Method of producing pyrrolidinone derivatives

专利摘要:
The invention relates to heterocyclic compounds, in particular the preparation of pyrrolidinone derivatives (PR) of the general formula RjR4N-C (o) -NRi-CH2-CiH-Cii2-H (CH2R) -C (0) -bH2, where R is phenyl, topype; E g - EI, -C EfCI :, R - K or R and R together with N-4-methylpiperazine, which have a nootropic effect. Del - obtaining compounds with higher biological activity with low toxicity. To obtain the PR. compound of formula II. C Hj-0-C (0) -NR2-CHj-cS-CHj-N (CHjRjC (o) CH, where R and R. have the indicated meanings, are boiled with an amine of the general formula IV) RjNH-R, where R, R have the indicated values in the presence of acetonitrile. Yield 60-80%. The effective dose of the substance eliminating the R8NH-CHi-CH-CH2-N medium in dry medium with triethyl is boiled with compound I for 30 min. animal scopolamine, 75 mg / kg for PR (at the same time as for pirates, ie PR is more active (LDjo 7/2000. mg / kg
公开号:SU1360583A3
申请号:SU853900955
申请日:1985-05-29
公开日:1987-12-15
发明作者:Вебер Карл-Гейнц；Шнейдер Клаус；Вальтер Герхард；Гинцен Дитер；Йозеф Кун Франц；Лер Эрих；Энзингер Гельмут；Трегер Вольфганг
申请人:Берингер Ингельгейм Кг (Фирма)；
IPC主号:

专利说明:

The invention relates to the production of new pyrrolidinone derivatives of the general formula
3 /
.
RI
where R is phenyl, unsubstituted or substituted by methyl;
Rj is hydrogen, methyl;
RJ is methyl, chlorophenyl;
 R is hydrogen
or RS and R4 together with the atom. nitrogen means 4-methylpiperazine, which can be used as a nootropic agent, i.e. means of reducing or eliminating the state of limited cerebral functional capacity.
The aim of the invention is to develop, on the basis of known methods, a method for the preparation of new compounds possessing valuable pharmacological properties with enhanced biological activity at low toxicity. Example 1. 4- (N-Methylpiperazinyl-carbonylaminomethyl) -benzyl pyrrolidin-2-one. 76 g (0.37 mol) of 4-aminomethyl-1-b. Benzylpyrrolidin-2- it is dissolved in 1.2 liters of dry dioxane and 52 ml of triethylamine are added. While cooling with ice for 15-20 minutes, add a drop of 40 ml of a layer of phenolic ester chloroformic acid and then after 30 minutes, mix in a vacuum. The residue is taken up with methylene chloride and the organic solution is washed several times with water. The dried organic phase is aspirated.
25
thirty
on coal and evaporated. Owing to the addition of ether, 100 g of 4-phenoxycarbonated 1 crystallize out; aminomethyl-I-benzylpyrrolidin-2-one (82% of theory) with the melting point of VE-EO C. 100 g of this compound, together with 1.2 l of acetonitrile and 62 g of N-methyl piperaein for 2 hours; reflux condenser. The solvent is scorched, taken up in methylene chloride, washed with water, dried with magnesium sulfate, then re-rooted and recrystallized.
If from acetic ester.
Output: 78 g (80% of theory.) So pl. 124-1 26 C.
EXAMPLE 2. (+) 4- (M-Methyl-pi-perazinyl-carbonnlaminomethyl) - - b-.
20 zyl pyrrolidin-2-one.
    - -
The example is carried out analogously to example 1, but with the difference that the use of 36 g (0.18 mol) of (-) 4-aminomethyl-1-benzylpyrrolidin-2-one obtained from the racemate by cleavage of the antipodes using wine acids (, 1,, 0, methanol) and subsequent purification by column chromatography (SiO, solvent: methylene chloride and methanol 9: 1).
Therewith, 39.8 g (67.7% of theory) of the title compound are obtained as a colorless oil, I, 8 35 (, O, methanol).
PRI me R 3. (-) 4- (K-Methyl-pi-rasinyl-carbonylaminomethyl) -benzyl-pyrrolidin-2-one. Starting from (+) 4-amino-1-benzylpyrrolidin-2-one 40 (, 07 °,, 0, methanol) was prepared analogously to example 1, given with t compound,, 8 ° (, 0 methanol), yield 60% theory .
Analogously to Example 1, the compounds listed in Table 2 are obtained. one.
about
N-CH, -RI
CHfA
-N-CO-lSf-CHa H N
5 -O - N-CO- NON-CHj 139-N
6 - -TSl-CO-TSlQN-CH 134-136. SNS
1360583 4
Table I
117-118
140
The results of pharmacological experiments;
For the study of ycTpaHHioPtero, the effects of scopolamine-induced dedendia caused by the use of rats in experimental animals were trained to rescue a platform in a cage when current shocks are transmitted through the bottom grate. After some time, 80% of the animals learned that they were safe on the platform.
If animals are given scampamin (0.6 mg / kg intravenously), then in 80% of the rats a retrogenic effect can be established on short-term memory, i.e. animals have forgotten that they are safe on the platform.
A substance that is able to counteract cerebral insufficiency can eliminate this action. After scopolamine is given, animals are given a test substance and determined. How many percent of animals did not lose a short-term memory after scopolamine. In tab. 2 shows the dose of the test substances, eliminating, on average, 50% of animals have dementia caused by scopolamine (ED dose,;.
thirty
Table 2
Test compound, example, IP
Scopolamine, ED dose., Mg / kg (oral)
4 5
Piracetam (known)
ten
73
50
thirty
five
100
Comparison of data table. 2 suggests that novel pyrrolidinone derivatives exhibit better activity than the known analogue,
The novel compounds belong to low-toxic substances (mg / kg rat, by mouth).

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining pyrrolidinone derivatives of the general formula
-N-cH2 R.
f
N
0
CH
 . one
R, is phenyl, unsubstituted or
substituted with methyl;
hydrogen, methyl;
methyl, chlorophenyl;
hydrogen
R and H together with the nitrogen atom are 4-methylpiperazine, which is a compound of the formula
RJ - Kz - R.
R
HN-CH2
 V
one
where R and R have the indicated meanings, are reacted with a compound of the formula
C1-CO-0-Y,
where Y is phenyl, and the compound of the general formula thus obtained
Y-0-CO-N-CHo
 ABOUT
 15
where R, R, and Y have the indicated meanings,
subjected to interaction with the amine of the General formula
HN
R
25
where Rj and E have the indicated meanings, followed by allocation of the target product.
Editor Y. Sereda
Compiled by I. Bocharova Tehred M. Khodanych
6166/57
Circulation .372Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4
Proofreader V.Girn to

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE19843420193|DE3420193A1|1984-05-30|1984-05-30|NEW SUBSTITUTED PYRROLIDINONES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS|

---