• 专利附录
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    • 专利摘要:
    Die neuen Pyrrolidinderivate der allgemeinen Formel worin R1 Wasserstoff oder niederes Alkanoyl, R2 Wasserstoff oder niederes Alkyl und R3 Wasserstoff, niederes Alkyl oder einen Rest der Formel -(CH2)n-NR4R5, n eine ganze Zahl von 2 bis 4 und R4 und R5 je Wasserstoff oder niederes Alkyl oder zusammen mit Stickstoffatom einen gegebenenfalls durch eine oder zwei niedere Alkylgruppen substituierten Pyrrolidin-, Piperidin-, Piperazin- oder Morpholinrest bedeuten, und Säureadditionssalze von Verbindungen der Formel I, weiche basischen Charakter aufweisen, sind nützlich bei der Bekämpfung bzw. Verhütung der cerebralen Insuffizienz bzw. bei der Verbesserung der intellektuellen Leistungsfähigkeit. Sie können ausgehend von teilweise neuen Ausgangsstoffen hergestellt und, z.B. in Form von pharmazeutischen Präparaten, als Heilmittel verwendet werden.
    公开号:SU1281172A3
    申请号:SU823466582
    申请日:1982-07-22
    公开日:1986-12-30
    发明作者:Ашванден Вернер；Кибурц Эмилио
    申请人:Ф.Хоффманн Ля Рош Унд Ко Акциенгезельшафт (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new pyrrolidine derivatives of the general structural formula Rj, CO-TyAHDZ, where R, hydrogen or lower alkanoi and RI are hydrogen or lower alkyl; I.  .  - rt f Ri - hydrogen OR 2- (diisopropyl. j sim.   , amino) eth1 or 2- (2,6-dimethyl-1-piperidinyl) ethyl.  in the form of a mixture of diastereoisomers or their optically active antipodes or their acid-additive salts with valuable pharmacological properties.  The aim of the invention is to develop a process for the preparation of new pyrrolidine derivatives having improved pharmacological properties.   The method is illustrated by the following examples.  Example 1  a) To 51.9 g of (R / S) -3-trimethylsilyloxy-2-pyrrolidone and 136 ml of ethyl bromoacetic acid ester in 520 ml of anhydrous acetonitrile are added in portions with stirring at 45-50 ° C for 30 min. 38 , 3 g of 55% sodium hydride dispersion in minerals.  The mixture is then brought to reflux temperature for 30 minutes with stirring, stirred for an additional hour for 1 hour and then filtered.  I The filtrate is evaporated and the remaining residue, containing (R / S) -2- (3-trimethyl-silyloxy-2-o-co-1-pyrrolidinyl) acetic acid, is dissolved in 500 ml of tetrahydrofuran.  To this solution was added 71 ml of 1N.  hydrochloric acid and after 15 min-7.2 g of sodium hydrogen carbonate, then stirred for 7 min at room temperature and then evaporated.  The residue is extracted three times with acetonitrile and the combined acetonitrile extracts are evaporated.  The residue is chromatographed on silica gel (grain size 0.2-0.5 mm).  Eluted with methylene chloride and ethyl acetate (R / S) -2- (312 2 -oxy-2-oxo-1-pyrrolidinyl) acetic acid ethyl ester is crystallized from ethyl acetate / n-hexane (1: 2), t. square  80.5E1 ° g b) 11.5 ml of -v25% -Horo ammonium hydroxide solution is added to 2.50 g of (R / S) -2- (3-hydroxy-2-oxo-1-pyrrolidinyl) acetic ethyl ether acid, then stirred for 1 h at room temperature.  Acetonitrile is added to the reaction mixture and acetonitrile is added to the residue obtained five times and each time it is evaporated.  Receive (R / S) Ls1liyi-1 us13 yiiduinocinji.  Best of / „,,,.  -2- (3-hydroxy-2-oxo-1-pyrrolidinyl): acetamide, which, after recrystallization from methanol / diethyl ether (1: 2), melts at 163-164 ° C.  Example 2  4.5 g of (R / S) -2- (3-oxy-2-oxo-l-pyrrolidinyl) acetic acid ethyl ester are heated with 7.1 g of cis-2- (2,6-dimethyl-l-piperidinyl) ethylamine 3j5 h in a nitrogen atmosphere to 100C.  Then diethyl ether is added, stirred, filtered, and the filter residue (6.5 g) is chromatographed on 30 g of silica gel (grain size 0.2-0.5 mm).  