2,6-dimethylanilide of n-cyclohexylpyrrolidine-2-carboxylic acid hydrochloride, having surface, infiltration and conduction anaesthesia activity

FIELD: chemistry.

SUBSTANCE: invention relates to a novel biologically active 2,6-dimethylanilide of N-cyclohexylpyrrolidine-2-carboxylic acid, having surface, infiltration and conduction anaesthesia activity, considerably better than bupivacaine and ropivacaine with the same or less toxicity.

EFFECT: improved compounds.

2 tbl

 

The claimed connection relates to the field of organic chemistry class arylamido azacyclopentadecan acids, namely new biologically active 2,6-dimethylaniline N-cyclohexylpiperidine-2-carboxylic acid hydrochloride (I) of the formula:

which can find application as a medicinal poverkhnostnoaktivnykh tools.

As the standards of local anesthetic action used a well-known and widely used local anesthetics bupivacaine and ropivacaine [Mashkovsky PPM Medicines. - 15-ed., Rev., Corr. and supplementary): RIA "New wave": the Publisher Merenkov, 2008. - 1206 S.: ill.].

The aim of the invention is to obtain a new previously undescribed 2,6-dimethylaniline N-cyclohexylpiperidine-2-carboxylic acid hydrochloride, has anesthetic effects. This goal is achieved by the synthesized δ is haralanova acid, followed by its translation into the acid chloride with chloride tiomila. Then the acid chloride mineralsa 2,6-dimethylaniline and cyclized using cyclohexylamine 2.6-dimethylaniline N-cyclohexylpiperidine-2-carboxylic acid, which use gaseous hydrogen chloride is converted into hydrochloride. The scheme for synthesis of:

Synthesis of 2,6-dimethyl what nelida N-cyclohexylpiperidine-2-carboxylic acid hydrochloride carried out by well-known methods, with some modifications. [Lihosherstov A.M., Pryanishnikova N.T., A.S. Lebedev and other Azacycloheptane XIX. Synthesis and an anaesthetic activity of some Mezhidov pyrrolidinecarbonyl-2 acid. // Chem-Pharm. J., 1976, Vol.7, p.36-40.]:

α-bromo-δ-haralanova to-one (II). A mixture of 52.2 g of δ-haralanova acid (I), with 76.8 g of dry bromine and 4 ml of phosphorus trichloride was placed in a round bottom flask of 250 ml with a reflux condenser and was heated on a water bath for 20 h at 80°C and then 2 h at 100°C. the Reaction mass was washed with water in a conical flask (Erlenmeyer), 500 ml, the oily layer was separated using a separating funnel, 500 ml, and the aqueous was extracted several times with benzene. The benzene extracts were combined with the oil and the solution was dried with magnesium sulfate. After distillation of the benzene residue was awarded to 75.1 g II, the output of 90.7 percent.

The acid chloride, α-bromo-δ-haralanova acid (III). It is 103.6 g of chloride tiomila in a round bottom flask of 250 ml with a reflux condenser were added to 75.1 g II, and the mixture was boiled for 1.5 h in a water bath. Excess chloride tiomila drove, the output 73,9 g, 90.7 percent.

2,6-dimethylaniline α-bromo-δ-haralanova acid (IV). In a three-neck round bottom flask of 250 ml, equipped with a dropping funnel and electronically, was placed a solution of 12,94 g of 2,6-dimethylaniline and 10.8 g of triethylamine in 50 ml of chloroform. Next was added for 45 min dropwise a solution of 25.0 g of chlorine is hydride α-bromo-δ-haralanova acid in 40 ml of chloroform at a temperature of 0-10°C (temperature was achieved by placing the flask in cold water with ice), with constant stirring electronically. The resulting solution was heated in a round bottom flask 250 ml) under reflux on water bath for 1 h Precipitated precipitate was filtered. The filtrate was washed with 3% hydrochloric acid solution and then with water until neutral environment. After removal of the solvent amorphous powder of 2,6-dimethylaniline α-bromo-δ-haralanova acid, which is recrystallized from hexane, the yield was 20.4 g, 60%.

