RU2455284C1 - Method of producing 5-aryl-2-methyl-1,3-dioxo-2-azaspiro[5,5] undecane-4-carbonitriles and agent exhibiting analgesic activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 5-aryl-2-methyl-1,3-dioxo-2-azaspiro[5,5] undecane-4-carbonitriles of general formula:

where: Ar=Ph (a), 4-BrC₆H₄ (b), 4-ClC₆H₄ (c), 4-MeOC₆H₆ (d), 3,4-(MeO)₂C₆H₃ (e), which involves boiling methyl ether of 1-bromocyclohexane carboxylic acid with zinc and 3-aryl-2-cyano-N-methylpropenamide in the medium of benzene-ethylacetate-HMPA (10:5:1) for 4 hours. The invention also relates to an agent which exhibits analgetic activity, which is one of 5-aryl-2-methyl-1,3-dioxo-2-azaspiro[5,5] undecane-4-carbonitriles obtained using the method described above.

EFFECT: obtaining novel 5-aryl-2-methyl-1,3-dioxo-2-azaspiro[5,5] undecane-4-carbonitriles and an agent exhibiting analgesic activity.

2 cl, 2 ex, 3 tbl

Description

The invention relates to the field of organic chemistry, in particular to spiroheterocyclic compounds, and to a method for producing 5-aryl-2-methyl-1,3-dioxo-2-azaspiro [5.5] undecane-4-carbonitriles of the formula not described previously

Ar = Ph (a), 4-BrC ₆ H ₄ (b), 4-ClC ₆ H ₄ (c), 4-MeOC ₆ H ₄ (d), 3,4- (MeO) ₂ C ₆ H ₃ ( e) exhibiting analgesic activity, and which may find application in various organic syntheses and in practical public health.

Known structural analogs of the compound containing the spiro piperidinedione moiety obtained by the interaction of 2-cyano-2-cycloalkylideneacetamides with ethyl cyanoacetate or diethyl malonate in the presence of sodium ethylate exhibit weak analgesic activity [1].

Metamizole sodium was taken as a reference standard for analgesic activity for the proposed drug.

The objective of the invention is to develop a method for producing 5-aryl-2-methyl-1,3-dioxo-2-azaspiro [5.5] undecane-4-carbonitriles, exhibiting higher analgesic activity and which would be widely used as intermediates products in various organic syntheses, as well as in practical health care.

The problem is achieved in that the methyl ester of 1-bromocyclohexanecarboxylic acid is boiled with zinc and 3-aryl-2-cyano-N-methylpropenamides in benzene-ethyl acetate-HMFTA (10: 5: 1) for 4 hours. Target products are isolated by known methods with yields of 47-71%.

The process proceeds according to the scheme

Ar = Ph (a), 4-BrC ₆ H ₄ (b), 4-ClC ₆ H ₄ (c), 4-MeOC ₆ H ₄ (d), 3,4- (MeO) ₂ C ₆ H ₃ ( e).

The problem is solved by a means of exhibiting analgesic activity, which is one of the representatives of the series 5-aryl-2-methyl-1,3-dioxo-2-azaspiro [5.5] undecane-4-carbonitriles, of the general formula

где:

Where:

Ar = Ph (a), 4-BrC ₆ H ₄ (b), 4-ClC ₆ H ₄ (c), 4-MeOC ₆ H ₄ (d), 3,4- (MeO) ₂ C ₆ H ₃ ( e).

The following are examples illustrating the feasibility of the proposed technical solution.

Example 1. Synthesis of 5-aryl-2-methyl-1,3-dioxo-2-zaspiro [5.5] undecane-4-carbonitriles (I).

Into a round-bottom flask were placed 1.5 g of finely ground zinc, a catalytic amount of HgCl ₂ , 25 mmol of 1-bromocyclohexanecarboxylic acid methyl ester, 10 mmol of 3-aryl-2-cyano-N-methylpropenamide, 10 ml of anhydrous benzene, 5 ml of anhydrous ethyl acetate, 1 ml HMFTA. The reaction mixture was boiled for 4 hours, cooled, poured from excess zinc, hydrolyzed with a 5% solution of acetic acid, the organic layer was separated, and the reaction products were extracted from the aqueous layer twice with ethyl acetate. After the extract was dried with anhydrous sodium sulfate, the solvents were distilled off, and 5-aryl-2-methyl-1,3-dioxo-2-azaspiro [5.5] undecane-4-carbonitriles was twice recrystallized from ethanol. The yields, melting points, and elemental analysis data for the synthesized compounds are shown in table 1, and their spectral characteristics are shown in table 2.

Example 2. Pharmacological study of 5-aryl-2-methyl-1,3-dioxo-2-azaspiro [5.5] undecane-4-carbonitriles for the presence of analgesic activity.

The analgesic activity of compounds (I) was determined by the "hot plate" method on white outbred mice weighing 18-22 g [2]. The studied substances were administered intraperitoneally in the form of a suspension in 2% starch mucus at a dose of 50 mg / kg for 0.5 h before the animals were placed on a metal plate heated to 53.5 ° C. An indicator of pain sensitivity was the duration of the animal’s stay on the hot plate until the hind legs were licked, measured in seconds. The reference standard was metamizole sodium, administered intraperitoneally at a dose of 93 mg / kg (ED ₅₀ ). Statistical processing of the experimental material was performed using Student's t test [3]. The effect was considered significant at p≤0.05. The test results are presented in table 3.

