Extract of family dioscoreaceae and composition for preventing or treating peripheral neuropathy containing same

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to an agent for treating or preventing a peripheral neuropathy. An extract of a family Dioscoreaceae for preventing or treating the peripheral neuropathy recovered by extraction of a of the family Dioscoreaceae with a first extraction solvent selected from the group consisting of water, C1-C4 alcohol and a mixture of water and C1-C4 alcohol. The pharmaceutical composition for preventing or treating the peripheral neuropathy. A food composition for preventing or treating the peripheral neuropathy.

EFFECT: preparations are effective for treating or preventing the peripheral neuropathy.

8 cl, 9 dwg, 1 tbl, 11 ex

 

The scope of the invention

The present invention relates to an extract of the family dioscoreaceae (Dioscoreaceae) for the prevention or treatment of peripheral neuropathy, as well as to a pharmaceutical composition or a food composition containing the extract or compound derived from this extract.

The level of technology

Neuropathy is a disease caused by structural or functional disorders of the nervous system. The nervous system is divided into the Central nervous system, distributed in the brain and spinal cord and is involved in the control of their functions, as well as the peripheral nervous system, distributed in almost all organs, except the brain and spinal cord and is involved in the control of the functions of these organs.

The peripheral nervous system is divided into musculoskeletal nervous system, sensory nervous system and the autonomic nervous system. Peripheral nerve axons which extend beyond the brain and spinal cord and terminate in the torso, arms and legs, transmits sensations of the hands and feet in the Central nervous system (brain and spinal cord), and transmits the muscles commands of the Central nervous system.

Peripheral nerve may be damaged for various reasons; in the aggregate, this phenomenon is called peripheral neuropath is her. The term "mononeuropathy refers to the case when damaged single peripheral nerve, and the term "multiple neuropathy" - to the case of equally damaged many peripheral nerves. Mononeuropathy usually occurs when one of the peripheral nerve abnormally compressed or injured over the ends of the arms or legs. Mononeuropathy can be treated by surgical intervention.

Multiple neuropathy can be caused by various reasons, such as metabolic diseases (e.g. diabetes, renal failure, hypothyroidism), the effects of drugs (for example, anticancer agents, anti-TB drugs), or poisoning from toxic compounds (e.g., Pb, organic solvents), eating disorders (e.g. vitamin deficiencies, alcoholism), disorders of the connective tissues (e.g., rheumatoid arthritis, systemic lupus erythematosus), inflammatory diseases (Guillain-Barre syndrome) or genetically predetermined neuropathy. In addition, multiple neuropathy can be caused by cancer.

To date the neuropathy treated with drugs used for symptomatic therapy, which only acts on the symptoms; the fundamental treatment for neuropathy is practically absent. Management is about control of food products and medicines (FDA) has approved only epalrestat (epalrestat) - inhibitor alsoreported - for the treatment of diabetic peripheral neuropathy, one of the multiple neuropathy, but epalrestat not used due to poor therapeutic action (Foster DW., Harrison''s Principles of Internal Medicine 13, p.1979, 1999; Stephen LD, Applied Therapeutics: the clinical use of drugs. 6, p.48.1-48.62, 1996).

Protein that influence the growth, differentiation and survival of neurons in the Central nervous system (CNS) and peripheral nervous system (PNS), collectively called neurotrophic factor (NF), and he is one of the factors of control neurons that regulate growth, differentiation and death of neurons. Examples of NP are produced by the brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4 and NT-5. These NP are synthesized in different areas and have different differentiation, different expression and different areas of impact.

Nerve growth factor (NGF), one of the SF, inhibits the degeneration and death of neurons, in order to prevent decrease of the number of neurons, to protect neurons from damage and maintain the sources of Mature neurons (Hefti F.J. Neurosci., 6(8), pp.2155-2162, 1986; Levi-Montalcini R., et al., Proc. Natl. Acad. Sci. USA, 46, pp.384-391, 1960). It is known that in the normal development of the nervous system, about 50% of neurons in the growth process deleted as a result of cell death (Raff M.C., et al., Science, 262 (5134), pp.695-70, 1993), and that NGF, which allocates cell-target, determine Aut neuronal survival. For survival, growth and differentiation of neurons in the normal state required growth factor type NEF.

The feasibility of NGF led to the development of recombinant human nerve growth factor for the treatment of diabetic neuropathy, which is one of multiple neuropathies. However, recombinant human nerve growth factor still is not satisfactory from the point of view of safety and effectiveness (Apfel SC, et al., Journal of the American Medical Association 284(17), pp.2215-2221, 2000).

Disclosure of inventions

Technical task

The present invention provides herbal extracts and isolated from them compounds suitable for preventing or treating peripheral neuropathy caused by different reasons.

That is, the present invention provides an extract of the family dioscoreaceae (Dioscoreaceae) for the prevention or treatment of peripheral neuropathy.

The present invention also provides a pharmaceutical composition or food composition comprising the extract or compound isolated from this extract, as an active component.

Technical solution

According to one aspect of the present invention provides an extract of the family dioscoreaceae (Dioscoreaceae) for the prevention or treatment of peripheral neuropathy, with family dioscoreaceae (Dioscreaceae) represents at least one plant selected from the group consisting of Dioscorea nipponica, Dioscorea septemloba, Dioscorea quinqueoloba, Dioscorea batatas, Dioscorea japonica, Dioscorea bulbifera, Dioscorea tokoro, Dioscorea tenuipes.

