WO2011081567A1

WO2011081567A1 - Agent for treating multiple sclerosis

Info

Publication number: WO2011081567A1
Application number: PCT/RU2010/000784
Authority: WO
Inventors: Геннадий Алексеевич ВИЛКОВ; Борис Витальевич СТРАДОМСКИЙ
Original assignee: АВЕРИН, Константин Михайлович; СОЛОДУНОВ, Юрий Юрьевич
Priority date: 2009-12-29
Filing date: 2010-12-24
Publication date: 2011-07-07
Also published as: RU2414899C1

Abstract

The invention pertains to the field of psychoneurology and, more specifically, to agents for treating multiple sclerosis. Substances are proposed which exhibit high activity in the treatment of multiple sclerosis and are selected from the group of 1,3-dialkylbenzimizadole triiodide compounds of general formula (I), in which R₁, R₂ = methyl (Меt), ethyl (Et), propyl (Рrо).

Description

MEDICINES FOR THE TREATMENT OF MULTIPLE SCLEROSIS

FIELD OF TECHNOLOGY

The invention relates to the field of psychoneurology, in particular to means for the treatment of multiple sclerosis.

BACKGROUND

A well-known drug for the treatment of multiple sclerosis: Betaferon - recombinant human interferon beta-lb (Mashkovsky MD 2003. Medicines. M: New Wave, p. 324-325). Currently, Betaferon is the only drug whose effectiveness has been shown in a long-term (5 years) placebo-controlled study (Totolyan NA 2005. Betaferon in the treatment of multiple sclerosis: a standard of evidence of effectiveness // Journal of Neurology and Psychiatry. 7: p. 68 -71).

The disadvantage of this drug is the rather low efficiency of its use - a decrease in the frequency of exacerbations of the disease and their severity by only 30%, the presence of such side effects as increased depressive symptoms (Sokolova E.S., Totolyan N.A., Klimenko V.M. 2003. Psycho-emotional changes in the treatment of patients with multiple sclerosis with betaferone // "Stress and Behavior" VII Interdisciplinary Conference on Biological Psychiatry, Novosibirsk), as well as the very high cost of pharmacotherapy with Betaferon.

Also recently, in the treatment of multiple sclerosis, the drug Copaxone - glatiramer acetate (Zavalishin I.A., Schwartz G.Y. 2007. Copapson in the treatment of multiple sclerosis (collection of articles). M. Miklosh, pp. 5-8 ) However An undoubted disadvantage is the high cost of pharmacotherapy with the use of Copaxone.

The closest in combination of essential features of the method and composition for the same purpose is the technical solution according to RF patent JVs 2374234 "Benzimidazole derivatives containing their compositions, their preparation and use" (publ. November 27, 2009), according to which the compounds of the formula indicated in their patent a pharmaceutically acceptable salt, their diastereomers, enantiomers or mixtures thereof are used in the manufacture of a medicament for the treatment of multiple sclerosis. However, the compounds of this general formula are not derivatives of the benzimidazolium cation, which excludes the possibility of the formation of pharmacologically highly active polyhalides with an imidazole ring of these compounds.

SUMMARY OF THE INVENTION

The objective of the invention, which determines its purpose, is the creation of new drugs with pronounced pharmacological activity for the treatment of multiple sclerosis, with high therapeutic efficacy, while reducing unwanted side effects, reducing the cost of treatment.

The technical result of the claimed invention, which can be achieved by its implementation, is the creation of a group of compounds with high activity in the treatment of multiple sclerosis.

The technical result is achieved with substances in the treatment of multiple sclerosis substances from groups of compounds 1,3-dialkylbenzimisadolium triiodide of the general formula:

where Ri, R ₂ = methyl (Met), ethyl (Et), propyl (Pro).

The method of producing 1,3-dialkylbenzimidazolium triiodides for the treatment of multiple sclerosis is safe for individuals involved in the process.

MODES FOR CARRYING OUT THE INVENTION

The proposed funds are obtained as follows.

Example 1. Triiodide 1,3-dimethylbenzimidazolium triiodide:

59 g (0.5 M) of benzimidazole and 68 g (0.5 M) of sodium trihydrate are placed in 96 ml of ethyl alcohol 96%, 142 g (1 M) of methyl iodide are added and the reaction mixture is boiled for 3 hours. 127 g (0.5 M) of crystalline iodine are added, cooled on ice, the obtained crystalline product is washed with 96% ethyl alcohol and ice water, filtered and dried for 24 hours at + 55 ° C.

Dark green crystals with so pl. 134-135 ° C. Soluble in acetone, chloroform, dimethyl sulfoxide, slightly soluble in ethyl alcohol 96%, practically insoluble in water, ether, hexane. Resistant to acid, decomposed in alkali. Yield 74%.

Example 2. 1,3-diethylbenzimidazolium triiodide triiodide: 59 g (0.5 M) of benzimidazole and 68 g (0.5 M) of sodium trihydride are placed in 160 ml of 96% ethyl alcohol, 156 g (1 M) of ethyl iodide are added and boil the reaction mixture for 3 hours. 127 g (0.5 M) of crystalline iodine are added, cooled on ice, the resulting crystalline product is washed with 96% ethyl alcohol and ice water, filtered and dried for 24 hours at + 55 ° C.

Dark brown crystals with mp 82-84 ° C. Soluble in acetone, chloroform, dimethyl sulfoxide, slightly soluble in ethyl alcohol 96%, practically insoluble in water, ether, hexane. Resistant to acid, decomposed in alkali. Yield 70%.

