3-(4-methyl-2-thiazolyl)-6-propyl-7-(1-methyl-1-etoxycarbonyl) methoxypropan with hypoglycemic, hypolipidemic action and action analepticheskih

 

(57) Abstract:

Usage: in medicine, as analepticheskih, gipokaliemicheskogo and gipolipidemicheskoe funds. The essence of the invention: 3-(4-methyl-2-thiazolyl)-6-propyl-7-(1-methyl-1-etoxycarbonyl)-metaxia - mon (1) BF C21H23NO5's so square 103-103 deg. C. Reagent 1: bromohydrin 4-methyl-2-seanmeister. Reagent 2: 4-propylresorcinol. Process conditions: in the presence of epirate boron TRIFLUORIDE in a stream of dry HCl. Reagent 3: -(4-methyl-2-thiazolyl)-2,4-dihydroxy-5-propylacetophenone. Reagent 4: exploratory anhydride. Process conditions: 80-100 deg. C. Reagent 5: 3-(-methyl-2-thiazolyl)-6-propyl-7-hydroxychromone. Reagent 6: ethyl ether-bromopropionic acid. Process conditions: in the presence of potash in the environment of the abs. of acetone. LD50V/W is equal to 6100 mg/K. For compound (1) dose of 50 mg/kg, the average percentage reduction in blood sugar for 10 hours is 47%. and exceeds butamid by 32%. At the dose of 100 mg/100 g of live weight reduces by 44.2%. cholesterol and 49.6%. triglyceride. At the dose of 100 mg/kg reduces the time barbituric sleep up to 51.8 2,1 minutes 1 table.

The invention relates to new chemical compound, namely 3-(4-methyl-2-thiazolyl)-6-proper-7-(1-methyl-1-ethoxycarbonyl action. These properties suggest the use of this compound in medicine as a drug complex action.

The most similar chemical structure and pharmacological action of the compound 1 are 3-(4-thiazolyl)chromone [1-3] has hypolipidemic and neuroleptic action.

The purpose of the invention is a new derivative of 3-(2-thiazolyl)chromone with simultaneously higher hypoglycemic, hypolipidemic and analepticheskih activities.

This goal is achieved by connection I, which is obtained by condensation in the modified reaction conditions Gesha of bromhidrosis 4-methyl-2-cyanomethylene 4-propylresorcinol in epirate triftoridov boron, highlighting -(4-methyl-2-thiazolyl)-2,4-dihydroxy-5-propylacetophenone and exposing his subsequent heterocyclization of 3-(4-methyl-2-thiazolyl)-6-propyl-7-hydroxychromone (II), action explorerview anhydride. The condensation of ethyl ester of a-bromopropionic acid with chromosom II get the desired product I.

The invention is illustrated by examples:

Example 1. 3-(4-Methyl-2-thiazolyl)-6-propyl-7-(1-methyl-1-etoxycarbonyl)metaxalone (I).oC. Found, S 11,10; N 4,84. C15H17NO3S. Computed, S Br11.01; N 4,81.

Range of PMR in DMSO-d6the scale s, M. D. protons phenolic parts for ketonic form, 11,99 (2-HE), 6,40 (3-N), 10,66 (4-HE), 0,89; 1,54; 2,48 (5-WITH3H7), 7,72 (6-H), 4,70 (-CH2-); the proton of thiazole, 2,33 (4-Me), 7,18 (5-N); the protons of the phenolic parts for enol form: 12,25 (2-OH), 6,20 (3-H), 9,75 (4-OH), 7,26 (6-H), 14,37; 6,48 (-C(OH)=CH-); the proton of thiazole, 2,19 (4-Me), 6,40 (5-N).

Stage 2. 3-(4-Methyl-2-thiazolyl)-6-propyl-7-hydroxychromone (II).

A mixture of 2.9 g (10 mmol) of a-(4-methyl-2-thiazolyl)-2,4-dihydroxy-5-propylacetophenone and 10 ml Oxymorphone anhydride briefly stirred and then heated at 80-100oC 1,5 hours After cooling the reaction mixture, the precipitate is filtered off. Yield 2.8 g (98%). So pl. 226-227 of theoC (from alcohol). Found, N 4,57; S 10,70. C16H15NO3S. Calculated, With 4.64 N; S 10,63.

