SU1566684A1 - Hydrochlorides of amides of cinnamic acid, displaying antiallergic and cerebroprojector activity - Google Patents

Abstract

The invention relates to derivatives of aryl aliphatic unsaturated acids, in particular the hydrochlorides of cinnamic amides hydrochlorides of the general f: 2R ,, 4Rt-CbH, (0) -NH-06H4-4-C (0) -0- (CH,) 2-N - (C2Hy) 2 HC1, where a) R, Rt OCH5; b) c) P, -OCH,; R2 0-C (0) CH ,; d) R, H; R e 0-C (0) -CHj with nitallergic and cerebroprotective effects that can be used in medicine. The goal is to create new, more active substances of this class. The synthesis is carried out by the reaction of the substituted cinnamic acid chloride with novocaine hydrochloride P in pyridine (or toluene) medium. Output,%: so pl., With; gross l la; degree of inhibition of the allergen — histamine, serotonin,%; degree of pizhivayemost rats with igpemii brain after 6 and 48 h,%; GL5o mg / kg: a) 76; 197-198; Cr, H31S1KgO; 27.1} 31.0; 60 and 40; 325; b) 93; 192-194; C2, H2, C1N204; 20.4; 30.9; 66.7 and 66.7; 345; o) R5; I62-164; C2JHVC1N / V; 29.6; 41.1; 50.0 and 33.3; 375; d) 81; 169-170; C7, H49C1N 05; 34.7; 37.6; 83 and 83, 275, versus 3.8 and 5.6% for sodium cromoglycate and 100 and 62.5 for Cavinton, table 4. r to

Description

where Ia-R, Tb-R, IB-R,

 Rt OCH, j H; Pr OCH; OSI; R OCCHj j b

tr-R, H; R2 OSPN ,,

possessing antiallergic and therapeutic protective effect.

The purpose of the invention is to search for new z-i-cinnamic acid amides having improved antiallergic and cerebroprotective properties.

g

Example) Preparation of hydrochloride with ethyl ethyl oethyl ether 4- (3,4-dimethoxaneIaminoamide) benzoic acid (substance Ta),

A solution of 2.73 g (0.01 mol) of novocaine hydrochloride in 30 ml of pyridine is added to a solution of 2.2 (g (O. Ogmol) of 3,4-dimethoxycinnamic acid perehydride in 50 ml of toluene. The reaction mixture is left for 12 The “precipitate is filtered and washed with toluene, Crystallized from propanol-2.

Yield 3.5 g (76%). M.p. 197 - 198 ° C.

Found: C, 62.48; And 6.81; C1 7.80; N 6.20;

; c44H ,, caiito,

Calculated: C 62.27; H 6.70;

C1 7.68; N 6.05.

UV-spectral data: 252, 340 to them. IR spectra data: 3400, 1720, 1675, 1630, 1600, 1520, 1270, 1230, 1150, 1100, 1000, 850 cm 1.

Example 2 Preparation of 4- (4-methoxycinnamide) benzoic acid diethylaminoethyl ester hydrochloride (16).

To a solution of 1.97 g (0.01 mol) of 4-methoxycinnamic acid in 50 ml of toluene, a solution of -2.73 is added. g (0.01 mol) -novaine hydrochloride in 20 ml of pyridine. The reaction mixture is left for 12 hours. The precipitate formed is filtered, washed with toluene and crystallized from propanol-2.

The output of 4.03 g (93%). M.p. 192 -.

Found: C, 63.65; H 6.63; C1 8.21; N 6.60. Ct, Ht, ClHtO

Calculated: C 63,81; H 6.71; C1 8.09; N 6.47.

UV spectra data: 226, 332 nm. The data of the NC spectra: 3400, 1710, 1680, 1630, 1590, 1520, 1270.1240, 1160, 1100, 970, 820.

Example 3. Preparation of 4- (4-acetoxy-3-methoxycinnamamide) benzoic acid (TV) hydrochloride diethylaminoethnl ester.

A solution of 2.73 g (0.01 mol) of novocaine hydrochloride in 20 ml of pyridine is poured into a solution of 2.55 g (0.01 mol) of 4-acetoxy-3-methoxycinnamic acid in 50 ml of toluene. The reaction mixture was left for 12 hours.

,

five

0

This precipitate is filtered, washed with toluene and crystallized with propanol-2.

Exit 4.17 (R5). M.p. 162-164 ° C.

Found: C 61.28; H 6.48; C1 7.32; H 5.88.

C H ClNtOt

Calculated: C 61,16; H 6.32; C1 7.24; N 5.71.

UV spectra data: 240, 320 nm.

IR spectra data: 3400, 1720, 1680, 1595, 1520, 1260, 1235, 1150,

1100, 970, 890.

PRI me R 4. Preparation of 4- (4-acetoxycinnamide) benzoic acid diethylaminoethnyl ester hydrochloride (I g).

A solution of 2.73 g (0.01 mol) of novocaine hydrochloride in pyridine is poured into a solution of 2.25 g (0.01 mol) of acid 4-acetoxycinnamic acid in 50 ml of toluene. The reaction mixture is left for 12 hours. The precipitate formed is filtered, washed with toluene and crystallized from propanol-2.

Yield 3.73 g (81Z). M.p. 169 - 170 ° C

Found: C, 62.66; H 6.45} C1 N 6.22. Cz4Hz, ClNj05

Calculated,%: C 62.54} H 6.30; C1 7.71; N 6.08.

UV spectra data: 222, 312 nm.

IR data: 3400, 1770, 1675, 1590, 1530, 1250, 1230, 1160, 1090, 960, 850.

The study of the antiallergic effect of compounds of general formula (I) was carried out on the model of the reaction of passive cutaneous anaphylaxis (RPCA).