Eluted with methylene chloride and methanol (R / S) cis-N-2- (2,6-dimethyl-1-piperidinyl) (3-hydroxy-2-oxo-1-pyrrolidinyl) acetamide has, after recrystallization from ethyl acetate, t. square  131-132 C.  Example 3  4.5 g of (R / S) -2- (3-oKCo-2-oKco-1-nHprolidine) acetic acid ethyl ester is heated with 6.1 g of 2- (diisopropylamino) ethyl. on under nitrogen atmosphere for 3.5 hours to 100 C.  The crude reaction product is chromatographed with alumina (neutral, activity III).  A mixture of ethyl acetate / ethyl ether (1: 1) and ethyl alcohol was eluted with (R / S) -N-2- (diisopropylamino) (3-hydroxy-2-oxo-1 pyrrolidinyl) acetanide.  After stirring in diethyl ether, it has t. square  9193 ° С, t. kip  230-250 ° C / 0.01 mm Hg Art.  (tube with ball expansion).  Example4.  a) To a suspension of 34.0 g of (R) -4-amino-2-oxy-buty acid in 340 ml of anhydrous o-xylene, 89 ml of hexamethyldisilazane and 0.6 ml of trimethylchlorosilane are added.  The mixture is heated for 4 hours with stirring until boiling and then evaporated.  Balance 1 times extracted with toluene.  The combined toluene extracts were evaporated in vacuo, after which the residue was distilled off in three portions.  Receive (R) -3- (trimethyls lyloxy) -2-pyrrolidinone with t. kip  90 ° C / 0.01 mm Hg Art.  (tube with a ball extension).  b) Example 1 is repeated under point a with the difference that (R) -3- (trimethylsilyloxy) -2-pyrrolidinone is used as the starting product. After recrystallization from ethyl acetate / n-hexane, ethyl ether is obtained. K) - (+) - 2 - (3-hydroxy-2-oxo-1-pyrrolidine 1) acetic acid with t. square  84-85 ° C; "° + 68 °; W746 jg5 225 (dimethylformamide, s 1.0), c) From (R) - (+) - 2- (3-OXY-2-OXO-1-pyrrolidinyl) uxoic acid ethyl ester get According to the method (K) - (+) - 2- (3-hydroxy-2-oxo-1-pyrroli) as described in paragraph b of example 1. dinyl) acetamide with t. square  197-198 ° C; ,  (dimethylformamide, with 1.0).  Example 5 (From ethyl ester of (R) - (+) - 2- (3-OXY-2-OXO-1-pyrrho-lidinyl) acetic acid is prepared as described in example 2, method (R) -s) -cis-N- 2- (2,6-dimethyl-1-piperidinyl) (3-hydroxy-2-ca CO - I-pyrrolidinyl) acetamide with t. square  101- 102 ° C; m + 43 °; M ::,.  + ° (acetonitrile, with 1.00).  Example 6  a) The analogy in the method described in point a of example 4 is obtained from (5) - (-) - 4-amino -2-hydroxy-butyric acid ethyl ester (8) - (-) - 2- (3- oxy-2-oxo-1-pyr rolidinyl) acetic acid with t. square  85 - 85.50 s; M, ° -690; MS, -84 Mzb -259 ° (chloroform, c 1, C).  B) According to the method described in paragraph K) of Example 1, it is obtained from (S) - (-) - 2- (3-hydroxy-1-pyrrolidinyl) acetic acid ethyl ester of (S) - (-) - 2- (3 -oxy-2-oxo-1-pyrrolidinyl) a cetamide with t. square  197 - 198 C; W –82 °; L–, –99 °; M, “(dimethylformamide, s 1, CO).  Example 7  From ethyl (8) - (-) - 2- (3-hydroxy-2-oxo-1-pyrrolidinyl) acetic acid ethyl ester, it is prepared, as described in example 2, method (8) - (-). Cis-L-2- (2,6-dimethyl-L-piperidinyl) (3-OXI-2-OXO-1-pyrrolidinyl) acetamide Art. square  101 - 03 ° C; -44 °; (acetonitrile, with J0).  PRI me R 8.  a) 15.0 g of (R / S) -2- (3-hydroxy-2-oxo-l-pyrrolidinyl) acetic acid ethyl ester are dissolved in 150 ml of abs. alcohol and  Bavly 1.95 g of sodium dissolved in 38 ml of abs. alcohol.  1.5 ml of ion-free water is added, and then stirred overnight at room temperature.  250 ml of diethyl ether was added to the resulting suspension and then filtered.  The sodium salt (K / 8) -2- (3-hydroxy-2-oxo-1-pyrrolidinyl) acetic acid is obtained.  The salt is stirred in 200 ml of acetonitrile and 12 ml of 25% hydrochloric acid overnight at room temperature.  After that evaporated.  Acetonitrip is added twice to the residue obtained after evaporation and evaporated each time.  The residue is boiled in 320 ml of acetonitrile at reflux temperature, then filtered while hot and the filtrate is stirred for 3 hours in an ice bath.  