Method of producing benzamide derivatives

专利摘要:
The invention relates to benzamide derivatives, in particular compounds of the general formula I: c (OA2 l CRi-CH ((0) 1 cH) where R, is halogen; K is H, halo; R is lower alkyl; A, is a lower alkyl; A-C, -C, -acyl, which exhibit an antipsychotic effect and can be used to treat vomiting, psychosomatic diseases and mental disorders. The goal is to create new benzamide derivatives with improved properties. The compounds of formula I are prepared from the corresponding hydroxyl-containing compounds and acid chloride. -carboxylic acid in the medium trifluorox acidic tests at room temperature. Tests of new substances show that they are more active inhibitors of dopamine receptors in the brain than sulpiride, with similar toxicity. Table 1 I O) ate about N :)
公开号:SU1355122A3
申请号:SU833543247
申请日:1983-01-20
公开日:1987-11-23
发明作者:Леннарт Флорвалл Геста；Ола Густав Лундстрем Ян；Ингвар Рэмсби Стен；Ове Эгрен Свен
申请人:Астра Лэкемедель Актиеболаг (Фирма)；
IPC主号:

专利说明:

The invention relates to the synthesis of new biologically active chemical compounds, specifically to the preparation of new benzamide derivatives, which exhibit an antipsychotic effect, which suggests the possibility of their use in medicine for the treatment of vomiting, psychosomatic diseases and psychiatric disorders.
The purpose of the invention is to obtain new benzamide derivatives with improved therapeutic properties.
Example. (-) - 3, 5-Dichloro-H- (l-ethyl-2-pyrpolydinylmethyl) -6-methoxy-2-hexanoyl hydroxybenzamide,
To a solution of 3.74 g (Yu mmol) (t) -H-ethyl-2- (3 S, 5-dichloro-6-hydroxy-2-methoxy-benzamidomethyl) pyrrolidine in 30 ml of trifluoroacetic acid, stirring, add 2, 68 g (20 mmol) of hexanoyl chloride at room temperature. Stirring is continued at room temperature overnight. The solvent is evaporated in vacuo and the residue is dissolved in methylene chloride and washed with an aqueous saturated potassium carbonate solution, the methylene chloride solution is dried over magnesium sulfate and the solvent is removed under reduced pressure. 36 g (81% of theory) of the above compound are obtained as a dark brown viscous oil (compound I), R value = 0.27 (silica gel: 20% methanol in isopropyl ether).
Similarly, 3-6poM-N- (1-ethyl-2-pyrrolidinylmethyl) -6-methoxy-2-acetoxybenzamide is obtained with the melting point of 1P1Y156 C (yield 83%, hereinafter compound II).
(-) - 3,5-Dichloro-L- (1-ethyl-2-pyrrolidinylmethyl) -6-methoxy-2-propionyl-hydroxybenzamide as a yellow viscous oil (yield 79%, hereinafter compound III),
The value of Rr 0.48 (silica gel: 10% methanol in methylene chloride).
Rj value. for starting compound II, 0.35,
The antipsychotic action can be associated with the blockade of dopamin receptors in the subcortical and cortical marginal structures, while the general extraschrimidal side effects caused by neuroleptic
five
0
agents are a consequence of the blockade of dopamine receptors in the nygonostriatum system of dopamine.
To study the antipsychotic effect of new compounds, methods based on the ability of antipsychotics to block the actions caused by apomorphine are used.
Apomorphine causes a characteristic syndrome in rats, consisting of repetitive actions (stereotypes) and hyperactivity, which occur as a result of activation of postsynaptic dopamine receptors in the brain. Stereotypes (chewing, licking, biting) occur mainly as a result of the activation of dopamine receptors associated with the receptors of the non-striatum system, whereas the movement (hyperactivity) is mainly caused by the activation of dopamine receptors in the meso-edge 5 pax structure.
The experiments were carried out on rats weighing 22.275 g. Rats were kept in cages measuring 40x25x30 cm and their behavior was observed at the end of 5.20.40 and 60 minutes after giving an apomorphine. The test compounds were injected 60 minutes before giving apomorphine hydrochloride (I mg), which was injected subcutaneously into the back of the head. Since the dose and the form of administration, nonyHHtb provided a reliable response with simultaneous minor changes in the response rate. In addition, subcutaneous administration of apomorphine also allows for significant hyperactivity. Immediately after the injections of these compounds into each cage, one animal interfered. The stereotype was determined by two methods. One method was to determine the intensity of stereotype according to the following scale:
O - no change in behavior compared with control (saline) or calm behavior; 1 - periodic sniffing;
2- continuous sniffing;
3- continuous sniffing, chewing, licking, biting .. Another method was to determine the number of animals exhibiting hyperactivity caused by apomori
five
0
50
55
3 .1
finom. Each group consisted of 6 to 8 animals. Control experiments (giving salt solution) were carried out simultaneously. According to the first method, it represents a dose that reduces the intensity of stereotype by 50% after 60 minutes, and according to the second method, ED represents a dose that reduces the number of animals showing hyperactivity by 50% after 60 minutes. Doses were determined from dose and response curves, and the smallest squares of reactions for 4–6 doses at 6–8 animals per dose were taken into account.
The results of the experiments are summarized in the table.
The novel compounds were compared with sulpiride-I-ethyl-2- (3-sulfonylamino-6-methoxybenzamomethyl-) pyrrolidine. From the data in the table, it is clear that the novel compounds are more active inhibitors of dopamine receptors in the brain. Due to antagonism with respect to stereotype and hyperactivity caused by apomorphine, new compounds are likely to block dopamine receptors in striatum and edge structures.

权利要求:
Claims (1)
[1]
The novel toxicity compounds are not inferior to sulpiride DC, which is 440 µmol / kg when administered intraperitoneally (rats). Invention Formula
The method of obtaining benzamide derivatives of the general formula
R2 OAi VCO SHCHo-O
V4Tsi
Ri OA,
Editor G. Volkova
Compiled by M. Bibikova
Tehred M. Khodanich Proofreader M. Maksimishinets
Order 5719/57
Circulation 372Subscribe
VNII11I State Committee of the USSR
on cases of inventions and discoveries ° 113035, Moscow, Zh-35, Ra usushka nab. 4/5
Production and printing company, Uzhgorod, Projecto st., 4
224
where R, is halogen;
R is hydrogen or halo;
R is lower alkyl;
And, - lower alkyl;
A - C, -C, -acyl
characterized in that the compound of general formula
RZ OAi
f VcONHCH, -O N
PI OH
where H, E, R and A,
1 RP
have a decree
values, interact with the compound of the general formula
R - CO - C1,
where R - means lower alkyl, followed by separation of the target product.

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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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SE8101536A|SE8101536L|1981-03-11|1981-03-11|Benzamide derivative|

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