16 hours. After cooling, toluene (60 ml) and a suspension of sodium borohydride (4.79 g) in ethanol (125 ml) are slowly added to this mixture. The temperature of the mixture is increased to 70 ° C during the addition of the indicated components, the mixture is heated under reflux for 90 minutes. Ethanol is evaporated. After cooling, water (10 ml) was added dropwise, and then a mixture of concentrated hydrochloric acid (32 ml) and water (32 ml) was added, and the mixture was stirred for 1 hour. The organic phase of this mixture was washed with aqueous sodium hydroxide solution, dried and the solvent is removed by evaporation. The residue is distilled to give -fl- (4-methoxy-phenyl) -cyclobuty-3-methylbutyiamine with m.p. 124-1270С at 0.2 mm Hg.
    Example 9. 1- (4-Bromophenyl) -cyclobutyl (cyclopropyl) methylamine with t. Kip. 136-140 ° C at 0.1 mm Hg are prepared according to the indicated procedure with the exception that the product is separated from the aqueous phase of the reaction mixture.
    Example 10. A solution of butyl magnesium bromide is prepared from butyl bromide (6.25 g), magnesium; chips (1,135 g) and simple., ether (10 ml). The ether is then removed by evaporation and the cyxi is replaced by toluene (20 ml), a solution consisting of 1- (4-chlorofensh1) -1-cyclobutane-carbonitrile (6.13 g) in dry toluene (5 ml) is added. . The mixture was stirred and heated on a steam bath for 18 hours, after which the mixture was cooled to room temperature and the suspension consisting of sodium borohydride (1.89 g) in an absolute volume was slowly added.
    alcohol (50 ml). During the addition, the reaction temperature increased from 30 to 65 ° C, after which the mixture was gently heated under reflux for 2 hours and 30 minutes, the alcohol was distilled off and the residue was cooled, and at that time a mixture of concentrated hydrochloric acid (12.5 ml) and water (2.5 ml) is added dropwise. After stirring for 30 minutes, the toluene layer is separated and the aqueous phase is extracted from ether. Next, the toluene phase and the ether phase
    15 ras are put together, rinsed with water and alkalinized. The product is extracted with ether and the extracts are watered with water, dried and blown-off as a result of 1-H1- (4-chloro-20-phenyl) -cyclobutyl pentylamine.
    (4-Chlorophenyl) -cyclobutyl pentopamine is converted to N, N-dimethyl-l- (4-chlorophenyl) -cyclobutyl 1 penta 1-amine hydrochloride with m.p. 182-184 C, 25 as a result of the reaction between the specified amine, formaldehyde and formic acid in accordance with the method indicated in example 2.
    Example 11. A solution of 1- (3-30-chloro-4-methylphenyl) -1-cyclobutanecarbonitrile (7.4 g) in dry ether (400 ml) is added dropwise to a stirred solution of propyl magnesium bromide prepared by add 35 propshtbromid (6.2 g) in dry ether (10 ml) to magnesium chips (1.2 g) in dry ether (80 ml) at room temperature. The solvent is replaced with anhydrous toluene and the mixture is heated 40 on a steam bath for 2 hours. The solvent is then evaporated in vacuo to a small volume and ethanol (50 ml) is added. The stirred mixture is treated with a suspension consisting of 5 ns sodium borohydride (3.22 g), in absolute ethanol (100 ml) at room temperature. The mixture is heated to 50 ° C for 1 hour, then cooled, treated with water (30 ml) and 5N-hydrochloric acid (30 ml). The resulting solution is extracted with ether, washed with water, dried and ground until the oil is obtained. This oil is dried by repeated azeotropic distillation with propan-2-Ol to obtain
    as a result, 1-f1- (3-chloro-4-methylphenyl) -cyclobutyl butylamine hydrochloride having a m.p. more than 300 s, k (this is converted into H, H-dnmethyl-1-Cl - (3-chloro-4-methylphenyl} -cyclobutyl butylamine hydrochloride, having a melting point of 225-226 Cf by the reaction of the hydrochloride with formaldehyde and - rabia acid in accordance with the method similar to that specified in example 2.