I.  (R / S) -2- (3-OXY-2-OXO-1-pyrrolidinyl) acetic acid was isolated by filtration with m. square  153-154 ° C.  (B) To 1.0 g (R / S) -2- (3-hydroxy-2-oxo-1-pyrrolidinyl) acetic acid and 1.03 g of 94.7% cis-2- (2.6- dimethyl-1-piperidinyl) ethylamine dissolved in 20 ml of dimethylformamide, added dropwise at 1.30 g of dicyclohexylcarbodiimide dissolved in 6 ml of dimethylformamide.  The mixture is stirred at room temperature for 4 days, 0.23 g of ion-free water is added to the reaction mixture and evaporated in a vacuum obtained by means of a water-jet pump.  Toluene is added to the residue five times and each time it is evaporated.  Chloroform-soluble residue fractions are chromatographed on 60 g of alumina (degree of activity, lit, neutral).  The alcoholic eluate is again chromatographed on I5 g of alumina (activity level III, neutral).  Elution with acetonitrin and.  ethanol fractions contain (K / 8) -cis-K-2- (2,6-dimesh-1-1-piperidinyl) (3-hydroxy-2-oo-1-pyrrolidinyl) acetamide according to gas chromatography and mass spectrometry.  Example9.  a) 4.0 g (R / S) -2- (3-hydroxy 2-oxo-1-pyrrolidinyl) acetic acid, 80 ml of abs.  tetrahydrofu wound and 5 ml of acetyl chloride are boiled for 4 hours with stirring at reflux temperature.  After that, the mixture is evaporated.  The residue is filtered on silica gel (grain size 0.2 - 0.5 mm). The residue, obtained by evaporation of the fraction eluted with ethyl acetate, is stirred with diethyl ether.  Filter out (. R / S) -2- (3-acetoxy-2-oxy-l-pyrrolidinyl) cyclic acid with t.  t. square  95-) 6 ° C, b) 1.81 g of 2-chloro-1-methyl-pyridinium iodide is weighed in 10 ml of methylene chloride and 1.20 g of (R / S) -2- (3 - & Cethoxy-2-oxo-pyrrolidinyl) acetic acid.  A solution of 0.98 g of 94.7% cis-2- (2,6-dimethyl-1-piperidinyl) ethylamine and 3.02 ml of triethylamine in 20 ml of chloride are added dropwise at 0 ° C over 15 minutes. methylene, after which the permeate for 18 h at room temperature.  Then it is evaporated and the residue is chromatographed on alumina (activity level III, neutral). The material eluted with chloroform is chromatographed on silica gel (grain size 0.2-0.5 mm) ,. Eluted with alcohol (R / S) -CIS-X2- (2,6-dimethyl-1-piperidinyl) -ethyl -2- (3-acetoxy-2-oxo-1-pyrrolidinyl) acetamide has after crystallization from diethyl extract. P: 120 -.  Example 10  1.0 (R / S) -2- (3-acetoxy-2-oxo-pyrrole dinyl) acetic acid in 15 ml of abs. Tetrahydrofuran is used, after which 0.98 g of N, N - is added in one portion. carbonyl diimidazole.  Stir at room temperature until.  until gas generation is complete.  0.86 g of 94.7% cis-2- (2,6-dimethyl-1-piperidinyl) ethylamine is added, the mixture is left to stand overnight at room temperature and then evaporated.  The residue is chromatographed on 60 g of alumina (degree of activity III, neutral.  state).   Eluted with methylene chloride (R / S) -cis-N-2- {2.6 dimethyl-1-piperidinyl) (3-acetoxy-2-OXO-1-pyrrolidinyl) acetamide after stirring, t. square  121,122 ° C.  Example P.  a) 1.70 gztirovogo ester (R / S) -2- (3-hydroxy-2 - (:, co-1-pyrrolidinyl) acetic acid: Y and t with stirring for 2.5 h at a temperature of reflux distilled in 30 ml of chlorine methylene and 0.53 ml of acetylide. Then the mixture is added.  The residue is distilled in a step expansion tube.  Get (R / S) -2- (3-acetoxy-2-oxo 1-pyrrolidinyl) acetic acid ethyl ester with so on. square  225 ° C / 0.01 mm Hg. Art.  (B) To 0.40 g of (R / S) -2- (3-acetoxy-2-oxo-1-pyrrolidinyl) acetic acid / ethyl ester, 45 ml of a saturated solution of ammonia in methanol is added.  It is left to stand for 1 hour at room temperature and then the reaction mixture is evaporated, acetonitrile is added to the residue four times and each time it is evaporated.  (R / S) -2- (3-OXY-2-OXO-1-pyrrolidinyl) acetamide is obtained, which, after recrystallization from methanol / ethyl ether (1: 3), melts at 163-164 ° C.  