Serum containing specific homocytotropic antibodies was obtained in the third week after sensitization of mywei of the CBA line with ovalbumin (0.5 μg) with aluminum hydroxide (2.5 mg / am). The obtained mouse serum at a dilution of 1:30 (after determining the titer of thrombocytotropic antibodies in RRCA) was injected intracutaneously in 6 clipped areas of the back of white rats - Wester male line (180-2 U g) in an amount of 30 μl. After 24 hours, a rat dose of ovalbumin (I mg / kg) was intravenously injected into the rats (in 1 ml of a 0.5 solution of Evans blue dye on physiological solution, after 30 minutes

rats under ether anesthesia were decapitalized, the skin was turned out, the colored areas were excised and the dye was extracted with Lormamid at 37 ° C for 4 days. The amount of dye in the extras was determined spectrophotometrically at 600 them by the calibration curve.

The analyte was administered intraperitoneally at a dose of 10 mg / kg 60 minutes before the resolving dose of antigen,

Antiallergic preparations of sodium cromoglycate, that agyl, and cvn-rasten were used as an object of comparison. Cromoglycate sodium injected at a dose of 50 mg / kg (5 times more than the compound (And, because at the dose of 10 mg / kg of the pronounced antilpergic effect in RPCA, he did not manifest) intraperitoneally 60 minutes before the administration antigen. Tavegil and suprapine were administered at a dose of 10 mg / kg. Control rats were injected intraperitoneally with a fichiological solution.

The percent inhibition of RPCA was calculated by Lormule:

(

mcg blue in the skin areas of rats treated with the test

compound

mkg simki p areas of the skin of control wings

The results of the experiments are statistically processed and are given in table.1.

Further, the effect of Aormul's (I) pride on the manifestation of a local vascular reaction caused by intracutaneous hygtenamine (1 series) and serotonin (2 series) was investigated.

White rats (210-240 g) were intravenously injected with 1 ml of a 0.5% solution of Evans blue and immediately thereafter in 30 pre-cut areas of the back skin - 30 μl of histamine (80 μg / ml) (1 seri) and serotonin (2 µg / ml) (2 seri) in physiological solution. After 5 min in rats depleted under electronic anesthesia, the intensity of the local vascular reaction was assessed by the amount of dye in extravasate determined by the method described above.

60 minutes before intradermal injections of histamine and serotonin, solutions were injected intraperitoneally with is6bf 4 + L

The following substances in a dose of 10 mg / kg. The quality of the object of comparison is nspedorpn-kromoglik t sodium, which was administered at a dose of 50 mg / kg in the same way. Control rats were intraperitoneally injected (physiological solution.

The percentage of skin reactions caused by the administration of his. JQ mine (| seri) and serotonin (2 seri) was calculated using the above Formula. The results of the experiments are statistically processed and are given in table. 2 and 3.

15

The effect of substances on the survival rate of wings with cerebral ischemia was studied, and the hypoxia method was studied using the method of tricornorcosis.

White arches (180–750 g) were drugged by intravenous administration of ethylminll-sodium (30 mg / kg). The carotid arteries, on which sensible ligatures were superimposed, emerged. After 24 hours, after the cessation of the action of anesthesia, the substances were administered intraperitoneally at a dose of 10 mg / kg.

After 60 min, the carotid arteries were tied up and the animals were monitored for at least 48 hours. The criterion 30 of the substance activity is the survival rate of animals after 48 h. Cvinton and Dibazol, administered at a dose of 2 mg / kg 60 min before transfer, were used as targets. zki carotid arteries.

The results of the experiments are given in table.4.

35

Determination of acute toxicity and calculations carried out using the Kerberl method.

White mice weighing 18-20 g were intraperitoneally injected with 0.5 ml of the solution of the investigated substances. For each dose in the experiment took 6 mice. Received the following value LD, ml / kg: 1A - 325; 16 - 345; Gu - 375; I g - 275.

The antiallergic activity of the compounds of the general formula (T) is 10-12 times higher than that of sodium cromoglycate. Moreover, unlike the latter, compounds (I) show antagonistic properties with respect to allergy mediators - histamine and serotonin, reducing skin reactions caused by them.

In addition, for compound 1c, properties to prevent death are revealed.

of guinea pigs from anaphylactic shock and anaphylactic bronchospasm, suppress the anaphylactic contracture of the isolated ileum of the guinea pig, and reduce the sensitivity of e to gstamine, acetylcholine, serotonin, inhibit the release of gnetanin from the fat cells of mice, induced by an antigen, and an arthropod. 80

In addition, compounds (I) increase the productivity of animals with ischemic brain. The most active cerebroprotective effect is observed in compounds 1g and 16 (83 and 66.7%, respectively), whose activity exceeds that of Cavinton (62.5%) and Dibazol (33.3%).

Claims (1)

Invention Formula Cindrochloride anides of cinnamic acid of the General formula: ; 2- -CH CH-C-NH- -C -0- (CH2) 2-N-lC2H5) 2-Hci () de 1a 16 gv - R - R " - R H; R,  OSI OCH} {  DOS I am RI OSSN; ABOUT Effect of compounds of general formula (t) on the manifestation of RPCA in rats 201g - R, H; B4 OSSI9, ABOUT possessing a allergic and cerebroprotective effect. Table 1 Table 2, The effect of the studied substances on the intensity of the local reaction caused by a / to the introduction of gstamine The effect of the test substances on the intensity of the local reaction caused by iv injection of serotonin Table3 X), 25 0.001 0.002 0.001 SO, 001 11156668412 Table Influence of duel "cure" on survival rate of rats with ischemia of the brain