    Example 12 Metnmagnium bromide is prepared by bubbling gaseous methyl bromide through a mixture consisting of magnesium chips (0.65 g) in dry ether (15 ml). Once the entire amount of magnesium is dissolved, the half-awn mixture, together with 1- (2-naphthyl) -1-cyclobutanecarbonitrile (3.9 g) in anhydrous ether (50 ml), is heated under reflux for 4 hours. monitored using thin layer chromatography. In order to complete the reaction, an additional amount of methylmagnesium bromide obtained from gaseous methyl bromide, magnesium C0.65g} in dry, m ether (20 nl) is added, and the reaction mixture is heated under reflux for 3 hours. A solution of borohydride is added sodium (3 g) in absolute ethanol (150 ml) and the mixture is heated with a reflux for 3 hours. After cooling, water and hydrochloric acid are added, and ethanol is removed by welding. The residue is washed with pro-. ether and alkalinize. The resulting basic solution is extracted with ether and the extract is dried. A gaseous, hydrogen chloride is passed through the dried extract, after evaporation, 1-E1- (2-naphthy1) cyclobutyl} eth1amine hydrochloride is obtained. 208-212 0.
    EXAMPLE 13 Isobutyl magnesium bromide is obtained by adding dropwise isobutyl bromide (15.34 g) in dry ether (20 ml) to a stirred mixture consisting of magnesium chips (2–9 g) in dry ether (20 ml).
    After the entire amount of magnesium is dissolved, a solution consisting of a 1- (4-fluorophenyl) - cyclobuy arb-nitrile tank (14.0 g) in dry ether (20 ml) is added to the mixture. The ether was removed by stripping and at the same time replaced with dry toluene (50 ml) until the temperature became 110 ° C. The resulting mixture is stirred.
    with heating under reflux for 2 hours, and then a solution of sodium borohydride (5.0, t) in absolute ethanol (200 ml) is added and the resulting mixture is heated under reflux for 2 hours. After cooling the mixture, water (50 ml) and the solution is acidified with 5N hydrochloric acid. Excess ethanol is removed by evaporation. The resulting solution is extracted with ether, the extract is then washed and dried. Then the hydrogen chloride gas is passed through the extract, which is evaporated to dryness to obtain in After solidification from petroleum ether, it has a boiling point of 60-80 s and is 1- (4-fluorophenyl) -cyclobut-1-3-methyl butylamine hydrochloride, melting at 203-210 ° C.
    Example 14. A solution consisting of isobutyl bromide (3.16 g) in dry ether (20 ml) was added dropwise to the stirred suspension,. consisting of magnesium shavings (554 mg) in dry ether, S20ml} under nitrogen. Stir for 30 minutes. The ether was removed by distillation, and dry toluene (30 ml) was added dropwise, then a solution consisting of 1- (4-biphenylyl) -1-cyclobutanecarbonitrile (5.0%) was added dropwise over 30 minutes. g) in dry toluene (50 ml). After the addition is complete, the reaction mixture is stirred and heated on a steam bath (up to 90 ° C) for 68 hours. The mixture is cooled before and a solution consisting of sodium borohydride (1.2 g) in absolute ethanol (60 ml) is added in portions. . The mixture is stirred for 1 hour without heating after reaching the temperature of the oven, equal to, and stirring is continued for 3 hours. The mixture is cooled until it is added, water (10 ml) is added dropwise and the mixture is left to stand overnight. After cooling, concentrated hydrochloric acid is added dropwise with stirring. The toluene layer is separated, the aqueous layer is extracted with ether. Then the organic layer is combined, washed with water and dried. The dry extract is concentrated to give an orange oil as a result.