Example 12  (R / S) -2- (3-aueTOXY-2-OXO-1-pyrrolidinyl) acetic acid is boiled for 2 hours at reflux temperature in 20 ml of toluene and 0.54 ml of thionyl chloride.  After evaporation of the reaction mixture, the residue was shaken 2 times with toluene and the toluene was evaporated in vacuo.  0.5 g of the residue, containing its crude (R / S) -2- (3-acetoxy-2-oxo-1-pyrrolidinyl) acetic acid chloride, is left overnight in a saturated solution of ammonia in methanol.  After evaporation of the solvent, the residue is chromatographed on 5 g of silica gel (grain size 0.2-0.5 mm).  Eluate (methylene chloride / methanol, 1: 1) contains (R / S) -2- (3-hydroxy-2-oxo-1-pyrrolidinyl) acetamide.  Il meper 13.  To 1.5 g of (R / S) -2- (3-acetoxy-2-oxo-1-pyrrolidinyl) acetic acid, 40 ml of chloroform and 0.86 g of N-oxysuccinimide were added. : 1.64 g of dicyclohexylcarbodiimide dissolved in 20 ml of chloroform at room temperature.  After 4 hours  the solid is filtered off, after which the filtrate is concentrated and filtered again.  The filtrate is evaporated. The residue is added at room temperature (40 ml of liquid) and an aqueous solution of ammonia in methanol.  Stir for 5 minutes at room temperature, then add 10 ml of water free from ions and stir for 30 minutes at room temperature.  The solid precipitate is filtered off.  The filtrate is evaporated, the residue is stirred in 30 ml of acetonitrile and the crystallized product is recrystallized two more times from acetonitrile.  Receive (R / S) -2- (3-OXI-2-OXO-1-pyrrolidinyl) acetamide with t. square  162 164 ° C.  Example 14  1.50 g of (R / S) -2I- (3-hydroxy-2-oKco-l-pyrrolidinyl) acetic acid is dissolved in 50 ml of chloroform and 10 ml of dimethylformamide.  To this was added 1.08 g of N-oxysuccinimide.  Then, 2.08 g of di cyclohexylcarbodiimide, dissolved in 25 ml of chloroform, is added.  The mixture is stirred for 4 hours at room temperature and then the precipitated solid is filtered off.  The filtrate is concentrated to a volume of 20 ml and then filtered again.  The filtrate is evaporated and 1.70 g of 94.7% cis-2- (2,6-dimethyl-1-piperidinyl) ethylamine is added to the residue.  The mixture was allowed to stand overnight at room temperature and the excess cis-2- (2,6-dimethyl-1-piperidinyl) ethylamine was removed in vacuo.  The residue is chromatographed on 60 g of alumina (activity level 1, before the main state is:.  neither).  The fractions eluted with chloroform and alcohol are evaporated.  The residue is stirred in 35 ml of a mixture of diethyl ether / ethanol (2: 1) at room temperature.  (K / 5) -cis-K- 2 - (2,6-dimethyl-1-piperidinyl) ethyl -2- (3-OXY-2-OXO-1-pyrrolidinyl) acetamide is obtained (t. square  116-120. C), which, after repeated chromatography on alumina (degree of CT activity, neutral state) and recrystallization from ethyl acetate, melts at 126-128 ° C.  Example 15  1.2 ml of ethyl chloroformate in 12 ml of chloroform is used, then added dropwise at -30 ° C over 30 minutes to 2.0 g (K / 8) -2- (3-hydroxy-2 -oxo-1-pyrrolidinyl) acetic acid and 1.74 ml of triethylamine dissolved in 50 ml of chloroform.  After ne, stirring for 120 min at.  at a temperature of from -20 to -10 ° C, 2.07 g of 94.7% cis-2- (2,6-dimethyl-I-pyperidinyl) ethylamine dissolved in 10 ml of chloroform is added dropwise.  Allow to stand overnight at room temperature.  Then evaporated and the residue (b g) chromatographic 120 g about. acid aluminum (G11 activity level, neutral state).  Eluted with acetonitrile and ethyl alcohol (R / S) -UHC-N- 2- (2,6-dimethyl-1-pipet-, ridinyl) (3-hydroxy-2-oxo-1-pyrrolidinyl) acetamide has, after repeated chromatography on alumina and recrystallization from ethyl acetate t. square  128-130 C.  