Range of PMR in DMSO-d6the scale s, M. D. protons of chromone, 9,05 (2-N), 7,85 (5-N), 0,97; 1,69; 2,68 (6-WITH3H7), 11,05 (7-OH), 6,98 (8-H); protons) potash in 150 ml of absolute acetone was added dropwise with 5.2 ml (40 mmol) of ethyl ester of a-bromopropionic acid and boiled under stirring 4 h The hot solution is filtered from the inorganic precipitate, the solvent is distilled off and crystallized target product (I) of alcohol. Yield 6.5 g (65%), so pl. 103-104oC. Found, S 8,07; N 3,75. C21H23NO5S. Computed, S 7,99; N 3,49.

Range of PMR in CDCl3the scale s, M. D. protons of chromone, 8,99 (2-N), 8,09 (5-N), 0,98; 1,71; 2,75 (6-WITH3H7), 1,71; 4,84; 1,26; 4,23 (7-OCH(CH3)COOC2H5), 6,72 (8-N); the proton of thiazole, 2,49 (4-Me), 6,99 (5-N).

Example 2. Study of the biological activity of the compounds I.

The resulting material was tested for hypoglycemic, gipolipidemicescoy, analepticheskih activity and acute toxicity.

Hypoglycemic activity was studied on rabbits of the Chinchilla breed weighing 2.5 to 3.0 kg of the diet of the animals during the experiment consisted of hay, oats and water. 36 hours before the start of the experiment, food was collected, the water, the animals received unlimited.

Studied compound 1 was administered to animals orally at a dose of 50 mg/kg, as the most effective, in the form of a powder. Blood for analysis was taken from the ear vein at 2, 4, 6, 8 and 10 h after a single injection of the drug in the dose. Served as control rabbits counterparts who did not receive the analyte. Content we investigated the hypoglycemic activity of oral antidiabetic drugs butamid [4] and hlorpropamid [5] is widely used in clinical practice, after a single injection at a dose of 50 mg/kg

The sugar content in the blood was determined orthotoluidine method. The drug was studied on 5 rabbits. The obtained experimental data are presented in the table

The table shows that 3-(4-methyl-2-thiazolyl)-6-propyl-7-(1-methyl-1-etoxycarbonyl)metaxalone (I) exceeds hypoglycemic activity drugs butamid and hlorpropamid. Hypoglycemic effect of this compound increases gradually over time, reaching a maximum (62%) after 6 h from the moment of introduction, which is 32% higher than the activity butamida and 21% of the activity of chlorpropamide. Then the activity gradually decreases, and after 10 h is 54%

As for the results determine the hypoglycemic activity according to average values of the five terms of study, then study the connection I exceeds the activity of the Comparators.

The claimed connection I was studied on the model of lipid-lowering activity. The experiments were carried out on white rats with hyperlipidemia was induced by intraperitoneal introduction of TV suspension test substance I, as well as the reference drug Mickleson to compare the lipid-lowering effect. Control group animals were injected only Triton WR-1339. After 12 h, the rats were decapitate. In all animals examined serum blood cholesterol and triglycerides.

As a result of tests it was found that the introduction of this substance inhibits the development of hyperlipidemia. The substance is 2.5 times lower cholesterol and triglycerides compared with maklarenom.

The connection I was studied on the model analepticheskih activity. The experiments were carried out on white rats of both sexes weighing 180-220 g as a hypnotic when the technique was used Nembutal at a dose of 25 mg/kg animal body weight. Recommended reference drug caffeine-sodium benzoate in the form of a 20% solution was administered subcutaneously at a dose of 100 mg/kg In the same dose and the same conditions were introduced and the connection I.

Compound I has a stimulating effect on the Central nervous system, shortens barbituric sleep 1.9 times compared with the control, and 1.3 times that of the reference drug is caffeine-sodium benzoate largest analepticheskih effect.

Acute toxicity of compound I was the La animal. According to the classification Sidorova this connection applies to practically non-toxic substances.

Thus, compound I has a pronounced hypoglycemic, hypolipidemic and analepticheskih effects and the magnitude of the impact exceeds the drugs used in medicine.

3-(2-Methyl-4-thiazolyl)-6-propyl-7-(1-methyl-1-etoxycarbonyl) methoxypropan formula

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possessing hypoglycemic, hypolipidemic and analepticheskih action.

 

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