Example 3. 1,3-dipropylbenzimidazolium triiodide triiodide: 59 g (0.5 M) of benzimidazole and 68 g (0.5 M) of sodium trihydrate are placed in 160 ml of 96% ethyl alcohol, 170 g (1 M) of propyl iodide are added and boil the reaction mixture for 3 hours. 127 g (0.5 M) of crystalline iodine are added, cooled on ice, the resulting crystalline product is washed with ethyl alcohol 96% and ice water, filtered and dried for 48 hours at + 30 ° C.

Black-brown crystals with so pl. 50-52 ° C. Soluble in acetone, chloroform, dimethyl sulfoxide, slightly soluble in ethyl alcohol 96%, practically insoluble in water, ether, hexane. Resistant to acid, decomposed in alkali. Yield 66%.

Experimental allergic encephalomyelitis (EAE) is widely used as a pathomorphological experimental model of multiple sclerosis (Cross A. H, Stark JL 2005. Humoral immunity in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis / ZImmunol. Res. 32, N 1-3. P. 8598).

For the development of autoimmune encephalomyelitis in animals, an encephalitogenic emulsion is prepared (homologous brain of animals in complete Freund's adjuvant), which is introduced into the pads of the hind legs of guinea pigs (Abdurasulova I.N., Serdyuk S.E., Gmiro V.E. 2007. // Neuroimmunology. V, N 1. P. 4-10 )

Ten animals were used as controls, i.e. only encephalitogenic emulsion was administered to them. The animals that make up the experimental groups, against the background of the introduction of encephalitogenic emulsion from the first day of immunization daily, for 15 days, triiodides of 1, 3-dialkylbenzimidazole were orally administered.

Experimental group 1.

The animals were orally administered 4 mg of 100% 1,3-diethylbenzimidazolium triiodide in suspension in water for injection in a volume of 4 ml.

Experimental group 2.

Animals were orally administered 4 g of 0.1% triiodide

1,3-diethylbenzimidazolium (mixture with polyvinylpyrrolidone in a ratio of 1: 1000, the content of 1,3-diethylbenzimidazolium triiodide in the administered mixture is 4 mg per animal).

Experimental group 3.

The animals were orally administered 4 mg of 100% 1,3-dimethylbenzimidazolium triiodide in suspension in water for injection in a volume of 4 ml.

Experimental group 4.

Animals were orally administered 4 g of 0.1% triiodide

1,3-dipropylbenzimidazolium (mixture with polyvinylpyrrolidone in a ratio of 1: 1000, the content of triiodide 1,3- dipropylbenzimidazolium in the injected mixture is 4 mg per animal).

To identify clinical efficacy, the neurological status of animals was evaluated daily. The timing of the onset of the disease, the severity of neurological disorders, which were scored by the clinical index and fatal cases, were recorded.

The clinical index (CI) was determined by the severity and prevalence of neurological manifestations: muscle weakness of one limb - 0.5 points, paresis - 1 point, paralysis - 1.5. With the defeat of several limbs, the points were summarized. In the presence of additional symptoms (paresis of sphincters), another 1 point was added for each symptom. The absence of visible violations was taken as 0 points, in case of death - 6 points.

To assess the effectiveness of the neuroprotective effect of the studied drug on the EAE model, the following indicators were calculated for each group of animals:

1) the total number of sick animals (in% of the number of guinea pigs in the group);

2) the average clinical index (CI) at the peak of the disease;

3) the number of fatal cases.

All indicators were compared with the corresponding indicators of animals of the control group (with induced EAE, but without drug administration).

The results of studies on the development of manifestations of allergic encephalomyelitis in animals are presented in the table and indicate a high potential clinical the effectiveness of 1,3-dialkylbenzimidazolium triiodides in relation to multiple sclerosis.

In the control group of ten guinea pigs, signs of the disease occurred in eight animals (80%). Five guinea pigs died during three weeks of observation (50%).

Table

The effect of 1,3-dialkylbenzimidazolium triiodides on the clinical manifestations of experimental allergic encephalomyelitis

Average

Clinical frequency of development. Encephalomyelitis index at the lethal peak of the disease outcome.

Control group

80% 5.2 50% (N = 10)

Experimental group 1.

1,3-di triiodide

40% 2.2 * 10% ethylbenzimidazolium

100% 4 mg

Experimental group 2.

Triiodide 1, 3-di

30% 2.0 * 20% ethylbenzimidazolium

0.1%, 4 mg

Experimental group 3.

1,3-di triiodide

40% 2.5 * 20% methylbenzimidazolium

100% 4 mg Experimental group 4.

1,3-dipropylbenzimidazole triiodide 40% 2.6 * 10%

0.1%, 4 mg

* - significance of differences with control at P <0.05.

At the same time, in the experimental groups, the incidence of encephalomyelitis decreased by 2.0-2.7 times compared with the control group with the use of 1,3-dialkylbenzimidazolium triiodides. In addition, in each experimental group, only one or two guinea pigs died (deaths decreased by 2.5–5 times).

A comparative analysis of the average clinical indices in animals of the control and experimental groups showed that the use of 1,3-dialkylbenzimidazolium triiodides reduces the CI by 2.0-2.6 times, i.e. significantly stops the development of clinical symptoms of experimental allergic encephalomyelitis in guinea pigs.

A significant difference between the experimental and control results indicates a pronounced preventive effect of 1,3-dialkylbenzimidazolium triiodides on the development of autoimmune encephalomyelitis in the simulation of multiple sclerosis in animals.

The claimed funds can be used as medicines for the treatment of multiple sclerosis in medicine.

Claims

CLAIM

Medicines for the treatment of multiple sclerosis of the general formula:

methyl, ethyl, propyl.