Example 16  In analogy to Example 15, 2 g of (R / S) -2- (3-acetoxy-2-oxo-1-pyrrolidinyl) acetic acid is prepared using ammonia solution in methanol instead of cis-2- (2,6-dimethyl-1- piperidinyl) ethylamine (R / S) -2- (Zgoxi-2-oxo-. 1-pyrrolidinyl) acetamide.  Purification is not carried out by chromatography, but by stirring the chloroform.  Get the product with t. square  161-163 ° C.  Example 17  Analogously to Example 15, a crude reaction mixture is obtained from 0.8 g (R / s) -2-Z-acetoxy-2-oxo-I-pyrrolidinyl) acetic acid, which is chromatographed on 40 g of alumina (activity level III, neutral ).  Eluted with chloroform (R / S) -cis-N-2- (2,6-dimethyl-1-piperidinyl) t.   (3-acetoxy-2-oxo-1-pyrrolidinyl acetamide) has, after stirring in diethyl ether, t. square  121, 122 ° C.  Example 18  a) From (R / S) -3-trimethylsilyloxy-2-pyrrolidinone and 2-bromopropionic acid ethyl ester is prepared according to the process described in paragraph 1 of Example 1 (R / S) -2- (3-OXI-2-Oxo) -1-pyrrolidinyl) propionic. acids with t. square  200 ° C / 0.05 mm Hg Art.  (tube with ball expansion).  B) According to the method described in paragraph b of Example 1, it is obtained from (R / S) -2- (3-oxy-2-oxo-1-pyrrolidinyl propionic acid ethyl ester after chromatography on silica gel) (grain size 0.2 - 0.5 mm), eluting with acetonitrile / ethanol (1: 1) and crystallizing from acetonitrile the amide (R / S) -29 1 - (3-OXY-2-OXO-1-pyrrolidinyl) propionic acid with m. square  139-141s.  Example 19  1.5 g of (R / S) -2- (3-OXY-2-OXO-1-pyrrolidinyl) propionic acid ethyl ester, O, stand together with 2.45 g of cis-2- (2,6-dimethyl -1-piperidinyl) ethylamine for 24 hours at room temperature Then excess cis-2- (2,6-dimethyl -1-piperidinyl) ethylamine is distilled off under high vacuum and the residue (3.5 g) is chromatographed on 230 g of silica gel. (grain size 0.2 - 0.5 mm).  After methanol eluted, the amide (R / S) -CIS-N- 2- (2,6-dimethyl-1-piperidinyl) ethyl 2- (3-hydroxy-2-oxo-1-pyrrolidinyl) propionic acid has, after recrystallization from ethyl acetate t. square  129 - 130 C.  For m  e 20.  a) From (R / S) -3- -trimethylsilyloxy-2-pyrrolidinone and 2-bromobutyric acid ethyl ester is prepared according to the process described in paragraph 1 of Example 1 (R / S) -2- (3-hydroxy-2) - co-pyrrolidinyl) butyric acid with m. square  205 ° C / 0.02 mm Hg. Art.  (tube with ball expansion).  B) From 2.05 g of (R / S) -2- (3-OXY-2-OXO-1-pyrrolidinyl) butyric acid ethyl ester, the procedure was not in accordance with the procedure described in Example 2 for chromatographic purification: R / S) -itH-N-2- (2 ,, 6-dimethyl-1-piperidinyl) ethyl -2- (3-OXY-2-OXO-1-pyrrolidinyl) butyric acid.  PRI me R 21.  Similarly, the process described in b) of Example 1 is obtained from (R / S) -2 - (3-hydroxy-2-oxo-1-pyrrolidinyl) butyric acid ester with a 25% solution of ammonium hydroxide after recrystallization from acetonitrile amide (R / S) - (3-OXY-2-OXO-1-pyrrolidinyl) -lacry acid with t. square  121-122 C.  Example 22  a) 2.0 g of (R / S) -2- (3-OXY-2-OXO-pyrrolidinyl) acetic acid ethyl ester is dissolved in 340 ml of pyridine, after which it is added at O - 5 ° C in portions 3.54 g of (-) - (3-oxo-4,7,7-trimethyl-2-oxabicyclo 2,2,2 -hept-1-yl) carbonyl chloride, -23 ° (CC, 2.0), After stirring overnight at room temperature, evaporated.  Toluene is added to the residue four times and each time it is evaporated.  The residue is chromatographed on 80 g of alumina (the activity level is 1115 neutral).  The fractions eluted with chloroform are evaporated and the residue is crystallized in ethyl ether.  A mixture of 2- {3- (3-oxo-4,7,7-trimethyl-2-oxabicyclo 2,2, rj-heppt-1-yl) carbonyloxy 1-2-oxo-1-pyrrolidinyl acetic acid ethyl ester diastereomers is obtained t. square  89 - 91С.  B) By high pressure liquid chromatography of a diaste mixture. 