1-(1,1-dissociator-3)-2-morpholinobenzenediazonium hydrochloride, increasing resistance to acute hypoxia with hypercapnia

 

(57) Abstract:

The invention relates to organic chemistry and pharmacology, and relates new connection - 1-(1,1-dissociator-3)-2-morpholinobenzenediazonium hydrochloride, increasing resistance to acute hypoxia with hypercapnia. The new connection has a high activity. 1 C.p. f-crystals, 4 PL.

The invention relates to medicine, namely to pharmacology and can be used to produce new drugs that increase resistance to acute hypoxia with hypercapnia.

The technical result - expanding Arsenal of biologically active substances, including increasing resistance to acute hypoxia with hypercapnia.

The essence of the invention: 1-(1,1-dissociator-3)-2-morpholino-benzimidazole hydrochloride formula

formula 1

increases resistance to acute hypoxia with hypercapnia.

1. As Comparators used bemythyl (2-ethylthiophenethylamine hydrobromide), Tamerza (5-etexilate-benzimidazole hydrochloride) (Kosolapov Century A. Protective effect of antioxidant substances in hypoxia and posthypoxic period. // The Diss. Kida. Biol. Sciences. - The ox who has also antiaggregatory, stimulating, immune system, act-protective action (Mashkovsky M. D. Medicines. So 1. - M., 2000, S. 122).

The inventive compound is synthesized as follows.

Boiling 1-(1,1-dissociator-3)-2-chlorobenzimidazole with morpholine in the environment butanol get 1-(1,1-dissociator-3)-2-morpholino-benzimidazole, rolling when added to a solution of the compound in dioxane 5% solution of hydrogen chloride in ethanol to pH 1-2 in the target salt.

Example 1. The synthesis of the claimed compounds.

Synthesis of 1-(1,1-dissociator-3)-2-chlorobenzimidazole carried out according to the method described in Chem. Pharm. J., - 1993, No. 3, S. 25-26. The solution to 2.57 g (10 mmol) 1-(1.1-dissociator-3)-2-chlorobenzimidazole in 80 ml of butanol added 4.35 g (50 mmol) of the research, boiled for 7 hours. The solution is cooled to 5-10 ° C, the precipitation is filtered off, washed with water, dried. Obtain 1.48 g (48%) of 1-(1,1-dissociator-3)-2-morpholinobenzenediazonium. Crystallized from ethanol.

An NMR spectrum1N (TFOC), , M. D.:

3,36 ush.with.(4H, O(CH2)2)

3.80 ush.with.(4H, N(CH2)2)

4,50-4,90 m (4H, 2S(CH)2)

5,12-5,54 M (1H,NCH)

? 7.04 baby mortality-7.80 m (4N, N arene.)

Elemental analysis.

The solution is 3.08 g (10 mmol) of 1-(1,1-dissociator-3)-2-morpho-linoperamata in 70 ml of dioxane is added a 5% solution of hydrogen chloride in ethanol to pH 1-2. The solution is cooled to 5-10 ° C, the precipitate filtered off, washed with dioxane and dried. Gain of 2.51 g (73%) of 1-(1,1-dissociator-3)-2-morpholinobenzenediazonium hydrochloride.

Found, %: From 49.1 N 5,5 12,0 N S 10,8-C14H17N3O3SHCL

Calculated, %: compared TO 48.9 N 5,3 N 12,2 S 10,6

Compound 1 is a white crystalline powder, soluble in water, insoluble in dioxane.

Range of antihypoxic activity of the claimed compounds and Comparators investigated in accordance with the Methodological recommendations for a pilot study of drugs proposed for clinical studies as antihypoxic funds. As laboratory animals used weinbrenner of male mice weighing 16-18 g, obtained from the kennel “High”, ,Moscow. The claimed compound and the Comparators were injected intraperitoneally once for 1 hour before testing. In each group were used for 6 animals.

Example 2. Acute hypoxia with hypercapnia (Ohshc) - by placing mice in St conditions Ohshc Comparators are not active. Connection 1 has a significant antihypoxic effect (P<0.01) in terms of this model at a dose of 1 mg/kg doses of 5 and 10 mg/kg declare the connection is not active.

Example 3. Acute hypobaric hypoxia (AGBG) was modeled in a flow chamber at ambient temperature +20 ° C by “lifting” of mice with a speed of 50 m/s at a height of 11000 m the Results are presented in table 2. Tamerza and antioxidant emoxipin had no protective effects in the studied conditions (11000 m). The bemythyl extends the lifespan of mice on 55,12% (P<0,05). Compound 1 did not change the lifespan of mice in any of the doses administered.

Example 4. Acute gemicescuu hypoxia (Ageg) reproduced by the introduction into the skin of the back of 4% aqueous solution of sodium nitrite at a dose of 400 mg/kg the Results are presented in table 3. The bemythyl and Tamerza in terms of Ageg show pronounced antihypoxic activity, increasing survival by 42.4% (P<0,05) and 39.7% (P<0,01), respectively. The emoxipin increases survival of animals by 29% (P<0,05). The connection in terms of this model of hypoxia was not effective.

Example 5. Acute histotoxic hypoxia (AGTG) reproduced by the introduction of a 1% solution of diproton (microprocessor and emoxipin increase the lifespan of mice in conditions OGTG by 30.2% (P<0,05), 19.7%) and by 33.0%, respectively. Compound 1 showed no activity.

Thus, compound 1 has a protective effect in acute hypoxia with hypercapnia at a dose of 50 times less than bemythyl and emoxipin, and 40 times - etomite. Pronounced antihypoxic effect under this model significantly outperforms the Comparators.

1-(1,1-dissociator-3)-2-morpholinobenzenediazonium hydrochloride, increasing resistance to acute hypoxia with hypercapnia.

1. 1-(1,1-dicotyledon-3)-2-morpholinobenzenediazonium hydrochloride formula

2. Substance under item 1, increasing the resistance to acute hypoxia with hypercapnia.

 

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