According to another aspect of the present invention is provided a pharmaceutical composition for prevention or treatment of peripheral neuropathy, which contains a therapeutically effective amount of the extract as well as pharmaceutically acceptable carrier.

According to another aspect of the present invention provides a food composition for preventing or treating peripheral neuropathy, which contains the specified extract as an active component.

According to another aspect of the present invention is provided a pharmaceutical composition for prevention or treatment of peripheral neuropathy, which contains a therapeutically effective amount of the compounds of formula 1 or salts thereof, and pharmaceutically acceptable carrier.

[Formula 1]

where R is a hydrogen atom, an alkyl group, a C1-C4or saccharide.

According to another aspect of the present invention provides a food composition for preventing or treating peripheral neuropathy, which contains a compound of formula 1 or its salt as an active ingredient./p>

Advantages

The extract of the family dioscoreaceae (Dioscoreaceae) and/or a compound isolated from this extract, stimulates endogenous nerve growth factor in the body, so it can be used in a wide range of applications for the prevention or treatment of peripheral neuropathy.

Description of graphic materials

Figure 1 and 2 shows the effect of compounds isolated from an extract in accordance with the exemplary embodiment of the present invention, the growth of axons.

Figure 3 is a graph illustrating the change in the level of nerve growth factor (NGF) in the serum of normal mice by injection of compounds isolated from an extract in accordance with the exemplary embodiment of the present invention.

Figure 4 is a graph illustrating the change in the level of NGF in serum of mice with induced diabetes by injection of the extract in accordance with the exemplary embodiment of the present invention, and compounds isolated from this extract.

Figure 5 and 6 shows the effect of compounds isolated from an extract in accordance with the exemplary embodiment of the present invention, the transmission speed by the motor nerve and sensory nerve in the sciatic nerve of mice with induced diabetes (Figure 5: treatment with DG within 1 IU is Aza, 6: treatment with DG in 2 months).

7 is a graph illustrating the change in the level of NGF in the sciatic nerve of mice with induced diabetes caused by the introduction of compounds isolated from the extract according to the exemplary embodiment of the present invention.

Fig is a graph illustrating the change in the level of sorbitol in the sciatic nerve of mice with induced diabetes caused by the introduction of compounds isolated from the extract according to the exemplary embodiment of the present invention.

Figure 9 presents images illustrating the histological changes in the sciatic nerve of mice with induced diabetes in the administration of an extract according to the exemplary embodiment of the present invention and the compounds isolated from this extract.

The BEST OPTION

In this description, the term "peripheral neuropathy" refers to the condition of the peripheral nerves (motor nerves, sensory nerves and autonomic nerves), damaged due to one reason or another. Peripheral neuropathy can be divided into mononeuropathy and PN (also called multiple neuropathy). Multiple neuropathy includes any neuropathy caused by metabolic diseases (e.g. diabetes, renal problems what tochnostu, hypothyroidism), medication (for example, anticancer agents, anti-TB drugs) or poisoning by toxic compounds (e.g., Pb, organic solvents), eating disorders (e.g., lack of vitamins, alcoholism, disorders of the connective tissues (e.g., rheumatoid arthritis, systemic lupus erythematosus), inflammatory diseases (Guillain-Barre syndrome) or genetically predetermined neuropathy. In addition, multiple neuropathy may include neuropathy, caused by genetic factors and cancer.

The extract of the family dioscoreaceae (Dioscoreaceae) in accordance with the exemplary embodiment of the present invention or a compound isolated from this extract, causes the growth of axons and increases the amount produced by endogenous nerve growth factor that leads to effective differentiation, protection and reinnervation is detected peripheral nervous system. In particular, the extract and/or connection allow oral administration, which promotes patient compliance with the regimen and the regimen.

The present invention provides an extract of the family dioscoreaceae (Dioscoreaceae) for the prevention or treatment of peripheral neuropathy.

The family dioscoreaceae (Dioscoreaceae) is, at least, one kind is astini, selected from Dioscorea nipponica, Dioscorea septemloba, Dioscorea quinqueoloba, Dioscorea batatas, Dioscorea japonica, Dioscorea bulbifera, Dioscorea tokoro and Dioscorea tenuipes. Preferably, the family dioscoreaceae (Dioscoreaceae) is a Dioscorea nipponica, Dioscorea quinqueoloba and/or Dioscorea tokoro. More preferably, the family dioscoreaceae (Dioscoreaceae) presents Dioscorea nipponica.

The extract in accordance with the present invention can be obtained by the extraction process, which includes the extraction of whole plants of the family dioscoreaceae (Dioscoreaceae), root or aerial parts (e.g., leaf or stem) using extraction solvent (first solvent extraction solvent)selected from the group consisting of water, alcohol With1-C4and mixtures of water with alcohol C1-C4. For example, the extract of the family dioscoreaceae (Dioscoreaceae) can be obtained by extracting the root of the family dioscoreaceae (Dioscoreaceae) the first extraction solvent. The first extraction solvent may be a mixed solvent of water and methanol or a mixed solvent of water and ethanol.

