SU522597A1 - Bis-(dialkylaminoalkylamides) of alpha-traxillic acid exhibiting curate-like activity - Google Patents

Description

The invention relates to the preparation of the adduct group of compounds possessing a high curariform active r-t Cllt {clH2) where R is hydrogen, alkyl; R - alkyl or together with the nitrogen atom forms a heteroshction | climatic radical, for example pyrrolidyl, piperidyl; X is an inorganic or organic acid residue, for example iodine, chlorine, (-Sft CH), CbHe W / These compounds are salts or quaternary salts of bis (dialkylaminoalkylamides) d, -truxyl acid of the general formula l 1Ч (СН2) d n ( ,) .I is an integer 2-5. Other types of compounds are also known to exhibit curare-like activity, for example, in 6-tubocuraria and some bis-quaternary salts of bis-alka foreign compounds of 1,3-diphenylcyclobutane-2, 4-dicarboxylic 352 acids. Two of the most active compounds of the latter type they have been studied experimentally and clinically and have been proposed for anesthesiology as non-depolarizing muscle relaxants of a short duration - anatruxon and L13 cyclobutoni 2 J. However, along with the positive qualities of anatruksonium and cyclobutoNII in myoparalytic These doses have an undesirable effect for cholinolytic action, which makes it difficult in some cases to use them. Therefore, the introduction of compounds of similar activity, but not Kurarepodna active with c-Truxillo

Cfrhl

n

n (jghg

((jH)

2x 4 with M-cholinolytic action has practical and theoretical importance. For the first time, it was found that the replacement of the “complex” group in the known compounds with an imide group for some derivatives of the bis-alkamine esters 1, 3-diphenylcyclobutane-2,4-dicarboxylic acids leads in several cases to active muscle relaxants (see structural formula I). In tab. Experimental data showing the effective non-depolarizing properties of compounds of the formula U) are given. -, Table 1 of acid amide derivatives

-M (.0, Ts5) 2SiZ

-M CCiHy)

"-YU

220-240

200-220 A5-50

25-30 18-20

sixteen

V - 44

 7 oL-tubocurarine As a reference, I compare G- -.en. (jHa (, -) "hsr. Record excitation transfer from the sciatic nerve to the gastrocnemius muscle (chloralose 60 mg / kg with urethra 300-400 mg intravenously). register in semi-isometric mode. Bis-quaternary salts of amides of o-truxyl acid are among the long-acting myorex laxants. No side effects were detected. With the administration of substances in myoparalitic doses, the arterial pressure does not change, the heart rate is not disturbed. Substances do not affect the vegetative ganglia and the AL-cholinergic receptors of the heart4 The release of histamine is not observed. The toxicity of the substance is low, the therapeutic latitude is significant.

