KR101384634B1 - A pharmaceutical composition for treating narcotics addiction comprising bergenin or bergenin derivatives - Google Patents

Abstract

The present invention relates to a vergenin and a vergenin derivative which can be usefully used for the treatment of drug addiction, and the composition according to the present invention is useful as a therapeutic agent for drug addiction because it not only has a therapeutic effect of drug and psychotropic drug addiction but also has fewer side effects. Can be used.

Description

A pharmaceutical composition for treating narcotics addiction comprising bergenin or bergenin derivatives}

The present invention relates to vergenin and vergenin derivatives which can be usefully used for the treatment of drug addiction.

In general, "narcotics" refers to compounds having similar effects to opiates and derivatives thereof, including addictive or addictive drugs such as morphine, codeine, noscapine, papaverine, thebaine, heroin, etc. Opiate drugs or opiate-like drugs, which are natural combinations derived from poppy plants (Stedman's Medical Dictionary, 26th edition, Williams & Wilkins Publ., 1995). To be classified as a drug, certain compounds must be able to induce "significant changes in feelings and behaviours", be able to induce a state of "coal pain" and present serious risks such as dependency, tolerance and / or addiction. It must be proved.

Most drug addicts initially use narcotic substances for pain relief, but gradually become addicted to narcotic substances to find more powerful drugs. Common pathological symptoms of these drug addicts include fatigue, emotional instability, anti-coma, and vomiting. If the symptoms worsen, antisocial and anti-ethical behaviors result, resulting in social problems. Generates. Thus, efforts to treat drug addicts are being carried out on a national level, but most drug addicts are not completely treated. This is because the drug addiction mechanism is complicated and various factors such as environment, genetics, race, dosage form, and drug type are involved.

To treat drug addiction, relief of withdrawal symptoms and suppression of re-administration are essential. Withdrawal symptoms do not have a special treatment and can be administered symptomatically. In addition, the understanding of the physiological function of addiction is important in terms of treatment to mitigate re-dosing. There are many theories about the cause of the condition, but the most commonly accepted one is an increase in craving. This is a major symptom of drug addiction, and it is the main target of treatment because it is a cause of easy re-administration even after many years of medication.

Continued administration of drugs results in activation of the brain reward system (especially the dopamine nervous system), and withdrawal of the drug results in the suppression of the central nervous system dopamine nervous system due to the sudden absence of dopamine nervous system stimulants. Due to this duality, dopamine neurological agonists and antagonists have been used in conventional drug addiction treatment. Specifically, dopamine receptor agonists relieve narcolepsy or discomfort after medication, but add a conditional stimulus (such as addicts increase their desire to consume drugs when exposed to a similar time, place, or stress as when administering drugs). There is a risk of recurrence of drug administration, and the drug itself is at risk of poisoning. Dopamine receptor antagonists, on the other hand, reduce the response to conditional stimuli and the rewarding properties of the drug itself, but have side effects that are typical dopamine nervous system suppression symptoms, such as feelings of discomfort, discomfort, Parkinson's disease or dyskinesia. In order to overcome these shortcomings, efforts have been made to develop therapeutics, but there are no results.

As described above, the conventionally developed dopamine neurological agonists or antagonists cause serious side effects, according to the need for a therapeutic agent that can minimize the side effects even if the therapeutic effect is lowered, extracts extracted from natural products or mixtures thereof Studies on the composition are also in progress.

For example, the Republic of Korea Patent Publication No. 10-1988-0001296, Gyeji, ginger, jujube, peony, Shiho, Banja, Bokryeong, Golden, Ginseng, rhubarb, licorice, cotyledon, seedlings and keel, then hot water extraction and concentration And a method for producing a composition capable of alleviating poisoning such as cigarettes and coffee, as well as addictive drugs, are disclosed in Korean Patent Laid-Open Publication No. 10-1990-0002793, which is rich, cinnamon, peppermint, gilcho root, licorice. There is disclosed a drug detoxifying agent, which is prepared by mixing pepper, peony, sandalwood, white paper, Hyunho color, Bokryeong, motherwort, Hyuncho and ginseng, and then extracting and concentrating it with hot water. In addition, the Republic of Korea Patent Publication No. 10-1992-0003986 discloses a mixture of sulfur, rich powders, gallium hair powder and alum powder at high temperature for a long time, and then immersed and filtered in water to obtain a filtrate, and dried After obtaining a dry powder, a licorice powder, ginseng powder and a drug for the treatment of narcotic intoxication prepared by mixing with the present invention and a method for manufacturing thereof are disclosed, Korean Patent No. 10-0054246, Sanjago, Shando-geun, Daegeuk, Sugija, Cheonsan Gap, A drug addiction antidote prepared by mixing ethanol extract, ginseng powder, and sanjoin powder of powder mixture of Angelica vulgaris, Cheongung, Chihwang, and Earl of Peony is disclosed. In addition, Korean Patent No. 10-0313454 discloses drugs, alcohol and tobacco obtained from a mixture of Kanghori, Ginseng, Hyunho color, Rich, Hemp, Cucumber, Cheonma sprout, Astragalus, Honeysuckle, Gurugi, White Samju, Cinnamon and Mint. Disclosed are compositions for inhibiting withdrawal symptoms and methods for their preparation. However, such extracts from natural products or mixed compositions thereof are excellent in safety and do not show fatal side effects, but the effects of treating drug addiction are extremely weak and are not used for practical drug addiction.