In the process of extraction of the whole plant of the family dioscoreaceae (Dioscoreaceae), the root or aerial parts, preferably the root of the family dioscoreaceae (Dioscoreaceae), cut into small pieces and then extracted with a first extraction solvent. This is the stage number of the first extraction solvent can be from 1-20 times preferably 3-10 times greater than the number of family dioscoreaceae (Dioscoreaceae). The first extraction solvent may be a mixed solvent of water and methanol (for example, a solution of methanol concentration of approximately 85%) or a mixed solvent of water and ethanol (for example, the ethanol concentration of approximately 85%). Extraction does not depend on temperature and can be performed in different temperature ranges, for example from 15°C to 100°C. this extraction can be carried out by methods of cold extraction, hot extraction, extraction with supercritical fluid, the centrifugal extraction, ultrasonic extraction or extraction with reflux. The duration of extraction may vary depending on the method of extraction. For example, extraction can be carried out once or repeatedly for approximately 1 hour to 10 days. Preferably, the extraction can be carried out 2 or 3 times at room temperature for about 2 days with the first extraction. The extract obtained by extracting the first extraction solvent may be in the form of liquid, which removes impurities from the usual method, for example by filtration or in powder form, obtained by concentrating ginkgoaceae under reduced pressure or traditional drying method.

In addition, if necessary, the extraction process may further include obtaining a fraction having a higher concentration of active components. That is, the extraction process further includes the dispersion of the extract obtained by extracting the first extraction solvent, in water, and extracting the resulting solution saturated with alcohol C1-C4(second extraction solvent), which increases the concentration of active components in the resulting extract.

When the dispersion in the water extract obtained by extracting the first extraction solvent, water may be dispersed directly in the liquid form, obtained by extraction of the first extraction solvent, or powder form, obtained by concentrating the liquid extract under reduced pressure and/or drying the liquid extract of the traditional method.

As the water-saturated alcohol C1-C4(second extraction solvent) can be used with water-saturated butanol.

In his volume the present invention includes a composition consisting of compounds isolated from the extract, i.e. steroid saponin or steroid sapogenin. That is, the present invention includes a pharmaceutical composition for the prevention or the ecene peripheral neuropathy, containing a therapeutically effective amount of the compounds of formula 1 or salts thereof, and pharmaceutically acceptable carrier.

[Formula 1]

where R is a hydrogen atom, an alkyl group, a C1-C4or saccharide.

In the compound of formula 1 radical R can represent hydrogen or methyl, preferably hydrogen. In other words, the compound of formula 1 may be a 3-β,25R-spirostomal-5-EN-3-ol.

The saccharide may be a monosaccharide, a disaccharide or a polysaccharide such as glucose, fructose, mannose, galactose, ribose, cellulose, glycogen, sucrose, maltose and lactose.

Salt of the compounds of formula 1 may be a formed by joining a widespread inorganic and/or organic acid salt, obtained from seizure ratio steroid saponin or sapogenin. Examples of salts of compounds of formula 1 include the salts disclosed in laid out in international patent publication no WO 2003/082893. These salts can be obtained in situ during the final separation and purification of compounds. In particular, the salt formed by the addition of acid, can be obtained by reaction of purified compounds as free base with a suitable organic or inorganic acid, followed by separation of the salts (see S.M.Berge, et al., Parmaceutical Salts, J. Pharm. Sci, 66: p.1-19 (1977)). Posted international patent publication number WO 2003/082893 and article M.Berge, et al. log used in the present invention as references. Salt, formed by joining the Foundation, can be obtained by reaction of purified compounds in the form of the acid with a suitable organic or inorganic base and separation of the salts. Salt, formed by joining the Foundation, may be a pharmaceutically acceptable salt of the metal or amine. Salt formed by the addition of acid may be a salt derived from one of the following acids: hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Salt, formed by joining the Foundation, may be a salt derived from one of the following bases: sodium hydroxide, potassium hydroxide, ammonium hydroxide.

The compound of formula 1 can be isolated from an extract in accordance with the exemplary embodiment of the present invention, synthesized using a known method (see Herbert O. House, Modern Synthetic Reactions, The Benjamin Cummings Publishing Company, 1972) or purchased (Sigma Co., USA).

The allocation method of the compounds of formula 1 from the extract may include the process of acid hydrolysis and the recrystallization process using the extract obtained according to example assests the of the present invention (for example, the extract obtained using the first extraction solvent and the second extraction solvent). For example, isolation of the compounds of formula 1 from the extract may include acid hydrolysis, for example 2,5 N. hydrochloric acid, at a temperature of 50-150°C., preferably approximately 94°C. for from 30 minutes to 3 days, preferably about 4 hours; the extraction of the obtained hydrolysis product (i.e. aliceooa sapogenin) an organic solvent, such as chloroform, acetone, benzene, or xylene, for 1-60 minutes, preferably about 15 minutes, and subsequent separation of the organic layer; if necessary, the concentration of the separated organic layer at a temperature of 10-100°C., preferably 30-35°With; the recrystallization of the organic layer or a concentrated solution of the organic layer with alcohol1-C4or alcoholic solution With1-C4(for example, 95%ethanol); and washing the obtained precipitate with water if necessary and recrystallization with acetone.

The present invention provides a pharmaceutical composition for the prevention or treatment of peripheral neuropathy, containing a therapeutically effective amount of an extract of the family dioscoreaceae (Dioscoreaceae) or the compounds of formula 1 or its salt, and Pharma is efticiency acceptable carrier.

