RU2773021C2 - Aminoalkyl derivatives of dibenzofuranone oxime exhibiting anticonvulsant activity - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a new group of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(aminoalkyl)oximes synthesised at the interaction of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime with aminoalkylhalides in the presence of sodium hydride.

EFFECT: production of new 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-ones O-(aminoalkyl)oximes with a pronounced anticonvulsant effect.

4 cl, 2 tbl, 6 ex

Description

The invention relates to medicine, in particular to pharmacology and pharmacy, biology and chemistry, specifically to a new group of O-(aminoalkyl)oximes 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1( 2H)-one, general formula (1)

where n can vary from 2 to 3, R - is an alkyl group or NR ₂ is a morpholine group, X is an organic acid, which can be used as pharmacological agents for the treatment of epilepsy and paroxysmal conditions.

Background of the invention

The creation of antiepileptic drugs (AEDs) continues to be an urgent task in the modern world due to the lack of universal highly effective anticonvulsants and with a wide variability in the forms of epilepsy. Treatment of epilepsy is carried out continuously for many years, and sometimes for the entire life of the patient, therefore, at the same time, AEDs have various side effects (Karlov V.A. Epilepsy in children and adult women and men: a guide for doctors / V.A. Karlov. M .: Medicine, 2010. - 717 p.).

Among the derivatives of oximes of the 3rd 4-benzoylpyridines constructed on the basis of a pharmacophore model of the structure of selective serotonin reuptake inhibitors with antiepileptic activity, active compounds were previously identified both in the group of Ο-aryloyl- and in the group of O-aminoalkyl-substituted compounds ( A and B, respectively) [L.A. Zhmurenko, T.A. Voronina, S.A. Litvinova et al., Khim.-farm. j., 52(1), 19-28 (2018)].

Structures of oxime derivatives of the 3rd 4-benzoylpyridines A and B, O-aryloyl derivatives of dibenzofuranone oxime (C) with anticonvulsant activity, and a new group of aminoalkyl derivatives of dibenzofuranone oxime (1).

Using these data, as well as taking into account information on the anticonvulsant activity of oxime derivatives from the literature, a group of O-aryloyl oxime derivatives was later proposed.

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one (C). Among the compounds of this group, molecules have been identified that have pronounced anticonvulsant and anti-ischemic activities and have low toxicity [L.A. Zhmurenko, S.A. Litvinova, I.S. Kutepova et al., Khim.-farm. journal, 53(11), 9-16 (2019)].

The present invention is based on the task of creating aminoalkyl derivatives of dibenzofuranone oxime 1 with potential anticonvulsant activity. Group 1 molecules include a previously unknown combination of pharmacophore groups: a hexahydrodibenzofuran heterocyclic pharmacophore, an oxime linker, and a dialkylaminoalkyl fragment.

The synthesis and successful results of studying the anticonvulsant activity of the aminoalkyl derivatives of dibenzofuranone oxime 1 constructed using the presented pharmacophore approach are the subject of protection of this patent.

Technical result

The technical result of the present invention is the expansion of the arsenal of anticonvulsants for the treatment of epilepsy and paroxysmal conditions with high activity using aminoalkyl derivatives of dibenzofuranone oxime (1),

The compounds of general formula (1), their properties and method of preparation are not described in the special and patent literature.

The proposed technical solution is O-(aminoalkyl)oximes 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one (1):

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(2-morpholinoethyl)oxime oxalate (GIZH-343)

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one (GIZh-344) O-(3-morpholinopropyl)oxime oxalate

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(2-(dimethylamino)ethyl)oxime oxalate (GIZH-345)

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(3-(dimethylamino)propyl)oxime oxalate (GIZH-346)

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(2-(diethylamino)ethyl)oxime oxalate (GIZH-347)

Obtaining the claimed compounds

Compounds of the general formula can be obtained according to the following general scheme:

The starting compound for the synthesis is oxime

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one, which is obtained from 2-chlorocyclohexanone and 1,3-cyclohexanedione. The interaction of oxime 2 in DMF with aminoalkyl halides in the presence of sodium hydride gives 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(aminoalkyl)oximes, which are isolated as salts with organic acids 1, for example, with oxalic acid.

Compounds 1 are white crystalline substances, insoluble in water, soluble in some organic solvents such as DMF. The structure of the substances of general formula 1 was confirmed by the data of NMR spectra, and their purity by the data of elemental analysis.

General procedure for the preparation of 3,4,6,7,8,9-hexahydrodibenzo[b,d]fuan-1(2H)-one O-(aminoalkyl)oxime oxalates.