    13
    which is mixed with a mixture consisting of ether (100 ml), petroleum ether (100 ml), having a boil. AO-C C and 5N sodium hydroxide solution (OO ml) for 1 hour. The ether layer is separated and the aqueous layer is extracted with ether. The ether layers are combined, washed out and in place. As a result of the removal, the solvent gives a creamy solid residue, which is distilled at 174 and a pressure of 0.5 mm Hg. The result is a fraction that is dissolved in 50 ml of ether and added to the solution consisting of maleic acid. (1.31 g ,:
    0.011 mol) in ether (100 ml), the solution is cooled to obtain a solid product, which is filtered off, washed with ether and dried in vacuo. The result is 1-Gl- (4-bifenilshI) -cyclobutnl-3-methylbutylamine maleate, having so pl. 135-138 €
    Example f5. A solution of isobu type magnesium bromide is obtained from isobutyl bromide (12.95 g), magnesium (2.3 g) and dry ether (50 ml). A solution consisting of 1- (2-naphthyl) -1-cyclobutanecarbonitrile (13.05 g) in dry toluene (30 ml) is added dropwise and at the same time the ether is distilled off. The resulting mixture was stirred at 95 ° C for 18 hours, cooled to room temperature, and then a suspension consisting of sodium borohydride (4.0 g) in absolute ethanol (125 ml) was slowly added. After the addition is complete, the resulting mixture is heated under reflux for 3 hours. After settling at room temperature for 2 minutes, the residue is cooled to room temperature. A mixture of concentrated hydrochloric acid (50 ml) and water (50 ml) is then added dropwise, and the product obtained is extracted with simple rum. The ether extracts are combined, precipitated on ice and alkalinized with 16N sodium hydroxide solution. The phases are separated and the aqueous layer is extracted with ether. The extracts are combined with a separated organic layer. rinse with water, dry and extrude to obtain an oil that is 14-160 ° C
    and pressure
    NI at 143 0.4 mm Hg.
    Hydrogen chloride gas g is bubbled through a solution consisting of 3 g of oil in dry ether. The solvent is removed by evaporation to give a white solid, which is dissolved in water, and then 10% concentrated hydrochloric acid is added. The solid precipitate, which crystallizes upon cooling, is collected and dried in vacuum at 60 C. Out of 2.7 g. This product is recrystallized from gasoline having m.p. 60-80 ° C, using hot filtration, which allows to obtain 1- E (2-naphthyl) -cyclobutyl-3-methyl-butylamine hydrochloride, having mp. (decomposition) and softened at.
    Example 16. A solution of isobutyl magnesium bromide is obtained from isobutyl bromide (21.78 g), magnesium chips (3.9 g) and dry ether (30 ml). The ether is distilled off and at the same time replaced with toluene (100 ml) until the temperature in the upper part of the apparatus 30 becomes equal. A solution of 1- (4- -bromophenyl) -1-cyclobutanecarbonitrile (25 g) in dry toluene (20 ml) to the hot mixture. The mixture thus obtained is stirred at reflux for 1.5 h. The mixture is then cooled to room temperature. A suspension of sodium borohydride (6.6 g) in absolute ethanol (170 ml) is added slowly and the mixture is held under nitrogen for 2 days and then heated under reflux for 2 hours, the mixture is cooled and a mixture consisting of ethanol is added dropwise to it; g 3 of concentrated hydrochloric acid
    20
    25
    (50 ml) and water (50 ml), and ethanol is removed by distillation. After cooling, the layers are separated and the aqueous phase is extracted with ether. Extracts
    50 is middle with the separated toluene phase, cooled in ice water and stirred together with 16N sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with ether. All organic phases are combined, washed with water, dried and evaporated to give a yellow oil, which is purified by distillation. Coy with 133 - and pressure

    14 - 160 ° С
    and pressure
    NI at 143 0.4 mm Hg.
    10 15
    20
    30 35 0 g
    25
    Example 16. A solution of isobutyl magnesium bromide is obtained from isobutyl bromide (21.78 g), magnesium chips (3.9 g) and dry ether (30 ml). The ether is distilled off and at the same time replaced with toluene (100 ml) until the temperature in the upper part of the apparatus 0 becomes equal. A solution of 1- (4- -bromophenyl) -1-cyclobutanecarbonitrile (25 g) in dry toluene (20 ml) to the hot mixture. The mixture thus obtained is stirred at reflux for 1.5 hours and then the mixture is cooled to room temperature. A suspension of sodium borohydride (6.6 g) in absolute ethanol (170 ml) is added slowly and the mixture is held under nitrogen for 2 days and then heated under reflux for 2 hours, the mixture is cooled and a mixture of g 3 concentrated hydrochloric acid is added dropwise to it
    (50 ml) and water (50 ml), and ethanol is removed by distillation. After cooling, the layers are separated and the aqueous phase is extracted with ether. Extracts
    The mixture is middle with the separated toluene phase, cooled in ice water and stirred together with 16N sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with ether. All organic phases are combined, washed with water, dried and evaporated to give a yellow oil, which is purified by distillation. Coy with 133 - and pressure
    0.2 mm Hg. The result is a fraction that is dissolved in 200 ml of ether. Hydrogen chloride gas is bubbled through this solution. The solvent is removed by evaporation in vacuo to give a white foam, which is dried by azeotropic distillation with propan-2-ol. The residue obtained is triturated with an insignificant amount of dry ether and a colorless solid is obtained, which is dissolved in hot water. "The solution is diluted to an insignificant volume and dissolved on ice to obtain l-f2-4-bromophenyl -cyclobuch-3-metsh1butsh1amin hydrochloride having so pl. .