The pharmaceutical composition according to the present invention includes a pharmaceutically acceptable carrier and can be included in the formulation of dosage forms for oral administration, dosage forms for external application, suppository or sterile solution for injection, for example in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups or aerosols. Pharmaceutically acceptable carrier may be a lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, aritra, ▫ maltitol, starch, gum Arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. The pharmaceutical composition may additionally include a diluent or filler, such as filler, extender, binder, humectant, raising agent, or surfactant. A solid composition for oral administration can be a tablet, pill, powder, granule or capsule. Such solid compositions may include at least one placeholder is selected, for example, of the following: starch, calcium carbonate, sucrose, lactose, and gelatin. In addition, such solid compositions may optionally include high sliding the General substance such as magnesium stearate or talc. A liquid composition for oral administration can be a suspension, solution, emulsion or syrup. In addition, the liquid composition for oral administration may further include a diluent, such as water, liquid paraffin; humidifier; sweetening agents; flavoring or preservative. The composition for parenteral administration can be a sterile aqueous solution, a nonaqueous solution, suspension, emulsion, liofilizovannye composition or suppository. Non-aqueous solvents or suspendresume agents can be propylene glycol, polyethylene glycol, natural oil, such as olive oil or injectable esters, for example etiloleat. As a base for suppositories may apply witepsol, macrogol, tween 61, cacao butter, lauric oil, glycoregulation.

In the pharmaceutical compositions of the present invention, the dosage of the extract of the family dioscoreaceae (Dioscoreaceae) or the compounds of formula 1 may vary depending on the condition of the patient or his body weight, severity of disease, dosage forms, routes of administration and duration of administration, and may be properly average specialist. For example, the extract of the family dioscoreaceae (Dioscoreaceae) or the compound of formula 1 may be used at a dosage of 0.0001-1000 mg/kg, preferably 0.001 to 000 mg/kg, in day. Receiving the pharmaceutical composition may be performed one or more times per day. The dose of the extract of the family dioscoreaceae (Dioscoreaceae) or the compounds of formula 1 in the pharmaceutical compositions of the present invention may be 0.001 to 50 wt.% per 100 wt.% pharmaceutical compositions.

The pharmaceutical composition may be introduced mammals such as rats, mice, livestock or people, in different ways, such as orally, rectally, intravenously, intramuscularly, subcutaneously, by intrauterine injection, injection through the hard shell of the brain, intracerebrally or ventricular injection.

The present invention includes in its scope of food composition for the prevention or treatment of peripheral neuropathy, containing as an active ingredient an extract of the family dioscoreaceae (Dioscoreaceae) or the compound of formula 1.

Food composition in accordance with the present invention can be used as a healing food. According to article 6727 Law of the Republic of Korea about healthful food, the term "health food" refers to food produced and processed using a source or component that have beneficial effects on the human body.

The term "impact" refers to the ingestion in order to achieve BL is favourable steps to health i.e. to control nutrients into the structure and functions of the human body or physiology.

Food composition in accordance with the present invention may include conventional additives. According to "dietary supplements" to the requirements determined in the absence of other standards, including standards and criteria for the corresponding product according to the General rules of the code on food additives and common tests approved by Management under the control over products and medicines of the Republic of Korea.

The products included in the list of code about food additives are substances synthesized by chemical means, such as a ketone, glycine, citrate potassium, nicotinic acid, cinnamic acid, natural additives, such as pigment persimmon, liquorice extract, crystalline cellulose, pigment kaulana, guar gum; or mixed composition, such as composition with L-glutamate sodium, alkaline additives for noodles, preservatives, composition with the pigment of tar.

Food composition in accordance with the present invention may include an extract of the family dioscoreaceae (Dioscoreaceae) or the compound of formula 1 in an amount of 0.01-95 wt.%, preferably 1-80 wt.%, per 100 wt.% food composition for the prevention and/or treatment of peripheral neuropathy. In addition, for the prevention and/or treatment per fericelli neuropathy food composition can be produced and processed to obtain tablets, capsules, powder, granules, liquids or pills.

For example, for the production of healthful food in the form of tablets, a mixture of extract of the family dioscoreaceae (Dioscoreaceae) or the compounds of formula 1, a filler, a binder, baking powder and other additives may be subjected to granulation in the traditional method, and then forming with a moving substance. Alternatively, the mixture can be directly subjected to molding. In addition, if necessary, the composition of healthful food in tablet form can include sweeteners, and if necessary, healthful foods in the form of tablets can be coated.

With regard to healthful foods in capsule form, the composition may be in hard capsules by filling a traditional hard capsules with a mixture of extract of family dioscoreaceae (Dioscoreaceae) or the compounds of formula 1 with an additive such as a filler, or granules to the mixture, or covered with granules of the mixture; or the composition may be in soft capsules by filling gelatin bases of the capsules with the mixture of the extract of the family dioscoreaceae (Dioscoreaceae) or the compounds of formula 1 with an additive such as a filler. If necessary, the composition for soft capsules may include a plasticizer, such as gli is Erin or sorbitol, dye and preservative.

Healthful foods in the form of pills can be produced by molding a mixture of an extract of the family dioscoreaceae (Dioscoreaceae) or the compounds of formula 1, aggregate, binder and baking powder suitable method. If necessary, healthful foods made in the form of pills may be coated with white sugar or other material to cover, or can be coated with the starch, talc or other materials.

Healthful foods in the form of granules can be produced by granulating a mixture of the extract of the family dioscoreaceae (Dioscoreaceae) or the compounds of formula 1, aggregate, binder and baking powder suitable method. If necessary, healthful foods made in the form of granules, may include flavoring and sweetener.

A filler, a binder, a leavening agent, a sliding agent, a sweetener and a flavoring used in the present invention, can be defined as relevant materials with the same or similar purpose and disclosed in sources known in the field (The Korean pharmacopoeia review, Moonsungsa Publication Co., Korea Pharmaceutical University Association, Fifth edition, p.33-48, 1989).