To 0.4 g (0.01 mol) of 60% sodium hydride in 10 ml of dry DMF, a solution of 1.03 g (0.005 mol) of oxime 3,4,6,7,8,9-hexahydrodibenzo [b ,d]furan-1(2Н)-one in 20 ml of dry DMF. The resulting mixture was stirred at room temperature for 2 hours, adding 10 ml of dry DMF upon precipitation in the reaction mixture. A solution of 0.0075 mol of an aminoalkyl halide base in 10 ml of dry DMF is added dropwise to the resulting mixture, an additional 10 ml of DMF is added if necessary, and the resulting mixture is stirred at room temperature for 2 hours, after which it is poured into 550 ml of water. The product is extracted with 2 times 200 ml of ethyl acetate, the combined solutions of ethyl acetate are dried over molecular sieves 4A, evaporated to dryness, the residue is dissolved in 5 ml of ethanol. A solution of 0.45 g of oxalic acid in 5 ml of ethanol and 5 ml of ether is added to the alcohol solution. The resulting mixture is diluted with ether, if necessary, the precipitate is filtered off and recrystallized from ethanol or aqueous ethanol.

Example 1

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(2-morpholinoethyl)oxime oxalate (GIZH-343)

Obtained by interaction of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-oxime with 4-(2-chloroethyl)morpholine. Yield 78%, crystallized from alcohol. Melting point 218-220°C (from 70% alcohol). Rf=0.68 [9.5:0.5 chlf:sp]. NMR spectrum ¹ Ή (DMSO, δ, ppm, J/Hz): 1.65 and 1.74 (4H, two m, CH ₂ -7, CH ₂ -8), 1.84 (2H, m , CH ₂ -3), 2.48-2.52 (4H, m, CH ₂ -6, CH ₂ -9), 2.54 and 2.63 (4H, two m, CH ₂ -2, CH ₂ -4), 2.90 (4H, m, 2NCH ₂ CH ₂ O), 3.06 (2H, t, NOCH ₂ CH ₂ N, J ³ =5.3), 3.71 (4H, m, 2NCH ₂ CH ₂ O), 4.24 (2H, t, NOCH ₂ CH ₂ N, J3=5.3).

Example 2

3,4,6,7,8,9-hexahydrodibenz[b,d]furan-1(2H)-one oxalate O-(3-morpholinopropyl)oxime (GIZH-344)

Obtained by interaction of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-oxime with 4-(3-chloropropyl)morpholine. Yield 81%, crystallized from alcohol. Melting point 208-210°C (from 70% alcohol). Rf=0.62 [9.5:0.5 chlf:sp]. 1H NMR spectrum (DMSO, δ, ^ppm , J/Hz): 1.64 and 1.73 (4H, two m, CH ₂ -7, CH ₂ -8), 1.83 (2H, m , CH ₂ -3), 1.94 (2H, m, CH ₂ CH ₂ CH ₂ N), 2.43-2.50 (4H, m, CH ₂ -6, CH ₂ -9), 2.54 and 2.62 (4H, two m, CH ₂ -2, CH ₂ -4), 2.84-3.01 (6H, m, 2 NCH ₂ CH ₂ O, CH ₂ CH ₂ CH ₂ N), 3 .73 (4H, m, 2NCH ₂ CH ₂ O), 4.03 (2H, t, CH ₂ CH ₂ CH ₂ N, J ³ = 6.1).

Example 3

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(2-(dimethylamino)ethyl)oxime oxalate (GIZH-345)

Obtained by the interaction of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-oxime with N,N-dimethyl-2-chloroethane-1-amine. Yield 60%, crystallized from alcohol. Melting point 205-207°C (from 70% alcohol). Rf=0.23 [9:1 chlf:sp]. ¹ H NMR spectrum (DMSO, δ, ppm, J/Hz): 1.65 and 1.74 (4H, two m, CH ₂ -7, CH ₂ -8), 1.85 (2H, m , CH ₂ -3), 2.46-2.54 (4H, m, CH ₂ -6, CH ₂ -9), 2.58 and 2.64 (4H, two m, CH ₂ -2, CH ₂ -4), 2.75 (6H, s, 2 CH ₃ ), 3.29 (2H, t, CH ₂ CH ₂ N, f=5.0), 4.29 (2H, t, CH ₂ CH ₂ N, J ³ =5.0).