ea-iQ

80-100 180-230 take - o -V-tubocurarin chloride / Tests carried out on cats, rabbits, blue and lions. The curative activity and duration of action are judged by the effect on nerve transmission and the ability to induce relaxation to & The mechanism of action will be investigated on the blue and isolated straight belly of the flax, as well as on interaction with prozerin. Heart rate, blood pressure, autonomic ganglia, and excitatory transmission from the wandering nerve to the heart are studied in experiments on cats. Toxicity is investigated under conditions of artificial respiration. From the data in the table it can be seen that all compounds have distinct curariform activity. It is most pronounced at i 3. These compounds are 5–10 pas superior in ot-tubocurarin chloride activity. With a 7 increase in the chain length to AND 4, the blocking effect on the neuromuscular transmission decreases by a factor of 3-5. The most effective are salts with II. According to the mechanism of action, all these substances are related to nondepolating agents, they cause paralysis in goluboy, do not cause contractures of the isolated direct muscle of the abdomen and the whole body and eliminate the stimulating effect on her acetylcholine and carbocholine. The antagonist of the compounds of formula (I) is prozerin. The proposed compounds could be obtained by the reaction of obruxilic acid or its derivatives (halo-anhydrides, ethers, etc.) with primary IHO-tertiary amines NHj (CH2) iNR2. and the subsequent conversion of the resulting aminoamides into salts by the action of acids HX or bis-quaternary salts by the action of alkylating agents. The isolation is carried out using known methods. Example I. A solution of 6.6 g of dichloroethane in 40 ml of dichloroethane is added to a solution of 6.2 g 1 4gM-piperidylbutylamine in 30 MP of dichloroethane at 3 ° C, incubated for 16-18 hours at 20 ° C, then 20 ml of water are added, the organic layer is separated and successively removed 3 times (10 ml each time) with a 5% solution of sulfuric acid and 1 time 10 ml of water. The aqueous extracts are combined, treated with activated carbon, the filtrate is made alkaline with ammonia solution to a pH of 9 at 3-5 ° C. An oil is liberated, which crystallizes on standing. Obtain 5.7 g of bis- (1,4-N-piperidylbutyl yes) about truxyl acid, so pl. 152-153 C (from acetone). Found,%: C 75.48; H 9.15; H 9.78. o Sz6% 0 Calculated,%: C 75.15; H 9.01; N 9.74. A mixture of 4 g of P1Noamide, 40 ml of methanol and 4 MP of ethyl iodide is heated for 1 hour while the alkaline reaction disappears, a precipitate is formed which is recrystallized from methanol. Bis (1,4-N-piperidylbutylamide) o-hruxyl acid diiodoethyl is obtained. M.p. 236-238 C (with decomposition). Found,%: a 28.78 Calculated,%: 328.68 (see tab. 1, compound 16), 8 Example 2. Analogously, bis- ((G-diethylaminopropylamide) "- trucxcic acid is obtained, m.p. 135Pb C. Found,%: C 73, 58; H 9.23; N 10.51. 4- ° g Calculated,%: C 73, 84; H 9.23; N 10.67. Dihydrochloride, m.p. 150 C. Found,%: C1 11.64. Calculated,%: CE 11.95, Diyozztilat, Tpl 246-248 C (with decomposition) Found:% 30.80 Calculated,%: D 30.65 (see table 1, compound 7). Example 3. A mixture of 6.5 g of dimethyl ester "-truxyl acid and 4.64 g of p) -diethylaminostillamine is heated in a round bottom flask at I40-150 C for 12 h. The reaction mass is triturated with 50 ml of water and acidified with concentrated hydrochloric acid, the remaining precipitate of unreacted ether is filtered off, washed with water, the combined filtrates are alkalinized with 25% aqueous ammonia. The precipitate formed is filtered, washed with water, dried and recrystallized from acetone. 4.7 g of aminoamide are obtained. M.p. 137-138 ° C. Found,%: C 72.76; H 8, 94; N 11.15. 3o4l2U 2Calculated,%: C 73, 14; H 9.00; M 11.36. Diodoethat. A mixture of 2 g of base is dissolved in 30 ml of methanol, 2 ml of ethyl iodide is added and the mixture is boiled for 6 hours until the alkaline reaction disappears in the sample. After evaporation of the methanol, the precipitate is triturated with acetone and recrystallized from alcohol. 2.1 g of bis quaternary salt are obtained. M.p. 254-256 C (with decomposition). Found,%:, 37. Calculated,%: 3 31.59 (see tab.1, compound 3). Example4. To a solution of 5.2 g of 1,3-y- (N-pyrrolidyl) propylamine in 40 ml of dichloroethane was added a solution of 6.6 g of dichlorohydride with (. Truxyl acid in 30 ml of dichloroethane, kept the mixture for 16 hours at 20 ° C, added 20 ml of water are separated, the organic layer is separated and successively extracted; 9 they are pressed 3 times in 10 ml of 5% sulfuric acid and 1 time by 10 pips of water. The extracts are combined, treated with activated charcoal, and 4 liters are added with ammonia solution An oil is formed, which crystallizes at one hundred g of the scientific research institute. 6.3 g of bis- is obtained (4-pyrrotsch l) about pylamide o.-truxyl acid C. 135. 135 ° C (from ztiratel acetate). Found: C, 74.33; H, 8.28; N, 11.10. C NddMlYagV1nitsa,%: C, 74.33; H, 8.58; N 10 , 85. A mixture of 0.5 g of base, 5 ml of methanol and 0.5 ml of ethyl ether

Claims (2)

Bis (dialkylaminoalkylamides) ci Claims H H + UVK2T "((5Ng) MN-N Truxyl acid of general formula V (JiHs H J - 2ffl {(iH8) KIlRiif H 710 h-toluenesulfonic acid is heated until the alkaline reaction disappears, upon cooling, the reaction mixture is dissolved in water, treated with activated carbon, the filtrate is evaporated, and in the residue, I-toluene sulfonate is obtained as a vitreous mass. Found,%: M 6.43; S 7.60. 46 69 4 Calculated,%: N 6.44; S 7.38 (see table 1, compound Yu). Other compounds of general formula (D) are also prepared in the same way, in which the values of -NR, XR, P ja and the temperatures of the melted base, salt or quaternary salt are presented in Table 2. Table 2, where R R X p and 52259712 are hydrogen, alkyl, exhibiting curare-like activalkyl or concurrently. The nitrogen atom forms a heterocyclic radical. Sources of information, such as pyrrolidyl, are piped into account in the examination of Ridil; 1. USSR author's certificate inorganic residue or 360343, Bulletin of inventions of organic acid, at-p 36, 1972. example iodine, chlorine, (- СDСНН), 2. USSR Author's Certificate (n-CH,); to№360849, Bulletin of Inventions integer 2-5, f, 27, 1973.