The implementation of the invention

The present invention will be described in more detail with reference to when it is possible to further examples. These examples are intended for illustration only and are not intended to limit the scope of the present invention.

Example 1: Obtaining extract

Plants of Dioscorea Nipponica has dried up and the roots cut into small pieces. The sample mass 500 g was added to 10 l of 85%aqueous solution of methanol and then was extracted three times each time for 2 hours at room temperature. The process of extraction was repeated twice. The obtained supernatant was combined and concentrated under reduced pressure, thus obtaining a 74 g of the crude extract.

Received 74 g of the crude extract was suspended in 1 l of distilled water and added 1 l of water-saturated butanol, after which the resulting organic layer was separated; this procedure was repeated 5 times. The obtained organic layers were combined and dried under reduced pressure. The result was 17 g of the extract of Dioscorea Nipponica.

Example 2: Obtaining extract

Plants of Dioscorea quinqueoloba have dried up and the roots cut into small pieces. The sample mass 500 g was added to 5 l of 85%ethanol and was extracted three times each time for 2 hours at room temperature. The process of extraction was repeated twice. The obtained supernatant was combined and concentrated under reduced pressure, thus obtaining a 90 g neocidin the CSO extract.

Obtained 90 g of the crude extract was suspended in 1 l of distilled water and added 1 l of water-saturated butanol, after which the resulting organic layer was separated; this procedure was repeated 5 times. The obtained organic layers were combined and dried under reduced pressure. The result was 26 g of the extract of Dioscorea quinqueoloba.

Example 3: extract extract

Dried plants of Dioscorea tokoro and their roots are cut into small pieces. The sample weight of 300 g was added to 3 l of 85%ethanol and was extracted three times each time for 2 hours at room temperature. The process of extraction was repeated 2 times. The obtained supernatant was combined and concentrated under reduced pressure, thus obtaining a 35 g of the crude extract.

Obtained 35 g of the crude extract was suspended in 0.5 l of distilled water and added to 0.5 l of water-saturated butanol and then the resulting organic layer was separated; this procedure was repeated 5 times. The obtained organic layers were combined and dried under reduced pressure. The result obtained 11 g of the extract of Dioscorea tokoro.

Example 4: Separation of active connections

1 g of the extract of Dioscorea nipponica obtained in Example 1 was subjected to hydrolysis at 94°C for 4 h by adding 10 ml of 2.5 N. HCl. The resulting hydroly the al was extracted with chloroform (10 ml) for 15 minutes. The chloroform layer was separated, was filtered and then concentrated under reduced pressure and a temperature of 30-35°C. the Obtained residue was recrystallize at 4°C using 5 ml of 95%ethanol. The recrystallized precipitate was filtered, washed with water, recrystallize at 4°C, using 3 ml of acetone and then filtered, and received about 100 mg of sediment. The precipitate was identified as 3b,25R-spirostomal-5-EN-3-ol represented by formula 2.

[Formula 2]

(1) Formula: C27H42O3

(2) Molecular weight: 414.62

(3) melting point: 204-207°C

(4) [d]25D- 129°

(5) NMR Data: see Table 1

Table 1
13CChemical shift (δ)1HChemical shift (δ)
C-137,6-37,7N-11,60-1,70; 0,87-of 0.91 (m,o)
C-230,3-30,4N-22,00-2,03; 1,75-to 1.79 (m,o)
C-378,1-78,7H-3 3,81-3,90 (m, J=4,7-5,6 Hz)
C-438,9-39,5N-4to 2.57-to 2.29 (m, J=13-14 Hz; J=5,0; 12.0 Hz)
C-5140,9-141,1
S-6121,9-122,0H-65,23 - of 5.26 (d, J=4,6-5,4 Hz)
C-732,4 with 32.5N-71,77-1,82; 1,41 of 1.46 (m,o)
S-8the 31.8-31.9 perN-8the 1.44 to 1.48 (m,o)
S-950,4-a 50.5H-90,80-0,83 (m)
C-1037,2-37,3
S-11~21,3H-111,35-to 1.38 (m,o)
C-1240,0-40,1N-121,60-of 1.62 (m,o)
S-1340,6-40,7
C-1456,8-56,8H-141,01 (m)
S-1532,4 with 32.5H-151,95-to 1.98 (m, J=5,9-6,1 Hz); of 1.31 and 1.35 (m,o)
S-1681,3-81,3H-164,45-4,48 (m, J=7,0-7,4 Hz)
C-1763,0-63,1H-171,72 is 1.75 (m,o)
S-1816,5-16,6N-180,73-0,76 (C)
S-1919,6-19,6H-190,80-1,00 ()
S-2042,1-42,2H-20of 1.88 (m)
S-2115,2-15,2H-211,05-of 1.07 (d, J=6.8 and 7.2 Hz)
S-22109,4-109,5
S-23 32,0-32,0H-231,57-1,63 (m)
S-2429,4 is 29.5H-241,48-of 1.52 (m,o)
S-2530,8-30,8N-251,50 (m)
S-2667,0-67,1H-263,50 is 3.40 (m, J=10,5; 3,0; 10,5 Hz)
S-2717,5-17,5H-27of 0.60 to 0.63 (d, J=4,7-5,8 Hz)

Experimental example 1: Measurement of axon growth

In the incubator under the conditions, including the CO2- 5% and a temperature of 37°C, cells were grown PC 12 pheochromocytoma, code ATS (American culture collection): CRL-1721) in medium RPMI 1640 with the addition of horse serum (10%vol), fetal bovine serum (5%vol.) and 1% penicillin-streptomycin.