    EXAMPLE 17 A solution consisting of isobutyrate bromide (29.45 g) in ether (30 ml) is added to a stirred mixture consisting of magnesium (5.15 g) and ether (20 ml). ml) After 1 h, a solution consisting of 1- (3,4-dihzh rfeip-1-cyclobutanecarbonitride C35.8 g) in ether (30 ml) is added. The ether is replaced by toluene (100 ml) and the mixture thus obtained is heated under reflux for 2 hours. Next, propa-2-ol (20 ml) is added, and then a suspension consisting of sodium borohydride (6 g) in propane-2-α-olene (125 ml), and the resulting crtecb is heated under reflux hV for 3 hours. Next, water is added, and then an excess amount of hydrochloric acid is added. The aqueous layer was washed with ether. the stretch and the organic phase are combined, su
    The boil and solvent are removed by evaporation. The residue is taken up in ether and the resulting solution is filtered. After removal of the ether by distillation, a residue is obtained, which is extracted with petroleum ether having a boiling point of 40-60 0. After removing the solvent, a pale yellow color solid is obtained, which is dissolved in a dilute sodium hydroxide solution. The aqueous solution is extracted with ether and the extract is mixed with an ester; solution of maleic acid. The result is 1-G1- (3,4-dichloro fensh1) -schsobutsh1 -3-methylbutyramine: maleate, having so pl. 153-154 C.
    The compounds obtained by the proposed method have antidepressant activity, which is defined as follows.
    The male strain of Charles River GDI weighing 18–30 g is divided into groups of five mice and they are filled with food and water. After 5 h, measure
    Oral body temperature of each mouse is administered intraperitoneally reserpine (5 mg / kg) in solution in deionized water containing ascorbic acid (50 mg / kg). The amount of injected fluid is 10 mg / kg of live weight. % cuts 9 h after the start of the experiment, feeding is stopped, but the water continues to be filled. 24 hours after the start of the experiment, the temperature of the mice was measured and the mixture was given a test compound suspended in a 0.25% solution of hydroxyethylcellulose in deionized water at a dose volume of 10 ml / kg body weight. For 3 hours, the temperature of the mice is measured again. Then calculate the percentage of recovery caused by reserpine decrease in body temperature 1 1.
    Calculate the average value for each group of five at various doses in order to estimate the value of the average dose that causes a 50% reduction (EDj-o). All compounds give an ED value of about 30 mg / kg, with these values showing no signs of toxicity.
    The known compound of 1-phenyl-2-α-aminocyclo-propane, which also has antidepressant activity, simultaneously acts as a tyraminase inhibitor (MAOI), which leads to side effects and the inability to use this compound for the treatment of pain in oppressed states.
    The proposed compounds do not possess tyraimiaz inhibitory activity.;
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining (1-arylcyclobutyl) -alkylamines of General formula (CHR2)
    ti.
    where n o or 1, and when n o
    R / - C, -C-alkyl, Cj-cycloalkyl or phenyl; when n is 1, R is hydrogen;
    R and R together with the phenyl ring form 4-chlorophenyl, 3-chloro-5-methyphenyl, 3,4-dichlorophenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 4-bromophenyl, 3-chloro-4- methylphenip 2-naphthyl, 4-fluorophenyl or 4-biphenig; .
    Ri - С, -С-alkyl ,;
    or their pharmacologically acceptable salts, characterized in that the carbonitrn of the formula
    (CHRi)
    where R, Rj, R and p have the indicated
    meanings
    interact with the reactive author L. Ioffe Editor O. Yurkovetskaya Tehred L. Oliynyk Proofreader c. Girn to
    Order 548/59
    Circulation 352
    VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab., D. 4/5
    Production and publishing plant Patent, Uzhgorod, st. Gagarin O
    BOM Grignard formula or RjrMgBr, where R and R have the indicated values, in the medium of ether or toluene at room temperature to the boiling point of the solvent to form a compound of the formula
    ten
    five
    where Z is a radical of the formula CRi NMgBr or CHR CRi NMgBr, where R, R, R c R have the indicated values, which are reduced with sodium borohydride in a solvent such as ethanol, methanol or diethylene glycol dimethyl ether, and the desired product is isolated in free form or as a pharmacologically acceptable salt.
