Derivatives of 6,7-dihydro-5h-dibenz (c, e)azepin-7-it manifesting garmentindustry activity


(57) Abstract:

Usage: as substances with garmentindustry activity. The inventive product: derivatives of 6,7-dihydro-5h-dibenz/C,e/azepin -7 - it General formula where R = F or CI, Reagent 1: substituted benzoyl chloride. Reagent 2: 6,7 - dihydro-5h - dibenz/C,e/azepin - 7 he. Reagent 3: pyridine. Reaction conditions: boiling under reflux for 4 hours at 120°C.

The invention relates to new chemical compounds with biological activity, particularly to derivatives of dibenzazepine-6,7-dihydro-5H-dibenz [c, e] azepin-7-it is a General formula

R (I)where R is F, Cl, which have garmentindustry activity against microsomal cytochrome P-450-dependent monooxygenase system, liver, metabolizing foreign compounds - xenobiotics. This property allows the use of these compounds in medicine as inducers of metabolism of xenobiotics.

The closest structural analog - 6,7-dihydro-5H-dibenz[c,e]azepin-7-it - has weak garmentindustry activity. As basic compounds taken reference garmentindustry drug - phenobarbital - 5-ethyl-5-panelbar the m views pharmacological activity and low toxicity.

The goal is achieved by introducing substituted with halogen sensornogo residue at the N-position.

P R I m m e R. Synthesis of N-o-chlorobenzoyl-6,7-dihydro-5H-dibenz[c,e]azepin-7-it.

to 5.2 g (0,025 mol) of 6,7-dihydro-5H-dibenz[c,e]azepin-7-OA, 0.03 mol o-chlorine substituted of benzoyl chloride and 20 ml of pyridine is boiled in odnogolosy flask, equipped with reflux, for 4 hours at 120aboutC. Then the reaction mass is then cooled, add to it 10% solution of hydrochloric acid until no odor of pyridine. The precipitation is filtered off, washed on the filter with water, dried and recrystallized from a mixture of ethanol:acetone = 4: 1. When TLC shows the presence of a source of 6,7-dihydro-5H-dibenz[c,e]azepin-7-it is after cleaning, repeat it again. Rfbenzoylpropionic of 0.7-0.8; Rfsource dibenzazepine 0.37 system benzene:ethanol = 8:2. Characteristics of the obtained N-o-chloro-benzoyl-6,7-dihydro-5H-dibenz[c, e] azepin-7-it is presented in a table. 1.

The synthesis of other halogen derivatives of N-benzoyl-6,7-dihydro-5H-dibenz[c,e] ATAPI Nona carried out analogously to example. The experimental and calculated data on these compounds are also presented in table. 2.

Biological testing of the compounds NN 10210791-10211091, EN zymes the soup xenobiotics, conducted baseline drug phenobarbital on white outbred mice-males and Wistar rats. The activity of compounds was evaluated by the test geksenalovy sleep, the content of cytochrome P-450 in liver microsomes, the metabolic rate of substrate type I - amidopirina and substrate type II - aniline. Was determined daily acute toxicity in mice.

Biological tests were carried out on outbred mice-males weighing 18-22 g, the group consisted of 6-12 animals and rats male Wistar rats weighing 150-200 g of tested compound was administered in equimolar doses of 110 mg/kg inside three times once a day in the form of a suspension in 1% starch mucus. Comparison drug phenobarbital inside in equimolar dose of 80 mg/kg according to the same scheme. Control animals were injected equiano amount of starch mucus. Geksenal were injected with intraperitoneal dose of 80 mg/kg every 24 h after the last injection of inductors. The duration of drug-induced sleep was assessed by the absence of reflex turning of animals. Shortening the duration geksenalovy sleep proves the induction of monooxygenase systems in the liver, which metabolism geksenala and other xenobiotic coming and aboratory animals conducted biochemical studies of microsomal fraction of the liver of Wistar rats, obtained by differential centrifugation of the homogenate. In microsomes was determined by the level of cytochromes P-450 and5metabolism amidopirina was assessed by the formation of formaldehyde in the incubation media, the p-hydroxylation of aniline - education p-aminophenol. The content of microsomal cytochromes P-450 and5the activity of N-demethylase amidopirina and p-aniline hydroxylase was calculated per 1 mg of microsomal protein. Protein was determined by micromethod Lowry. The obtained results were processed by the criterion Student. The results of the biological tests are given in table. 1, 3 and 4.

The results presented in table. 1 and 3, indicate that the three-time ingestion of all of the compounds I is a significant shortening of the duration geksenalovy sleep laboratory animals - mice and rats, comparable to the action of a reference preparation of phenobarbital. The most active is the compound N 10210791 - o-ftoroproizvodnykh of dibenzazepine, which is more active than phenobarbital. Do not yield garmentindustry activity phenobarbital, judging by the duration geksenalovy sleep, connection N 10210891 and N 10210991 (PL. 3). From table. 4 shows that these compounds in equimolar the N-demethylation amidopirina and n-hydroxylation of aniline, that also indicates the induction of monooxygenase systems in the liver, developing under the impact of the proposed connection.

Thus, compounds I - halogenated derivatives of dibenzazepine are strong inducers of microsomal system of the liver and do not yield on this type of biological activity of phenobarbital. In addition, compounds I are significantly less toxicity compared with phenobarbital LD50for mice, the oral administration is for all connections over 1500 mg/kg of phenobarbital - 320 mg/kg

Thus, for the first time among benzoylpropionic of dibenzazepine detected inducible monooxygenase system of the liver, with significant garmentindustry activity and low toxicity.


Derivatives of 6,7-dihydro-5H-dibenz(C,e)azepin-7-it General formula

< / BR>
where R is F or Cl,

showing garmentindustry activity.


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