To determine the effect of the compounds of formula 2 on axonal growth medium with addition of 2% horse serum, 1% fetal bovine serum and 1% penicillin-streptomycin was added to each 6-well plate coated with poly-d-lysine, then each well was inoculable 5×104PC 12 cells. After 24 hours these holes about amityvale 10 µl/ml ethanol, 10 mg/ml of the compounds of formula 2 and 50 ng/ml nerve growth factor (R&D system, USA), respectively. Then after 48 hours was measured by the length of the axon using an inverted microscope with a cold device (SC-2, Olympus, USA) 15 (Cm. Figure 1 and figure 2).

According to figures 1 and 2 the growth of axons were observed in the group injected with ethanol (control group), however, axonal growth was stimulated in the group treated with the compound of the formula 2 (DG)and in the group treated with nerve growth factor (NGF). Accordingly, it has been found that the compound of formula 2 stimulated the differentiation of PC 12 cells by stimulating the growth of axons.

Experimental example 2: Measurement of the level of nerve growth factor in mouse serum

The compound of formula 2 was dissolved in 0.2 ml dimethylsulfoxide:ethanol (3:1) and then the solution once orally was administered to male mice ICR (Institute of cancer research) 7 weeks of age (n=7) in an amount of 10 mg/kg After 24 hours the number of endogenous nerve growth factor was measured using ELISA method. In the control group mouse ICR once oral introduced 0.2 ml dimethylsulfoxide:ethanol (3:1). Then the number of nerve growth factor in the control group was measured as described above.

As can be seen in Figure 3, in the group that was administered the compound of formula 2 (DG 10 mg/kg orally), nerve growth factor in saw what the pigs were 2.5 times higher than in the control group. These results show that the compound of the formula 2 can carry out the treatment of neuropathy, inhibiting the degeneration and death of neurons in the mouse and thereby preventing the reduction in the number of neurons.

Experimental example 3: Measurement of the level of nerve growth factor in the serum of mice with induced diabetes

Prepared mouse with alloxan-induced diabetes as a model animal with diabetic neuropathy, one of the multiple neuropathy.

Male mice of ICR (Institute of cancer research) 7 weeks of age were subjected alimentary abstinence for 18 hours, then made them once intraperitoneally injection alloxan dissolved in physiological saline solution, with a dosage of 160 mg/kg) to induce diabetes. Mouse, preserving the contents of fasting blood sugar of 200 mg/DL or more within one week, i.e. mice with induced diabetes, were selected and then divided into control group (n=10), the group receiving the extract (n=10) and the group receiving the compound (n=10). In the control group was used in 0.2 ml of dimethylsulfoxide:ethanol (3:1); in the group receiving the extract was applied the extract obtained in accordance with Example 1 and dissolved in a solution of dimethylsulfoxide:ethanol (3:1), in the amount of 100 mg/kg, and in the group receiving the connection use the Yali compound of formula 2, dissolved in a solution of dimethylsulfoxide:ethanol (3:1), in the amount of 10 mg/kg In all groups receive carried out orally three times per week, and the total duration was one month. The amount of endogenous nerve growth factor in the serum were measured using ELISA method.

According to figure 4 the number of endogenous nerve growth factor in the serum of both groups receiving the extract (DN 100 mg/kg orally)and the group receiving compound (DG 10 mg/kg orally)were 3 and 4 times higher, respectively, than the control group, which was applied only filler. These results indicate that the extract and the compound of the present invention can be treated diabetic neuropathy by inhibiting the degeneration and death of neurons with nerve damage caused by diabetes, and thereby preventing the reduction in the number of neurons.

Experimental example 4: Measurement of transmission speed by the motor nerve and sensory nerve in the sciatic nerve of mice with induced diabetes

therapeutic effect of the compounds of the present invention to diabetic neuropathy, one of the multiple neuropathies, was determined by measuring the effect of the compound of the present invention on the transmission speed by the motor nerve and sensory nerve in the sciatic nerve.

Male ICR mice (And the Institute of cancer research) 7 weeks of age were subjected alimentary abstinence for 18 hours, then made them once intraperitoneally injection alloxan dissolved in physiological saline solution, with a dosage of 160 mg/kg) to induce diabetes. Mouse, preserving the contents of fasting blood sugar of 200 mg/DL or more within one week, i.e. mice with induced diabetes, were selected and then divided into control group (n=7) and the group receiving the compound (n=7). In the control group was used in 0.2 ml of dimethylsulfoxide:ethanol (3:1)and in the group receiving compound used compound of formula 2 is dissolved in a solution of dimethylsulfoxide:ethanol (3:1), in the amount of 10 mg/kg male mice of ICR 7 weeks of age at which diabetes was not induced, were United in the normal group (n=7), and in the normal group was used in 0.2 ml of dimethylsulfoxide:ethanol (3:1). In all groups, the admission was made orally three times per week, and the total duration was 2 months. Upon completion of the application of the mice killed by displacement of the cervical vertebrae and then quickly removed the skin and muscles in the hip area. After that separated respectively the left and right sciatic nerves length of 20 mm or more and have kept them in a physiological saline solution, through which passed the air. Isolated sciatic nerves was placed on a 20-millimeter round, u is positive plate. Then to the respective ends of the nerves connected to the sensor and stimulating probe and measured the electrical conductivity using a digital oscilloscope with memory for determining the speed of nerve transmission (see Figure 5 and 6).