2- | 3- (3-Bxo-4, 7,7-trimethyl-2-oxabicyclo 2.2, Q-hept-1-yl) carbonyloxy 2-oxo-1-pyrrolidinyl acetic acid ethyl ester ester on Hibar pre-spring columns -Lichrosorb.  RTDJOL (250 x 4 mm, grain size 10 µm), by elution of 12% with 12% tetrahydrofuran and 0.2% isopropylamine in n-hexane.  T. square  (R) (3-oxo-4, 7,7-trimethyl-2-oxabicyclo 2,2,1 -hept--yl) -carbonyloxy -2-oxo-1-pyrrolidinyl acetic acid ethyl ester 107108 C after recrystallization from a mixture benzene / n-hexane (1: 2).  c) 0.60 g of (R) (3-oxo-4,7,7-trimethyl-2-oxabicyclo 2,2, 1-hept-1-yl) -carbonyloxy -2-oxo-1-pyrrolidinyl acetic ethyl ether the acids are stirred in 25 ml of a saturated solution of ammonia in methanol for 2 hours at room temperature.  The reaction mixture is evaporated.  Acetonitrile was added to the residue four times and each time it was evaporated.  By stirring the residue twice in ethyl acetate, (R) - (4) -2- (3-hydroxy-2-oxo-pyropolydinyl) -acetate is obtained with t. square  190 - 195 ° C.  Y +78; g; 1 2 °, P / ° G, T 2O + 94 °; oil ° Sof (dimethylformM546 + W-b (.  amide, with 1.0).  Example 23  a) K1, Og (R / S) -Ei; ncrN-2- (2,6-dimethyl-1-piperidinyl) (3-OXI-2-OXO- -pyrrolidinyl) acetamide dissolved in 10 ml of pyridine, 0.86 g of (-) - (3-oxo-4,7,7-trimethyl-2-oxabicyclo 2, 2, Q-hept--yl) carbonylchloride was added at 0 ° in portions. oi3 5 ° g -23 (SCC,. with 2.0).  After stirring for 4 hours at room temperature, the pyridine is evaporated.  Toluene was added to the residue three times and each time scorched.  The residue was chromatographed on 1112 g for 30 g of alumina (activity level 111, neutral).  Chloroform eluate contains mixtures of diastereoisomers of cis-N-p- (2,6-dimethyl-1-piperidinyl) ethyl 1-2-. 3- (3-oxo-4, 7,7-trimethyl-2-oxabicyclo 2.2, l-hept-1-yl) carbonyloxy -2-ca co-1-pyrrolidinyl acetamide.  This product is further processed without further purification.  b) By high pressure liquid chromatography of a mixture of cis-N-2- (2,6-dimethyl-1-piperidinyl) diastereoisomers (3-oxo-4,7, 7-trimethyl-2-oxabicyclo 2,2,1J-hept -1-Sh1) carbonyloxy -2-oxo-1-pyrrolidinyl adamethamide on preloaded Hibar-Lichrosorb RTDJOL columns (250 x 4 mm, grain size 10 µm) was carried out with 24% tetrahydrofuran and 0.4% isopropylamine in n-hexane zoned separation of both components.  c) From (K) -Cis-L-2- (2,6-dimethyl-1-piperidinyl) methyl (3-oxo-4, 7,7-trimethyl-2-oxobicyclo 2,2, -hept-1- yl) carbonyloxy -2-oxo-1-pyrrolidinyl acetamide can be obtained by treatment with aqueous ammonia (R) -CIS-N-2- (2,6-dimethyl-1-pipernggdinyl) (3-OXY-2-OXO-1- pyrrole single) ace tamid.  T. square  1 01 + 52 °; ci f +162 (acetonitrile, s 1.00).  d) From (S) -cis-N- 2- (2,6-dimethyl-1-piperidinyl) 3 - D (3-oxo-4, 7, 7-trimethyl-2-oxabicyclo 2,2, ij-j -hept-1-yl) carbonyloxy -2-oxo-1-pyrrlidinyl acetamide can be obtained by treatment with aqueous ammonia (S) -cis-N- 2- (2,6-dimethyl-1-piperidinyl) (3-hydroxy-2 -oxo-1-pyrrolidinyl) acetamide.  T. square  101103 ° С (from ethyl acetate G) 4 tp.  лЛ7 (- rt 20.  t O G / 5-45 5; And -165 (acetonitrile, with 1.0).  Prm and me 24.  2.97 g of (R / S) -cis-N- 2- (2,6-dimethyl-1-piperidinyl) methyl-2- (3-OXY-2-OXO-1-pyrrolidinyl) acetamide is dissolved in 10 ml ethanol.  To this solution was added 1.26 ml of 7.93 n.  solution of hydrogen chloride in ethanol.  After that, the wort is evaporated and the residue is dried under high vacuum.  Receive (K / 3) -cis-N- 2- (2,6-dimethyl-1-piperidinyl) ethyl -2- (3-hydroxy-2-oKco-l-pyrrolidinyl acetamide-hydrochloride with t. different  97 ° C.  Calculated,%: C 53.96; H 8.45; 12.59.  C ,, Oj. HCl, MG 333.86; Found: C, 53.98; H 8.57; N 12.40.  In tab. 1 shows the structure of soy
    8 1.4
    - (
    (R, S)
    13
    128117214
    Table 2 shows the output target
    Continued tabl, 1
    products in examples 1-2A, table 2
    Example 25. Preparation of tablets from compounds of general formula 1.