Example 4

3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(3-(dimethylamino)propyl)oxime oxalate (GIZH-346)

Obtained by the interaction of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-oxime with N,N-dimethyl-3-chloropropan-1-amine. Yield 68%, crystallized from alcohol. Melting point 223-225°C (from 70% alcohol). Rf=0.2 [9:1 chlf:sp]. ¹ H NMR spectrum (DMSO, δ, ppm, J/Hz): 1.65 and 1.74 (4H, two m, CH ₂ -7, CH ₂ -8), 1.84 (2H, m , CH ₂ -3), 1.98 (2H, m, CH ₂ CH ₂ CH ₂ N), 2.44-2.53 (4H, m, CH ₂ -6, CH ₂ -9), 2.55 and 2.63 (4H, two m, CH ₂ -2, CH ₂ -4), 2.72 (6H, s, 2 CH ₃ ), 3.06 (2H, m, CH ₂ CH ₂ N), 4 .04 (2H, t, OCH ₂ CH ₃ , J ³ = 6.1).

Example 5

O-(2-(diethylamino)ethyl)oxime oxalate 3,4,6,7,8,9-hexahydrode ibenzo[b,d]furan-1 (2H)-one (GIZh-347)

Obtained by the interaction of O-oxime 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one with N,N-diethyl-2-chloroethane-1-amine. Yield 90%, crystallized from alcohol. Melting point 160-162°C (from alcohol). Rf=0.42 [9:1 chlf:sp]. ¹ H NMR spectrum (DMSO, δ, ppm, J/Hz): 1.17 (6H, t, 2CH ₃ , J ³ =7.2), 1.65 and 1.74 (4H, two m , CH ₂ -7, CH ₂ -8), 1.85 (2H, m, CH ₂ -3), 2.46-2.54 (4H, m, CH ₂ -6, CH ₂ -9), 2 .57 and 2.64 (4H, two m, CH ₂ -2, CH ₂ -4), 3.12 (4H, q, 2 CH ₂ CH ₃ , J ³ = 7.2), 3.33 (2H , t, CH ₂ CH ₂ N, J ³ =5.0), 4.31 (2H, t, CH ₂ CH ₂ N, J ³ =5.0).

Example 6. Experimental pharmacological part

The organization and conduct of work was carried out in accordance with the order of the Ministry of Health of Russia No. 199 dated April 01, 2016 "On approval of the rules of good laboratory practice". The animals were kept in accordance with SP 2.2.1.3218-14 "Sanitary and epidemiological requirements for the arrangement, equipment and maintenance of experimental biological clinics (vivariums)" dated August 29, 2014 No. 51.

The experiments were approved by the Commission on Biomedical Ethics of the V.V. Zakusov.

The experiments were carried out on outbred male mice weighing 22–26 g, obtained from the nursery “Stolbovaya” of the State Institution of the National Center for Biomedical and Biotechnological Research (Moscow Region).

Statistical processing of the results was performed using MS Excel 2010 and BioStat 2009 (Analyst Soft Inc.). The normality of data distribution was determined by the Shapiro-Wilk test. The significance of differences in values between groups was determined using nonparametric tests: Kruskal-Wallis and Fisher's exact test.

Example 6.1

Anticonvulsant effect of dibenzofuranone oxime derivatives on the model of primary generalized convulsions caused by maximal electric shock (MES)

The anticonvulsant effect of dibenzofuranone oxime derivatives was studied in models of primary generalized convulsions caused by MES, simulating the so-called "large" (Grandmal) convulsive seizures [T.A. Voronina, L.N. Nerobkova, Guidelines for the study of anticonvulsant activity of pharmacological substances. "Guidelines for conducting preclinical studies of medicinal products" Part. 1. FSBI "NCEMSP", Grif i K, Moscow (2012), pp. 235-250; W. Loscher, SR. Fassbender, B. Nolting, Epilepsy Res., 8(2), 79-94 (1991); E.A. Swinyard, Epilepsia, 10, 107-119 (1969).].