In the General case, the myelin is a phospholipid membrane, several layers which surrounds axons; it is also called the myelin sheath. Like plastic-coated electric wire myelin thanks to the white lipid material prevents leakage and scattering of the electrical signals transmitted by neurons. Myelin is evenly distributed among the nodes of Ranvier (part forming the nodes of myelin), in which myelin is formed and surrounds axons. An electrical signal is transmitted through space, the pulses can be quickly transmitted to neurons and myelin increases the speed of passage of electrical impulses. Accordingly, when the destruction of myelin from nerve damage as a result of neuropathy caused by diabetes, axons cease to function and the speed of transmission along the nerves is reduced.

Within one month of the period with induced diabetes group receiving compound (DM-DG) showed a transmission rate on sensory nerve is 25% higher than the control group with induced diabetes (DM), which was used only filler (see Figure 5). Within two months of the period and dozirovannym diabetes group receiving compound (DM-DG) showed a transmission rate on sensory nerve 45% higher than the control group with induced diabetes, as well as the signal transmission speed by the motor nerve is 40% higher than the control group (see Fig.6). Thus, found that the compound of the present invention has a therapeutic effect on the nerve damage caused by diabetic neuropathy, by increasing the speed of transmission of sensory and motor nerves in mice with induced diabetes.

Experimental example 5: Measurement of the level of nerve growth factor in the sciatic nerve of mice with induced diabetes

Male mice of ICR (Institute of cancer research) 7 weeks of age were subjected alimentary abstinence for 18 hours, then made them once intraperitoneally injection alloxan dissolved in physiological saline solution, with a dosage of 160 mg/kg) to induce diabetes. Mouse, preserving the contents of fasting blood sugar of 200 mg/DL or more within one week, i.e. mice with induced diabetes, were selected and then divided into control group (n=5) and the group receiving the compound (n=5). In the control group was used in 0.2 ml of dimethylsulfoxide:ethanol (3:1); and in the group receiving compound used compound of formula 2 is dissolved in a solution of dimethylsulfoxide:ethanol (3:1), in the amount of 10 mg/kg In all groups receiving exercise the conduct oral three times a week, the total duration was one month. The amount of endogenous nerve growth factor in the sciatic nerve was measured using ELISA method (see Fig.7).

According to Fig.7, it was found that nerve growth factor in the sciatic nerve of the group receiving compound (DM-DG 10 mg/kg orally) was about 30% higher than in the control group, which was introduced only a filler. Thus, it is concluded that the results shown in Figure 5 and 6, are the result of the protective action of nerve growth factor.

Experimental example 6: Measurement of changes in the content of sorbitol in the sciatic nerve of mice with induced diabetes

therapeutic effect of the compounds according to the present invention for the neuropathy was determined by measuring changes in the content of sorbitol in the sciatic nerve.

Male mice of ICR (Institute of cancer research) 7 weeks of age were subjected alimentary abstinence for 18 hours, then made them once intraperitoneally injection alloxan dissolved in physiological saline solution, with a dosage of 160 mg/kg) to induce diabetes. Mouse, preserving the contents of fasting blood sugar of 200 mg/DL or more within one week, i.e. mice with induced diabetes, were selected and then divided into control group (n=3) and the group receiving the compound (n=3). In the control group was used in 0.2 ml of dimethylsulfoxide:ethanol (3:1), and in the group receiving compound used compound of formula 2 is dissolved in a solution of dimethylsulfoxide:ethanol (3:1), in the amount of 10 mg/kg male mice of ICR (Institute of cancer research) 7 weeks of age at which diabetes was not induced, joined in the normal group (n=3) and in the normal group was used in 0.2 ml of dimethylsulfoxide:ethanol (3:1). In the normal group, control group and the group receiving the connection was made orally three times per week, and the total duration was two weeks. Upon completion of the application of the mice killed by displacement of the cervical vertebrae and then measured the content of sorbitol in the sciatic nerve by high performance liquid chromatography (HPLC) (see Fig).

Paleology path is the process by which glucose is converted to sorbitol under the action of alsoreported, and sorbitol is converted to fructose by the action of sarbadhikary. Under hyperglycemic condition, such as diabetes, excess glucose gets into the cells, and sorbitol is produced and accumulated in paleologou way. At this stage, the nerves can be damaged due to the osmotic effect, causing entrainment of water into the cells. Thus, the measurement result of the influence of the compounds according to the present invention on the accumulation of sorbitol in the sciatic nerve of a mouse is induced diabetes as shown in Fig, it was found that the content of sorbitol in the sciatic nerve in the control group with induced diabetes (DM-CON) was approximately 40% higher than that of the normal group, but the content of sorbitol in the sciatic nerve in the group receiving compound (DM-DG)was 10% lower than in the control group with induced diabetes (DM-CON). These results show that the compound of the present invention may partially reduce aggressive factors that cause damage to the nerves.

Experimental example 7: Histological comparison of the sciatic nerve of mice with induced diabetes

therapeutic effect of the compounds according to the present invention for the neuropathy was determined by measuring the histological changes in the sciatic nerve.