    (R / S) -uHc-l5- 2- (2, & - Dimethyl-1-piperidinyl) ethyl -2- (3-hydroxy-2-oxo-1-pyrrolidinyl) acetamide can be used as an active ingredient to make tablets of the following composition, mg:
    Acting
    start1
    Lactose100
    Corn
    starch68.5
    Magnesium stearate 0, 5
    Total170
    Finely milled active principle, powdered lactose and 1 hour of cornstarch are mixed
    Continuation of table 2
    40 friends a friend. The mixture is sieved through a sieve, after which it is processed with corn starch paste. Then it is processed into granules, dried and sieved through a sieve.
    45 The sieved granulate is mixed with magnesium stearate and tablets weighing 170 mg are pressed from the mixture.
    Example 26. The pyrrolidine derivatives of general formula 1 are new compounds with very valuable pharmacological properties. They are only slightly toxic and are able to counteract experimentally.
    55 caused by brain failure.
    The experimental apparatus is a box of type Skinpeg box with a trellised bottom (30 x 40 cm) and a gray plastic board 17, 128 in shape (15 X 15 X 0.8 cm) in the right front corner. Male rats (100-120 g) are placed on the platform. As soon as the rat descends onto the lattice bottom, its paws are subjected to electric discharge (0.8 mA). Usually the rats jump back onto the platform. Since the rats try to descend to the grid several times, the electric discharge is repeated 3 to 5 times, after which the rats give a so-called passive avoidance response, i.e. no longer try to descend on the railing. After training, animals are divided into three groups of 30 animals each. The first group is injected intraperitoneally (ip) with 0.3 mg / kg of scopolamine and orally administered (p.o.) distilled water (2 ml / kg) is administered. The second group of i / b injects 0.3 mg / kg of scopolamine and b.p. enter the test substance. The third group give only distilled water (p. O.). After 2 hours, each rat is once placed on the platform of the Skinner box. The criterion for assessing the positive effect of the drug on the short-term memory is the stay of the animal for 60 seconds on the platform. The statistically characteristic difference between the results obtained in the first and second groups is determined using experience x 70-75%. In animals that received only dis. tilirovanny water (oral), after 2-4 hours after training, the passive reaction avoiding response, i.e. they remain on the platform. In 85–92% of animals that received scopolamine amine (0.3 mg / kg i.p.) and distilled water (p.o.), a retrograde effect on a short-term memory, i.e., is observed for 3–4 hours. they do not remain on the platform. A substance that counteracts cerebral insufficiency is capable of removing the blockage of short-term memory caused by the injection of 0.3 mg / kg of scopolamine (ip). The dose of the drug is considered active relative to scopolamine if the number of positive results differs significantly from the number of positive results in the control experiment, i.e. on animals, having received N72 shi from 5 to about 5 5 -2 -2 Li SI G 55 Li SI ly 18 scopolamine (0.3 mg / kg i.p.) and distilled water (p.o.). Table 3 shows the active doses of inn of formula (1) used in the tested experiment, as well as data on toxicity (mish: one-time administration of po). Table 3 A - (E / 3) -cis-K- 2- (2,6-dime-1-piperidinyl) -ethyl -2- (3-hydroxy-1-pyrrolidinyl) acetamide; (S) -2- (3-OXY-2-OXO-1-pyrroinyl) acetamide; B - (E) -2- (3-o2-OXO-1-pyrrolidinyl) acetamcd; (R / S) -2- (3-OXY-2-OXO-1-pyrroinyl) acetamide; D - (R / S) -N-2-iisopropylamino) ethyl -2- (3-ca2-OXO-1-pyrrolidinyl) acetamide. Thus, compounds of form I and their pharmaceutically acceptable 8 acid addition salts, which are basic, can be used as pharmaceuticals. Pharmaceutical formulations may be administered by p. for example, in the form of tablets, lacquer tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, for example, in the form of suppositories, or parenterally, for example, in the form of solutions for injections. Table 4 shows the pharmacological activity of the total pho substance. mules 1 (X) and substances close in structure (Y and Z). Table
    RrCH-CO-WHR,
    H 1
    Table 5
    Known 1000 (test with v5000 (patent application
    Switzerland, 1 mg / kg sk2 20 Continuation of the table. 4 The test with intramuscular injection of I mg / kg of scopolamine. cis-N- 2- (2,6-dimethyl-1-piperidinyl) (2-oxo-1-pyrrolidinyl) acetamide; Y is 2- (2-oxo-1-pyrrolidinyl) acetamide; Z - (Diisopropylamino) (2-oxo-I-pyrrolidinyl) -acetamide. Of. Table 4 shows that the substances of general formula 1 are distinguished by a higher activity compared to those known to those with TB. Pharmacodynamic properties obtained according to the proposed method of compounds of General formula 1 are given in table.5.