As can be seen from the table, these compounds significantly increased the threshold of pain sensitivity in animals under thermal exposure, exceeding metamizole sodium in activity. Acute toxicity (LD ₅₀ , mg / kg) of compounds (I) was determined by the method of G. N. Pershin [4]. Compounds (I) were administered intraperitoneally to white mice weighing 16-18 g as a suspension in 2% starch mucus. For the studied compounds LD ₅₀ > 1000 mg / kg According to the classification of the toxicity of drugs [5], compound (I) belongs to class V of practically non-toxic drugs. The proposed compounds can be used in medical practice as analgesic drugs.

Table 1 Yields, melting points, and elemental analysis of 5-aryl-2-methyl-1,3-dioxo-2-azaspiro [5.5] undecane-4-carbonitriles (I) Compound-
nie Exit % Mp ° C Found,% Formula Calculated,% C H N C H N Ia 68 144-145 73.09 6.91 9.27 C ₁₈ H ₂₀ N ₂ O ₂ 72.95 6.80 9.45 Ib 65 214-215 57.78 4.99 7.33 C ₁₈ H ₁₉ BrN ₂ O ₂ 57.61 5.10 7.47 Ic 71 216-218 65.22 5.89 8.61 C ₁₈ H ₁₉ ClN ₂ O ₂ 65.35 5.79 8.47 Id 47 169-170 70.14 6.61 8.42 C ₁₉ H ₂₂ N ₂ O ₃ 69.92 6.79 8.58 Ig 51 136-137 67.21 6.92 8.04 C ₂₀ H ₂₄ N ₂ O ₄ 67.40 6.79 7.86

table 2 IR and ¹ H NMR spectra of 5-aryl-2-methyl-1,3-dioxo-azazpiro [5.5] undecane-4-carbonitriles (I) Compound-
nie IR spectrum, ν, cm ^{-1 1} H NMR spectrum, δ, ppm C = o (CH ₂ ) ₅ , m CH ₃ N, s CHAr, d CH ₃ O, s CHCN d Ar Ia 1680, 1725 1.24-1.95 3.30 3.60 - 4.45 7.00 ears. Signal, 7.31-7.36 m (5H, Ph) Ib 1675, 1715 1.21-1.88 3.29 3.58 - 4.42 6.89 ears Sign., 7.48 d (4H, 4-BrC ₄ H ₄ ) Ic 1665, 1720 1.19-1.93 3.32 3.64 - 4.52 7.03 ears. Sign., 7.52 d (4H, 4-ClC ₄ H ₄ ) Ig 1680, 1710 1.23-1.97 3.29 3.56 3.78 4.16 6.84 d, 6.90 ears. signal (4H, 4-MeOC ₆ H ₄ ) Id 1660, 1715 1.28-1.97 3.29 3.54 3.81
3.84 4.44 6.52 ears signal, 6.80 d [3H, 3,4- (MeO) ₂ C ₆ H ₃ ]

Table 3 Analgesic activity of 5-aryl-2-methyl-1,3-dioxo-2-azaspiro [5.5] undecane-4-carbonitriles No. p / p Compound Dose mg / kg The time of the defensive reflex at the peak of action, s one Ia fifty 19.80 ± 0.34 p <0.05 2 Ib fifty 19.30 ± 1.36 p <0.05 3 Ic fifty 18.70 ± 1.09 p <0.05 four Ig fifty 25.70 ± 1.56 p <0.01 5 Id fifty 19.70 ± 2.56 p <0.05 6 Metamizole sodium 93 16.33 ± 3.02 p <0.05 7 Control, 2% starch. slime 10.20 ± 0.37 p - in relation to control.

Information sources

1. El Batran S.A., Osman A.E.N., Ismail M.M., El Sayed A.M. // Inflammopharmacology. 2006. V.14. P.62-71.

2. Radell Z. O., Selitto J J. // Arch. Intermat. Pharmacodun Et ther. 1957. Vol. 11. Number 4. S.409-419.

3. Belenky M.L. Elements of a quantitative assessment of the pharmacological effect. 2nd ed. L. 1963. P.152.

4. Pershin G.N. Methods of experimental chemotherapy. - M., 1971. S. 100, 109-117.

5. Izmerov N.F., Sanotsky I.V., Sidorov K.K. Toxicometry parameters of industrial poisons. - M .: Medicine, 1977. P.196.

Claims (2)

1. The method of obtaining 5-aryl-2-methyl-1,3-dioxo-2-azaspiro [5.5] undecane-4-carbonitriles of the General formula:

where Ar = Ph (a), 4-BrC ₆ H ₄ (b), 4-ClC ₆ H ₄ (c), 4-MeOS ₆ H ₄ (g), 3,4- (MeO) ₂ C ₆ H ₃ (e) that 1-bromocyclohexanecarboxylic acid methyl ester is boiled with zinc and 3-aryl-2-cyano-N-methylpropenamides in benzene-ethyl acetate-HMFTA (10: 5: 1) for 4 hours. 2. An agent showing analgesic activity, which is one of the representatives of the series 5-aryl-2-methyl-1,3-dioxo-2-azaspiro [5.5] undecane-4-carbonitriles, of the general formula

where Ar = Ph (a), 4-BrС ₆ Н ₄ (b), 4-СlС ₆ Н ₄ (c), 4-MeOS ₆ Н ₄ (d), 3,4- (МеО) ₂ С ₆ Н ₃ (e).