In addition, the Republic of Korea Patent Registration 10-0715939 was tested the inhibitory effect of drug addiction with a substance extracted from natural products, by this experiment the place-dependence of the golden extract, betaine or a mixture thereof formed by the combined administration of morphine and nalbuphine In addition, it is disclosed to inhibit hypersensitivity formation and climbing behavior of dopamine receptors. However, the use of vergenin as a control of the climbing behavior, but the results of these experiments can only reduce the number of climbing by about 0.5 times compared to the group administered only saline, which can be seen as a drug addiction inhibitory effect There was no situation.

Bergenin is a compound that can be extracted from natural products, and when used in humans, its stability is very high and there are few side effects (Malaysianol A, a new trimer resveratrol oligomer from the stem bark of Dryobalanops aromatica. Wibowo A, Ahmat N, Hamzah AS, Sufian AS, Ismail NH, Ahmad R, Jaafar FM, Takayama H. Fitoterapia. 2011 Jun, 82 (4), pages 676-81). That is, bergenin can be isolated from natural sources such as baekryechae, roe deer or yeast tree, or can be chemically synthesized (Lim et al., J Ethnopharmacol. 70 (1): 69-72 2000 Apr) .

Efficacy studies on the various biological activities of the vergenin have been continued in order to prepare drugs using the stability of the vergenin and the possibility of oral administration. Until now, Bergen has been known to have various physiological effects such as antioxidant, anti-inflammatory and anticancer effects (Nighat Nazir, Surrinder Koul, Mushtaq A. Qurishi., Etc., 2007. Journal of Ethnopharmacology 112, 401). (405) Immunomodulatory effect of bergenin and norbergenin against adjuvant-induced arthritis-A flow cytometric study Nighat Nazira, Surrinder Koulb, Mushtaq A. Qurishia, Sachin C. Tanejab, Sheikh F. Ahmadc, Sarang Banic and Ghulam N. Qazi, Journal of Ethnopharmacology, 112 (2007), 401-405, 2) Antiulcer activity of naturally occurring pyrano-coumarin and isocoumarins and their effect on prostanoid synthesis using human colonic mucosa, RK Goel, RN Maiti, M Manickam, AB Ray, Indian journal of experimental biology (Indian J Exp Biol) Vol. 35 Issue 10 pg. 1080-3, 3) In vitro inhibitory effects of bergenin and norbergenin on bovine adrenal tyrosine hydroxylase, Yong-He Zhang, Lian-Hua Fang, Myung-Koo Lee, Bao-Shan Ku, Phytotherapy research: PTR (Phytother Res) Vol. 17 Issue 8 pg. 967-9). However, there is no known effect related to the treatment of drug addiction, and there is little research on the use of vergenin derivatives.

Accordingly, the present inventors completed the present invention by confirming that, while studying various pharmacological effects on the vergenin derivatives, the vergenin and the vergenin derivatives exhibited excellent inhibitory activity against drug addiction.

The present invention is to provide a vergenin and bernine derivative compounds that are excellent in the therapeutic effect of drug addiction and its side effects can also be useful in the treatment of low drug addiction.

In order to solve the above problems, the present invention provides a pharmaceutical composition for treating drugs and psychotropic drugs comprising a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

Wherein R is hydrogen or acetyl.

In addition, a pharmaceutically acceptable carrier may be further included.

As used herein, the terms "drug" and "psychotropic drug" refer to compounds that have similar effects to opiates and derivatives thereof, and are addictive such as morphine, codeine, noscapine, papaverine, thebaine, heroin, or the like. Opiate drugs or opiate-like drugs, which are natural combinations derived from poppy plants, including addictive drugs (Stedman's Medical Dictionary, 26th edition, Williams & Wilkins Publ., 1995). To be classified as a drug, certain compounds must be able to induce "significant changes in feelings and behaviours", be able to induce a state of "coal pain" and present serious risks such as dependency, tolerance and / or addiction. It must be proved.

As used herein, the terms “drug addiction” and “psychotic drug addiction” refer to a condition in which a normal life can not be achieved without using drugs by prolonged use of drugs or psychotropic drugs. Symptoms of drug addiction vary slightly depending on the type of drug, but the World Health Organization (WHO) defines common features as follows. First, they continue to use the drug and have a strong desire to get it by any means. Second, there is a tendency to continue to increase capacity. Third, there is a tendency to mental and physical dependence on drugs. Fourth, it harms society as well as individual.