    Subscription
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1461372A3|1989-02-23|Method of producing |-alkylamines or pharmacologically acceptable salts thereof
    DK143275B|1981-08-03|METHOD OF ANALOGY FOR THE PREPARATION OF 1- | -PHTHALANDER DERIVATIVES OR ACID ADDITION SALTS THEREOF
    DE2018135A1|1970-10-22|New 1-aminobenzocycloalkane derivatives
    PL101951B1|1979-02-28|A METHOD OF PRODUCING NEW ETHER DERIVATIVES OF OXIME
    Chapleo et al.1984|. alpha.-Adrenoceptor reagents. 2. Effects of modification of the 1, 4-benzodioxan ring system on. alpha.-adrenoreceptor activity
    HU182224B|1983-12-28|Process for producing cys-4-phenyl-1,2,3,4-tetrahydro-naphtyl-amine derivatives of antydepressive activity
    EA024425B1|2016-09-30|Method for preparation of 2-|-1-propanal with chloroacetone
    MATOBA et al.1984|Structural Modification of Bioactive Compounds. II. Syntheses of Aminophosphonoic Acids
    SU479290A3|1975-07-30|The method of obtaining 2- | -6,7 benzomorfan
    US3253034A|1966-05-24|Amino-phenylethanols
    SU602112A3|1978-04-05|Method of producing amines, their salts, racemates or optically-active antipodes
    CN1257067A|2000-06-21|Process for preparing 2-|-3-|-2-ester acrylate
    JPH07291974A|1995-11-07|Epi-epibatidine derivative and its preparation
    EP0612716B1|1996-05-08|Process for the preparation of an optically pure aminoalcohol
    US3564016A|1971-02-16|Method of decarbonylation
    US3215739A|1965-11-02|Method of producing dibenzo | cyclohepta | dienes
    US3222399A|1965-12-07|Cyclopentylbenzylamines
    DK156391B|1989-08-14|ANALOGY PROCEDURE FOR PREPARING 3-AMINOPYR ROLLER DERIVATIVES
    US3149108A|1964-09-15|Preparation of derivatives of 1, 4-benzodioxan
    FI64580C|1983-12-12|FORM OF THERAPEUTIC ACTIVATION OF THERAPEUTICALLY ACTIVE, N-DIMETHYL-3- | -3- | -ALLYLAMIN -ETEN
    SU487484A3|1975-10-05|The method of obtaining derivatives of 1-phenoxy-3-aminopropan-2-ol
    Miura et al.1985|Ozonolysis of 1-methylindenes. Solvent, temperature, and substituent electronic effects on the ozonide exo/endo ratio
    US3951984A|1976-04-20|3-Benzazocine compounds
    JP4221782B2|2009-02-12|Method for purifying dihalotrifluoroacetone
    US2668856A|1954-02-09|P-methoxy benzhydryl ethers
    同族专利:
    公开号 | 公开日
    GB2098602A|1982-11-24|
    AT382612B|1987-03-25|
    NL8201347A|1982-11-01|
    PT74580B|1983-12-23|
    YU6385A|1985-08-31|
    ES8406413A1|1984-08-01|
    UA7838A1|1995-12-26|
    PL235832A1|1983-09-12|
    NO156785C|1987-11-25|
    BG40652A3|1986-01-15|
    SU1482522A3|1989-05-23|
    MY8800048A|1988-12-31|
    CH652117A5|1985-10-31|
    RO89436A2|1986-06-30|
    IL65257D0|1983-12-30|
    DE3212682C2|1992-03-26|
    YU75082A|1985-08-31|
    HU186582B|1985-08-28|
    ES8403097A1|1984-03-01|
    PL139120B1|1986-12-31|
    KR830010065A|1983-12-26|
    LU84070A1|1983-06-07|
    CS244672B2|1986-08-14|
    CA1248955A|1989-01-17|
    IT1235758B|1992-09-28|
    ES519031A0|1984-08-16|
    YU44253B|1990-04-30|
    IE52768B1|1988-02-17|
    ES519029A0|1984-08-01|
    GR76697B|1984-08-28|
    FR2504920A1|1982-11-05|
    HK13888A|1988-02-26|
    RO84802A|1984-09-29|
    ES8406414A1|1984-08-01|
    UA7589A1|1995-09-29|
    FI77223B|1988-10-31|