Male mice of ICR (Institute of cancer research) 7 weeks of age were subjected alimentary abstinence for 18 hours, then made them once intraperitoneally injection alloxan dissolved in physiological saline solution, with a dosage of 160 mg/kg) to induce diabetes. Mouse, preserving the contents of fasting blood sugar of 200 mg/DL or more within one week, i.e. mice with induced diabetes, were selected and then divided into control group (n=5), the group receiving the extract (n=5) and the group receiving the compound (n=3). In the control group note is issued in 0.2 ml of dimethylsulfoxide:ethanol (3:1), in the group receiving the extract was applied the extract obtained in accordance with Example 1, dissolved in a solution of dimethylsulfoxide:ethanol (3:1)and in the group receiving compound used compound of formula 2 is dissolved in a solution of dimethylsulfoxide:ethanol (3:1), in the amount of 10 mg/kg In all groups receive carried out orally three times per week, and the total duration was two months. Upon completion of the application of the mice killed by displacement of the cervical vertebrae and then the sciatic nerve was separated, colored according to the conditions below and visually examined under a confocal microscope at magnifications of 600× 1200×.

(1) prefixal: 2.5% glutaraldehyde, 12 hours or more

(2) leaching: pH of 7.4; 0.1 M phosphate buffer solution, 2 times in 15 minutes

(3) postfixation: 1% osmium tetroxide OsO460 minutes

(4) washing: a pH of 7.4; 0.1 M phosphate buffer solution, 2 times for 5 minutes

(5) dehydration:

50, 70, 80, 90% alcohol: 10 minutes in each solution

100%alcohol: 2 times in 15 minutes

(6) substitution: propylene oxide, 2 times in 15 minutes

(7) impregnation: propylene oxide (1), EROC 812 (2), 12 hours or more

(8) conclusion: cleaned EROC 812 (polymerization at 80°C): 12 hours or more

(9) partitioning: partition of medium thickness, 35-95 mcm

(10) contrast: 1% toluidine blue

Figa and 9B shows the results indicate, obtained at 600-fold (9A) and 1200-fold increase (9B), respectively. In the group with induced diabetes (DM), the axon and the myelin in the Central part of the sciatic nerve were largely destroyed. However, in the group receiving compound (DM-DG) and in the group receiving the extract (DM-DN) axon and myelin in the Central part of the sciatic nerve were clearly visible. The results show that the extract or the compound in accordance with the present invention can protect and heal the nerves are damaged due to neuropathy.

Of the compounds of the present invention were prepared with the compositions described below. However, these examples the compositions are intended for illustration only and are not intended to limit the scope of the present invention.

Example composition 1: Composition of tablets

The compound of formula 2200 mg
Lactose100 mg
Starch100 mg
Magnesium stearateon demand

These compounds were mixed and compressed into tablets in the usual method of manufacture of tablets.

Example composition 2: a Liquid composition

The compound of formula 21000 mg
CMC-Na20 g
Isomerized sugar20 g
Lemon flavouron demand

Added purified water to a total volume of the solution to 1000 ml of the Above components were mixed in accordance with the usual method of preparation of liquid compositions, filled in a brown bottle and sterilized, thus obtaining a liquid composition.

Example of compound 3: Composition capsules

The compound of formula 2300 mg
Crystalline cellulose3 mg
Lactose14,8 mg
Magnesium stearate0.2 mg

These components were mixed in accordance with the usual method of preparation of the composition for capsules and filled with a mixture of gelatin capsules, thus obtaining a composition for capsules.

Example of part 4: Composition for injection

Connect four is uly 2 300 mg
Mannitol180 mg
Sterile distilled water for injection2974 mg
Na2HPO412H2O26 mg

An injection containing components in the above amounts per ampoule (2 ml), prepared in the usual method of manufacture of injection.

1. The extract of the family dioscoreaceae (Dioscoreaceae) for the prevention or treatment of peripheral neuropathy, with family dioscoreaceae (Dioscoreaceae) represents at least one type of plant selected from the group consisting of Dioscorea nipponica, Dioscorea septemloba, Dioscorea quinqueoloba, Dioscorea batatas, Dioscorea japonica, Dioscorea bulbifera, Dioscorea tokoro, Dioscorea tenuipes, with the specified extract is obtained by extraction of the root of a plant of the family dioscoreaceae (Dioscoreaceae) the first extraction solvent selected from the group consisting of water, alcohol C1-C4and mixtures of water with alcohol C1-C4.

2. The extract according to claim 1, in which the family dioscoreaceae (Dioscoreaceae) is a Dioscorea nipponica, Dioscorea quinqueoloba or Dioscorea tokoro.

3. The extract of claim 1, wherein the peripheral neuropathy is a multiple neuropathy.

4. The extract according to claim 1, in which the first extraction the solvent is a mixture of water and methanol or a mixture of water and ethanol.

5. The extract according to claim 1, in which the extraction process further comprises the dispersion of the extract obtained by extraction of the first extraction solvent, water, and extraction with water-saturated alcohol C1-C4(second extraction solvent).

6. The extract according to claim 5, in which the second extraction solvent is a water-saturated butanol.

7. Pharmaceutical composition for prevention or treatment of peripheral neuropathy, containing a therapeutically effective amount of an extract according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. Food composition for preventing or treating peripheral neuropathy containing extract according to any one of claims 1 to 6 as an active ingredient.



 

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2 ex, 3 tbl

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2 ex, 3 tbl

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SUBSTANCE: invention aims at improving pharmacological activity of an antidiabetic composition. Said technical effect is ensured by the fact that there is offered a polypharmaceutical herbal tea which contains herbs comprising vitamins and digestible sugars and metabolism-regulation plants. The tea contains: goat's rue (Galega) herb, European walnut leaf, knotgrass herb, dense mullein blossom, dandelion root, tillet blossom, white mulberry leaf, horseheal root, cowberry leaf, bean valves, common periwinkle leaf, common argimony herb in various proportions. The offered composition can be presented in the form of phyto tea in filter bags 2.0 g.

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