前苏联专利SU1498385A3 Method of producing derivatives of pyrrolidinone

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专利摘要:
The invention relates to pyrrolidinone derivatives, in particular, compounds of the general formula 1: HO — CH 2 —CH — CH 2 —C (O) —N (CHR 1 R 2 ) -CH 2 , where R 1 -H or CH 3 R 2 - pyridyl or phenyl or monosubstituted CH 3 , CH 3 O F, CL, CF 3 , benzyloxy group is phenyl, or disubstituted phenyl, in which both substituents are methoxy, or one is methoxy, and the other is benzyl-hydroxy, having psychotropic activity that can be used in medicine. The purpose of the invention is the creation of new active and low-toxic substances of the specified class. The synthesis is carried out by reduction of an ester of the formula P: R 3 O - C (O) - CH - CH 2 -C (O) -N (CHR 1 R 2 ) -CH 2 , where R 1 and R 2 have the indicated meanings, R 3 - lower alkyl, using complex alkali metal borane. New substances have nootropic activity with low toxicity LD 50 = 2 g / kg. 2 tab.
公开号:SU1498385A3
申请号:SU843767329
申请日:1984-07-20
公开日:1989-07-30
发明作者:Вебер Карл-Гейнц；Вальтер Герхард；Шнейдер Клаус；Хинцен Дитер；Иозеф Кун Франц；Лер Эрих
申请人:Берингер Ингельгейм Кг (Фирма)；
IPC主号:

专利说明:

This invention relates to the preparation of novel pyrrolidinone derivatives of the general formula
BUT-NOS
D) about
N
R.-CH
L
where R is hydrogen or methyl;
RJ is phenyl, unsubstituted or monosubstituted by methyl, methoxy, fluorine, chlorine, trifluoromethyl, benzyloxy, or disubstituted.
wherein both substituents are methoxy, or one substituent is methoxy, and the other benziphoxy, or pyridyl, has neotropic activity,
The purpose of the invention is the development, on the basis of known methods, of a method for the preparation of new compounds with a given pharmacological property with low toxicity.
The invention is illustrated by the following examples.
Example J 1- (3,4-dimethoxibenzyl) -4-oximetr-pyrrolidin-2-one 8.0 g 1- (3,4-methoxybenzyl)

00
CO oo ate

04
4-ethoxycarbonyl-pyrrolidin-2-one is dissolved in 100 ml of methanol. Mechanically stirring, drop by drop for 20 minutes while adding a solution of 2.8 g of sodium borane in 30 ml of water and continue stirring for a further 5 hours at 0-10 C.
15
t
Then, excess borane is carefully dispersed by adding glacial acetic acid to a pH value of 5 and until the evolution of gas ceases and the methanol is distilled off in vacuo. A small amount of water is added and the reaction product is taken up with methylene chloride. The methylene chloride phase is washed, dried and evaporated. The residue is subjected to chromatography on silica gel (98: 2 by methylene chloride). From the eluate, 4.8 g (62% of the theoretical) of the indicated compound are obtained with mp. 78-79 C. Example 2. 1- (p-Fluorobenzyl) - A-hydroxymethyl-pyrrolidin-2-one,
A, O g (16 mol) 1- (p-fluorobenzyl) -25 4-ethoxycarbonyl-pyrrolidin-2-it is dissolved in 60 ml of tertiary butanol. And then 1.5 g of sodium borane is added. The mixture is brought to reflux temperature and 12 ml of dry methanol is gradually added over a period of 1 hour. After another 1 hour, the reaction mixture is evaporated in vacuo, the residue is diluted with water, the desired product is shaken with methyl chloride, and the mixture is worked up as in Example 1. The yield of the pure compound is 2.5 g with a melting point of 121-122 ° C (72 % theory in terms of crude ester),
Similarly receive the target products listed in the table. one.
The pyrrolidinone derivatives obtained were studied in animals for their activity in reducing or eliminating the state of organic cerebral functional capacity, as well as in their toxicity. In addition, the compounds were given to mice at doses up to 2 g / kg (single oral application). The observation time was 14 days, and acute toxicity was absent. In animal experiments, compounds have excellent effect on spontaneous cognitive functions, for example, experimentally limited learning and storage processes in memory. In experiments with the limitation of short-term memory to long-term memory pu3)
,,
Q
45
5 С
55
five
By giving muscarinic chloe} 1 an epic antagonist (0.6 mg / kg in crowds} 1a, intraperitoneally), the obtained compounds counteract pharmacologically induced cerebral insufficiency and even preserve it.
Biological experiments. Experience A, Mice are planted on the platform. When jumping from a platform, they are subjected to electric shock. Thus, people are accustomed to the fact that 1. 1 11 form provides protection against electric shock.
Animals given scopolamine (0.6 mg / kg, intraperitoneally) begin to forget that on the platform they are safe and more often jump off of it.
During the subsequent giving to the animals of no-oropic means of memory, despite the dacha, the scopoling is preserved. This experience determines the percentage of animals that are under the influence of a neo-roropic agent, despite the scopolamine cottage, keeps a memory that they are safe on the platform and therefore do not want to jump off the platform. This Nrocene is given in Table 2 as a% delay.
Experience B. Rats familiarize themselves with an unfamiliar environment of the ny, the continuous run, sniffing, etc., etc. in a state of increased motility. If, after a certain time, absences of animals return back to the old surrounding
Q environment, then many of them recognize the former environment, animals behave calmly at the same time, their motility in this case is on average lower than it was before
Cottage Nootropic
five
WITH
five
should lead to an increase in the percentage of animals that recognize the former environment. This experiment allows us to determine what percentage of experimental animals that were given nootropic agent, recognize the previous environment, compared with the control group of animals. This percentage is given in table. 2 as a percentage of recognition.
The pyrrolidinone derivatives obtained according to the invention are compared with the known pyrro-lidinone derivatives, in particular, with 1-carbamide.
ylmethyl-pyrrolidin-2-one (piracetam), which finds use as a nootropic agent. The data table. 2 indicate that the new pro-water pyrrolidinones have a beam of 11; their activity, the known, the toxicity has the same as the known, i.e. The dose of D is 2 g / kg (orally, baby).
five
ten

权利要求:
Claims (1)
[1]
Formula invented
The method of obtaining pyrrolidinone derivatives
N I NA RI
R2
where K J is hydrogen or mpyl;
Rj phenyl, unsubstituted or monosubstituted by methyl.
methoxy, fluorine, chlorine, trifluoromethyl, benzyloxy, or disubstituted, in which both substituents are methoxy, or one substituent is methoxy, and the other is benzyloxy, or pyridyl,
characterized in
compound of general formula
Poison-1- (
i. J .--. 0
to
what
20
HC-RI
Rz
where R and R
have the indicated values: 1
25
Ri is lower alkyl,
subjected to recovery of complex alkali metal borane.
no-ngc
Table
-0-0
63-64
.188-190
165-168
165-168
77-78 162-165
95-96
: :::: i: :: r ...:.: 3
, (o}
1A98385
I;
eight
1 I
12
13
OSSN
foV-O-CHj-CeHs
Kh
Editor M. Nedoluzhenko
Compiled by I. Bocharova
Tehred M. Didyk Proofreader M. Maksimishinets
Order 4463/58
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. 4/5
Long duration of tA1a i
L :: tg
1A6-147
170-172
178-182
79-80
160-163
Butter
-105
84-86
Subscription

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法律状态:

优先权:

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