    JO1184B1|1983-11-30|
    AU8221382A|1982-10-14|
    NL192201B|1996-11-01|
    NL192201C|1997-03-04|
    BG40651A3|1986-01-15|
    GB2098602B|1984-08-22|
    KR900000274B1|1990-01-24|
    IT8248157D0|1982-04-02|
    DD208348A5|1984-05-02|
    FI821197L|1982-10-07|
    ES511152A0|1983-04-16|
    DK161770C|1992-02-10|
    DE3212682A1|1982-10-21|
    FR2504920B1|1985-06-28|
    AU545595B2|1985-07-18|
    DK146482A|1982-10-07|
    ES519030A0|1984-08-01|
    SG67287G|1988-02-19|
    IE820481L|1982-10-06|
    PT74580A|1982-04-01|
    ES8305678A1|1983-04-16|
    FI821197A0|1982-04-05|
    NZ200178A|1985-07-31|
    KE3753A|1987-10-02|
    CS245782A2|1985-08-15|
    ZW4982A1|1982-11-03|
    PH22762A|1988-12-12|
    RO84802B|1984-10-30|
    CY1408A|1988-04-22|
    ES8407002A1|1984-08-16|
    ES519032A0|1984-03-01|
    IN155773B|1985-03-09|
    YU44336B|1990-06-30|
    PL240079A1|1983-09-12|
    NO821087L|1982-10-07|
    PL136242B1|1986-02-28|
    NO156785B|1987-08-17|
    SE452611B|1987-12-07|
    ATA132582A|1986-08-15|
    SE8202166L|1982-11-25|
    FI77223C|1989-02-10|
    DK161770B|1991-08-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EA007746B1|2004-05-19|2006-12-29|Ле Лаборатуар Сервье|Process for the synthesis of-4,5-dimethoxy-1--benzocyclobutane|
    EA015777B1|2008-08-29|2011-12-30|Ле Лаборатуар Сервье|New method for resolution of enantiomers of nitrile and their application to the synthesis of ivabradine|
    RU2462451C2|2006-09-15|2012-09-27|Ривайва Фармасьютикалс, Инк.|Method of producing, methods of using and composition of cycloalkylmethylamines|
    MD4375C1|2012-07-17|2016-05-31|Les Laboratoires Servier|Process for the enzymatic synthesis of -1--N-methyl-methanamine and application in the synthesis of ivabradine and salts thereof|DE1124485B|1960-02-12|1962-03-01|Hoechst Ag|Process for the preparation of analeptically active phenylcycloalkylmethylamines|
    US3526656A|1967-05-25|1970-09-01|Parke Davis & Co|carbonyl carbamic acid derivatives|IE56000B1|1982-09-30|1991-03-13|Boots Co Plc|1-arylcyclobutylalkylamine compounds|
    IE56001B1|1982-09-30|1991-03-13|Boots Co Plc|1-arylcyclobutylmethylamine compounds|
    GB8412480D0|1984-05-16|1984-06-20|Elliott M|Pesticides|
    DK58285D0|1984-05-30|1985-02-08|Novo Industri As|PEPTIDES AND MANUFACTURING AND USING THEREOF|
    GB8501192D0|1985-01-17|1985-02-20|Boots Co Plc|Therapeutic agents|
    US5157021A|1985-03-15|1992-10-20|Novo Nordisk A/S|Insulin derivatives and pharmaceutical preparations containing these derivatives|
    DK119785D0|1985-03-15|1985-03-15|Nordisk Gentofte|INSULIN PREPARATION|
    GB2184122B|1985-12-17|1989-10-18|Boots Co Plc|N,n-dimethyl-1-[1-cyclobutyl]-3-methyl butylamine hydrochloride monohydrate|
    GB8531071D0|1985-12-17|1986-01-29|Boots Co Plc|Therapeutic compound|
    GB8704777D0|1987-02-28|1987-04-01|Boots Co Plc|Medical treatment|
    JP2675573B2|1988-03-31|1997-11-12|科研製薬株式会社|Brain function improver|
    EP0647134A4|1992-06-23|1997-07-30|Sepracor Inc|Methods and compositions for treating depression and other disorders using optically puresibutramine.|
    GB9309749D0|1993-05-12|1993-06-23|Boots Co Plc|Therapeutic agents|
    US5459164A|1994-02-03|1995-10-17|Boots Pharmaceuticals, Inc.|Medical treatment|