2,6-dimethylaniline N-cyclohexylpiperidine-2-carboxylic acid (V). To a solution 7,37 g IV in 100 ml of toluene in a three-neck round bottom flask equipped with addition funnel and electronically, was added dropwise a solution of 3,44 g cyclohexylamine and 4.6 g of triethylamine (to save cyclohexylamine) in 100 ml of toluene. Then the reaction mass was made 0.2 g of potassium iodide and the mixture was heated on a sand bath in a round bottom flask with reflux for 28 hours. Next, the precipitation was filtered. The filtrate was shaken with a saturated solution of potash. Toluene layer was separated and evaporated to dryness. Output V amounted to 3.67 g, 53%.

The hydrochloride of 2,6-dimethylaniline N-cyclohexylpiperidine-2-carboxylic acid (VI). The remainder of the V was dissolved in 200 ml of ether, and let dry hydrogen chloride. The precipitation of the hydrochloride VI was filtered, repeatedly washed with acetone, dried, and p is recrystallization of ethyl alcohol, output 3,70 g, 90%.

The inventive compound is a white crystalline substance with a melting point 278-280°C (decomposition)slowly soluble in ethanol, water, soluble in DMSO, insoluble in acetone, hexane, diethyl ether. The NMR spectrum1H (Mercury - 300 MHz) in DMSO, internal standard TMS) of compound (I) includes: three multiplet six protons of methylene groups tsiklogeksilnogo radical at the nitrogen heteroatom pyrolidine cycle in the area of 1.06-1,63 ppm, multiplet two protons of methylene group pyrolidine cycle when 1,79 is 2.01 ppm, multiplet four protons of methylene groups tsiklogeksilnogo radical at the nitrogen heteroatom pyrolidine cycle when 2,01-2,12 ppm, singlet six protons of the two metal groups of the aromatic ring at 2,17 ppm, multiplet two protons of methylene group pyrolidine cycle when 2,54-2,62 ppm, multiplet two protons methylene group pyrolidine cycle at 3.25 to 3.40 in ppm, multiplet CH-group tsiklogeksilnogo radical at the nitrogen heteroatom pyrolidine cycle in the field 3,55 at 3.69 ppm, a triplet of one proton CH-group pyrolidine cycle when 4,690-4,780 ppm, multiplet three protons of the aromatic ring in the area 7,07-7,16 ppm, a singlet proton-NH - group at 9,34 ppm, a singlet proton chloroethanol acid at 10,65 ppm

The study of biological the activity

Research activity at the surface anesthesia was performed according to the method of Rainier [Manual on experimental (preclinical) study of new pharmacological substances / Under the General editorship of Corr-cor. The RAMS, Professor RU Khabriev. - 2 ed., revised and enlarged extra - M., 2005. - 832 C.]. Generalizirovanny rabbits were placed in a special box with a hole, the locking head. We determined the sensitivity threshold of the cornea of the rabbit to tactile impact. With this purpose we applied a thin metal wire in the form of a loop, without injuring the cornea. Connection and transfer standards (bupivacaine and ropivacaine) was administered in the conjunctival SAC of the eye of the rabbit in the form of a 0.5% solution (in 0.9% sodium chloride). Determined the start time of anesthesia. The first definition of surface anesthesia was performed on 8 minute experience and repeated at 10, 12, 15, 20, etc. up to 60 minutes, a total of 13 measurements. The activity of the substances was evaluated by 2 parameters: index Rainier, a measure of the depth of anaesthesia and the duration of anesthesia. Each substance was investigated in 6 rabbits (12 eyes). The experimental results were processed statistically using student's criterion with p≤0,05.

The active substances in block anesthesia was determined in experiments, the application of a 0.5% solution (in 0.9% sodium chloride) compounds and benchmarks comparison to Segal snye nerves of rats [Manual on experimental (preclinical) study of new pharmacological substances / Under the General editorship of Corr.-cor. RAMP, Professor RU Khabriev. - 2 ed., revised and enlarged extra - M., 2005. - 832 C.]. Electrical irritation of the nerves produced using pacemaker ECL-2 above the site of blockage. Determined the irritation threshold, i.e. the minimum voltage that causes muscle contraction. Then the nerve is wrapped with a cotton clutch and inflicted 0.2 ml of the analyte or standard. Determined the duration of anesthesia in minutes and the depth of anesthesia to increase the threshold of irritation, expressing it in percentage to the original threshold value (the excess of the initial threshold of irritation more than 2 times counted for 100% of the depth of anesthesia). Each substance was evaluated in 4 rats (8 experiments). The experimental results were processed statistically using student's criterion with p≤0,05.