    21
    1281172
    22 Continuation of table.5
    - (CH) 2-Ny3
    he N
    - (CH), jN (i-Pr) 2 n
    - (CH) j-N (i-Pr) 2 (R, S) 3
    he N
    As can be seen from the data of Table 5, to obtain the same pharmacodynamic effect of the compounds of the general formula I, it is required 101000 times less than the known compound.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining pyrrolidine derivatives of the general formula I
    - lt - h0
    -N
    R-CH-CO-NHfij,
    where R is hydrogen or lower alkanoyl; Rj is hydrogen or lower alkyl; RJ is hydrogen or 2- (diisopropylamino) ethyl or 2- (2,6-dimethyl-1-piperidinyl) ethyl, as a mixture of diastereoisomers or their optically active antipodes or
    4,000
     0.1; 0.3; 1
    (S) 7.30
    50 + 100 mg / kg (test
    2000 with the use of 1 mg / kg 4000 scopolamine / b).
    5000
    their acid addition salts, o t: characterized by the fact that the compound of general formula II
     - R,
    where R has the specified value, is subjected to interaction with the carboxylic acid of General formula III
    OR4
    g
    N /
    I
     CH-COOH
    RJ has the indicated value;
    4 hydrogen or lower alkanog-,
    or, if R is hydrogen,. then additionally R - (3-oxo-4, 7,7-trimethyl-2-oxabicyclo 2, 2,1 -hept-1-yl) -carbonyl, or with its ethnpine ester, or an acid of general formula III is subjected to sequential interaction with N, N -carbonyldiimidazole or thionyl chloride or ethyl chloroformic acid and with an amine of general formula II, to obtain a mixture of diastereoisomers, which, if necessary, is divided into the corresponding racemates, followed by splitting the racemates into optically active 22 If necessary, convert to the appropriate salts. by treatment with aqueous ammonia. Priority signs: 24407.81 when R is hydrogen or lower alkanoyl; 05.05.82 when R4 is 3-oxo-4,7,7-trimethyl-2-oxa- (bicycle 2,2, ij-hept-1-yl) carbonyl.
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    同族专利:
    公开号 | 公开日
    FI75158B|1988-01-29|
    ZW14482A1|1983-02-09|
    SE8204445D0|1982-07-23|
    DD202540A5|1983-09-21|
    MTP915B|1985-12-28|
    EP0071216A3|1983-09-07|
    IT1152287B|1986-12-31|
    DE3227649A1|1983-02-10|
    IE821768L|1983-01-24|
    SG22788G|1988-07-15|
    GB2152038B|1986-01-02|
    BG38334A3|1985-11-15|
    US4476308B1|1987-03-10|
    RO84097B|1984-06-30|
    DE3274851D1|1987-02-05|
    GB8426076D0|1984-11-21|
    IT8222335D0|1982-07-09|
    FI75158C|1988-05-09|
    HU187777B|1986-02-28|
    AT384424B|1987-11-10|
    US4476308A|1984-10-09|
    ES8307743A1|1983-08-16|
    ES514267A0|1983-08-16|
    IE53428B1|1988-11-09|
    NO822222L|1983-01-25|
    DK157848B|1990-02-26|
    GB2110207A|1983-06-15|
    PT75314A|1982-08-01|
    AU8615882A|1983-01-27|
    NO159592B|1988-10-10|
    PT75314B|1985-11-29|
    US5034402A|1991-07-23|
    GB2152038A|1985-07-31|
    US4650878A|1987-03-17|
    NO159592C|1989-01-18|
    OA07151A|1984-03-31|
    ATA286382A|1987-04-15|
    EP0071216B1|1986-12-30|
    SE8204445L|1983-01-25|
    RO84097A|1984-05-12|
    FR2515179B1|1985-01-18|
    DK157848C|1990-07-23|
    FI822543L|1983-01-25|
    CS226746B2|1984-04-16|
    NL8202922A|1983-02-16|
    FR2515179A1|1983-04-29|
    HK53788A|1988-07-22|
    MC1476A1|1983-06-17|
    DK317382A|1983-01-25|
    AT24488T|1987-01-15|
    EG15921A|1986-09-30|
    EP0071216A2|1983-02-09|
    CA1176251A|1984-10-16|
    PH19149A|1986-01-15|
    AU557651B2|1987-01-08|
    LU84294A1|1984-03-22|
    NZ201297A|1985-12-13|
    IL66341D0|1982-11-30|
    GB2110207B|1985-09-04|
    FI822543A0|1982-07-19|
    IL66341A|1986-12-31|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH4849/81A|CH647234A5|1981-07-24|1981-07-24|Pyrrolidine derivatives|
    CH276882|1982-05-05|
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