    DE19518988A1|1995-05-29|1996-12-05|Basf Ag|Use of aryl substituted cyclobutylalkylamines to treat obesity|
    GB9524681D0|1995-12-02|1996-01-31|Knoll Ag|Chemical process|
    GB9619757D0|1996-09-21|1996-11-06|Knoll Ag|Chemical process|
    GB9619962D0|1996-09-25|1996-11-13|Knoll Ag|Medical treatment|
    GB9619961D0|1996-09-25|1996-11-13|Knoll Ag|Medical treatment|
    GB9727131D0|1997-12-24|1998-02-25|Knoll Ag|Therapeutic agents|
    US6399826B1|1999-08-11|2002-06-04|Sepracor Inc.|Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain|
    US6339106B1|1999-08-11|2002-01-15|Sepracor, Inc.|Methods and compositions for the treatment and prevention of sexual dysfunction|
    US6331571B1|1998-08-24|2001-12-18|Sepracor, Inc.|Methods of treating and preventing attention deficit disorders|
    US6974838B2|1998-08-24|2005-12-13|Sepracor Inc.|Methods of treating or preventing pain using sibutramine metabolites|
    AU2007200334B8|1998-08-24|2010-10-21|Sepracor, Inc.|Methods of using and compositions comprising dopamine reuptake inhibitors|
    US6476078B2|1999-08-11|2002-11-05|Sepracor, Inc.|Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction|
    BG65170B1|1999-03-17|2007-05-31|Knoll Gmbh|Use of n-substituted derivatives of 1-[1-cyclobutyl]-3-methylbutyl amine for the production of a medicine for treating eating disorders|
    US6552087B1|1999-03-19|2003-04-22|Abbott Gmbh & Co. Kg|Therapeutic agent comprising -sibutramine|
    GB9915617D0|1999-07-05|1999-09-01|Knoll Ag|Therapeutic agents|
    WO2002036540A2|2000-11-02|2002-05-10|Torrent Pharmaceuticals Ltd|PROCESS FOR PREPARATION OF β-PHENETHYLAMINE DERIVATIVE|
    US6610887B2|2001-04-13|2003-08-26|Sepracor Inc.|Methods of preparing didesmethylsibutramine and other sibutramine derivatives|
    KR100536750B1|2002-10-05|2005-12-16|한미약품 주식회사|Pharmaceutical composition comprising crystalline hemihydrate of sibutramine methanesulfonate|
    KR100606533B1|2004-08-27|2006-08-01|한올제약주식회사|An improved synthetic method of sibutramine|
    KR100606534B1|2004-11-01|2006-08-01|한올제약주식회사|An improved synthetic method of sibutramine|
    KR100618176B1|2004-12-02|2006-09-01|휴먼팜 주식회사|Sibutramine tartrate, its preparation process and phamaceutical composition comprising it|
    JP2008526836A|2005-01-06|2008-07-24|シージェーチェイルジェダンコーポレーション|Sibutramine inorganic acid salt|
    CN101555214B|2008-04-08|2012-07-11|北京嘉事联博医药科技有限公司|Phenylcyclobutylacylamide derivative as well as optical isomer, preparation method and application thereof|
    WO2010082216A2|2008-12-08|2010-07-22|Matrix Laboratories Ltd|Novel salts of sibutramine and their crystal forms|
    EP2496583B1|2009-11-02|2014-12-10|Pfizer Inc|Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives|
    WO2012003501A2|2010-07-02|2012-01-05|Reviva Pharmaceuticals, Inc.|Compositions, synthesis, and methods of using cycloalkylmethylamine derivatives|
    BR112014016122A8|2011-12-30|2017-07-04|Reviva Pharmaceuticals Inc|compound and pharmaceutical composition|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8110710|1981-04-06|
    GB8110709|1981-04-06|LV931267A| LV5454A3|1981-04-06|1993-11-25|Method of obtainingalkylamine or their pharmacologically acceptable islands|
    [返回顶部]