An electroconvulsive seizure was created using a certified device "RodentShockerRS", type 221 (Harvard Apparatus, GmbH, Germany): animals received electrical stimuli through special corneal electrodes (mode 1: 250 V, 11 mA, duration 0.2 s; mode 2: 500 V , 144 mA, duration 0.3 s). The following indicators were recorded: clonic convulsions, tonic extension of the hind and forelimbs, and death of animals. The anticonvulsant effect of the claimed compounds was evaluated by the ability to prevent the death of animals and on a point scale: 0 points - no convulsive reactions, 1 point - clonic convulsions without loss of the rolling reflex, 2 points - clonic convulsions with loss of the turning reflex, 3 points - tonic convulsions, 4 points - tonic convulsions ending in the death of the animal. Test compounds were dissolved in saline with Tween-80 and administered intraperitoneally (ip) 40 minutes before MES. The reference drug valproic acid (substance, Sigma) was dissolved in saline and administered at a dose of 60–200 mg/kg in a similar regimen. The effectiveness of the compounds was evaluated by reducing the severity of convulsive reactions (points), increasing the number of animals without tonic seizures and the proportion of survivors (%) after MES relative to the corresponding control groups.

In an experiment to evaluate the anticonvulsant activity of compounds in the MES test using a current of 144 mA, a voltage of 500 V and an exposure time of 0.3 sec, the following results were obtained (table 1). At doses of 5 and 50 mg/kg, GIZH-345 had no effect on current-induced convulsive responses. With an increase in the dose to 100 mg, GIZH-345 significantly reduced the severity of convulsive manifestations by almost two times to 2 points, protecting animals from the development of tonic limb extension, and increased the survival rate of mice up to 87.5%, not inferior in efficiency to valproic acid (150 mg/day). kg). Compounds GIZH-343 (5, 50 and 100 mg/kg) and GIZH-344 (5, 50 and 100 mg/kg) did not significantly reduce the severity of convulsive manifestations, expressed in a point scale. At the same time, in terms of the percentage of survival of animals, there was a tendency to increase it in both compounds. With 12.5% of surviving animals in the control group, 62.5% of surviving animals were observed at a dose of 50 mg/kg against the background of the administration of the GIZH-343 compound at a dose of 5 mg/kg, and 37.5% at a dose of 50 mg/kg. With the introduction of the compound GIZH-344 at a dose of 50 mg/kg, the number of surviving mice was 37.5%, and at a dose of 100 mg/kg - 50%.

In another experiment using the MES test with lower electroshock characteristics (mode 1: current strength 11 mA, voltage 250 V, duration of exposure 0.2 sec), the GIZh-343 compound significantly reduced the severity of convulsive manifestations at a dose of 60 mg/kg (i.v.). b) up to a value of 2.11 points, preventing the appearance of tonic extension of the limbs (table 2). Substance GIZH-346 under these conditions did not show any effect in any of the studied doses (20 and 60 mg/kg). At the same time, the compound GIZH-347 significantly reduced the severity of convulsive manifestations at a dose of 60 mg/kg to a value of 1.17 points, preventing the occurrence of tonic convulsions and loss of the rollover reflex, surpassing both valproic acid in efficiency and activity. It should also be noted that with a survival rate in the control group of 86%, when using compounds GIZH-343 and GIZH-347 at doses of 60 mg/kg, this indicator increased to 100%.

Thus, in the group of aminoalkyl derivatives of dibenzofuranone oxime, the compounds GIZH-343, GIZH-345, GIZH-347 have a pronounced anticonvulsant effect in the MES test on mice, preventing the development of tonic convulsions and the death of animals. The anticonvulsant effect of the compounds GIZH-343 and GIZH-347 develops at a dose of 60 mg/kg, while the reference drug valproic acid develops at a dose of 200 mg/kg. Analyzing the structure-activity relationship in the MES test, it should be noted that the anticonvulsant effect was observed only in compounds containing an ethylene bridge as an aliphatic chain linking the oxime oxygen atom with the dialkylamine group. Compounds containing a propylene chain showed no activity. Among substances with an ethylene bridge, the most active compound is GIZH-347 with a morpholine aminoacyl fragment, which is superior in activity to the first-line drug valproic acid.

Claims (6)

1. O-(aminoalkyl) oximes 3, 4,6,7,8, 9-hexahydrodibenzo[b, d]furan-1(2H)-one, general formula

, where n can vary from 2 to 3, R - is an alkyl group or NR ₂ is a morphine group, X is an organic acid. 2. The method of obtaining compounds according to p. 1, which consists in the interaction of cosim 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one with aminoalkyl halides in the presence of sodium hydride. 3. O-(2-morpholinoethyl)oxime oxalate of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one (GIZH-343), O-(2-( dimethylamino)ethyl)oxime 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one (GIZH-345), O-(2-(diethylamino)ethyl)oxime oxalate 3 ,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one (GIZH-347), which have an anticonvulsant effect. 4. A method for the treatment of epilepsy and paroxysmal conditions by administering effective amounts of the compounds according to claim 3.