Studying the activity of the substances in infiltration anesthesia was evaluated in experiments on rats according to the method of Bulbring and Waida (Bulbring E., J. Wajda Biological comparison of local anaesthetica. J. Pharmacol. and Exp. Therap., 1945, vol.85, No.1, p.7-84). White rats intradermally (0.05 ml) and subcutaneously (0.45 ml) was injected 0.5% solution (in 0.9% sodium chloride) of the investigated substances. Analgesic effect they have studied at a metered electrical stimulation of the skin of the animal. Determined the irritation threshold, i.e. the minimum voltage that causes muscle contraction. Was determined by the duration of anesthesia in minutes and the depth of anesthesia to increase the threshold of irritation, expressing it in percentage to the original threshold value (the excess of the initial threshold of irritation more than 2 times counted for 100% of the depth of anesthesia). Each substance was evaluated in 4 rats (8 experiments). The experimental results were processed statistically using student's criterion with p≤0,05.

Acute toxicity subcutaneous (s/C) was determined by nonlinear white mice of both sexes weighing 19-25, the test substance and the Comparators were introduced in the form of a 0.5% solution (based on 0.9% sodium chloride solution) in increasing doses. The results were processed by Prozorovsky calculation of the median lethal dose (LD50) when P≤0,05 [Prozorovsky CENTURIES, Prozorovsky BTW, Demchenko V.M. Pharmacol. toxicol., v.41, №4, s-502, 1978].

The results of the study poornathrayeesa activity and acute toxicity of compounds I, bupivacaine and ropivacaine presented in table 1.

Table 1
Poornathrayeesa activity and acute toxicity of compounds I, bupivacaine and ropivacaine.
ConnectionSurface anesthesiaLD50p/K, mg/kg
Index RainierThe duration of anesthesia, min
Bupivacaine939,2±48,751,0±2,970,8 (50,0-92,5)
Ropivacaine596,8±53,932,0±3,2112,0 (64,8-185,9)
I1215,1±25,8of 80.6±4,3112,0 (64,8-185,9)
P1*in comparison with bupivacaineP1≤0,05P1≤0,05
P2*in comparison with ropivacaineP1≤0,05P1≤0,05
* for the 12 experiments

The results of the research activity at infiltration and block anesthesia of compound I, bupivacaine and ropivacaine presented in table 2.

Table 2
Infiltration and conduction an anaesthetic activity is connected to the I I, of bupivacaine and ropivacaine.
ConnectionInfiltration anesthesiaConduction anesthesia
The depth of anesthesia %The duration of anesthesia, minThe depth of anesthesia %The duration of anesthesia, min
Bupivacaine100120,0±5,4100117,5±3,6
Ropivacaine10075,0±7,1100107,5±5,4
I100116,3±4,3100168, 8mm±6,3
P1*in comparison with bupivacaineP1≥0,05P1≤0,05
P2*in comparison with ropivacaineP2≤0,05/td> P1≤0,05

As can be seen from table 1, the inventive compound of formula (I) is 1.3 times that of bupivacaine and 2.0 times ropivacaine depth poverkhnostnoaktivnykh actions. The substance of formula (I) in 1.6 times in comparison with bupivacaine and 2.5 times in comparison with ropivacaine manifests longer poverhnostnoaguoe activity. In addition, the compound of formula (I) exhibits a toxicity equal to the toxicity of ropivacaine and is less toxic than bupivacaine in 1.6.

As can be seen from table 2, the inventive compound of formula (I) in 1.6 times in comparison with ropivacaine manifests longer infiltration.otherwise activity, not yielding to the same indicator of the bupivacaine. The substance of formula (I) is 1.4 times that of bupivacaine and 1.6 times ropivacaine duration prednisonesinusah effect.

Thus, 2,6-dimethylaniline N-cyclohexylpiperidine-2-carboxylic acid hydrochloride exhibits a more pronounced and longer poverhnostnoaguoe action at equal or lesser toxicity than bupivacaine and ropivacaine. The substance of formula (I) greatly exceeds the duration of the activity of ropivacaine and bupivacaine at block anesthesia, surpassing, in addition, the duration of effect of ropivacaine in detail ltrations anesthesia. Therefore, the claimed compound (I) can be used in medicine as a local anesthetic drugs for surface infiltration and block anesthesia.

2,6-Dimethylaniline N-cyclohexylpiperidine-2-carboxylic acid hydrochloride,

active at the surface, infiltration and block anesthesia.



 

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