In the present invention, "treatment" means any action that improves or advantageously changes the symptoms caused by drug addiction and psychotoxic drug addiction by administration of the composition.

Compound represented by the formula (1) according to the present invention, pharmaceutically acceptable salts thereof can reduce the number of jumps measured after administering naloxone to the mouse which is an indicator of the therapeutic effect of drug addiction, treatment of drug addiction This can be useful for. Existing experiments to measure the number of climb of the mouse is a method mainly used to measure the dopamine function, dopamine function is related to drug addiction, but dopamine function change does not evaluate the suppression of drug addiction.

In addition, the present invention provides a method for preparing a compound of formula 2 by reacting a compound of formula 3 with a compound of formula 4 in a solvent.

(2)

(3)

[Chemical Formula 4]

The preparation process according to the present invention is shown schematically in Reaction Scheme 1 below.

[Reaction Scheme 1]

The compound of Chemical Formula 2 according to the present invention may be prepared in one step through a condensation reaction of the Bergenin compound of Chemical Formula 3 with the acetyl chloride of Chemical Formula 4.

It is known in the literature about the method for producing the bernine compound of Formula 3, it can be used to prepare or purchase the benzine by a known method (Takahashi et al., Bioorg. Med. Chem. 11 : 1781-1788, 2003; Jung et al., Chem. Bio.Drug Des. 78: 725-729, 2011).

It is preferable to react the Bergenin compound of Formula 3 with the acetyl chloride compound in an equivalent ratio of 1: 1, and the organic solvent that can be used at this time is dichloromethane, chloroform, acetonitrile, pyridine, dimethylformaldehyde, dimethyl Sulfoxides or mixtures thereof may be used, preferably dichloromethane or pyridine. In addition, the reaction is preferably carried out for 1 to 72 hours at 0 ℃ to 90 ℃. More preferably, the reaction is carried out at a temperature of 0 ℃ to 30 ℃.

Upon completion of the reaction, the compound of formula 2 may be recovered from the reaction mixture using conventional methods well known in the art, such as column chromatography, solid precipitation, recrystallization, and the like. Among them, column chromatography is the most common and high recovery rate, solid precipitation method or recrystallization method is an economically useful recovery method.

According to the preparation method there is an advantage that the reaction occurs in a one-step reaction and use the mild reaction conditions, there is an advantage that can be prepared in the compound of formula 2 in high purity and high yield.

The term "pharmaceutically acceptable salt " as used herein refers to salts prepared according to methods conventional in the art, and such methods of preparation are known to those skilled in the art. In particular, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following inorganic and organic acids and bases which are pharmacologically or physiologically acceptable. Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include alkali metals such as sodium, or potassium, alkaline earth metals such as magnesium.

In the composition for treating drug addiction of the present invention, it is preferable to mix or dilute the active ingredient with the carrier or to enclose the carrier in the form of a container. In addition, the composition for treating drug addiction of the present invention may be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like, oral preparation, suppository or sterilized injection solution, Can be used. In detail, when formulating, it can be prepared by using diluents or excipients such as fillers, weighing agents, binders, humectants, disintegrants, surfactants and the like which are generally used. Solid formulations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. Such a solid preparation may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration, liquid paraffin, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Examples of the suppository base include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The composition for treating drug addiction of the present invention may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage is based on the condition and weight of the patient, Depending on the severity of the disease, the form of the drug, the route of administration and the time of day, it may be appropriately selected by those skilled in the art.

The composition for treating drug addiction of the present invention may be formulated in the form of powder, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral formulations, external preparations, suppositories, or sterile injectable solutions according to conventional methods. Can be used. In detail, when formulating, it can be prepared by using diluents or excipients such as fillers, weighing agents, binders, humectants, disintegrants, surfactants and the like which are generally used. Solid formulations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. Such a solid preparation may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration, liquid paraffin, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Examples of the suppository base include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The composition for treating drug addiction of the present invention may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage is based on the condition and weight of the patient, Depending on the severity of the disease, the form of the drug, the route of administration and the time of day, it may be appropriately selected by those skilled in the art.

Also preferably, the compositions of the present invention can be formulated using well known methods to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. The dosage of the active ingredient, such as the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, depends on the subject to be treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. The compound represented by the general formula (1) as an active ingredient is administered once or divided once a day to a mammal including a human in an amount of 1 to 100 mg / kg (body weight), preferably 5 to 50 mg / kg May be administered via the oral or parenteral route. In some cases, doses less than the above-mentioned ranges may be more suitable, and more doses may be used without causing harmful side effects, and more doses may be dispensed in several smaller doses per day do.

The compounds of formula (I) of the present invention include both pharmaceutically acceptable salts thereof and possible solvates and hydrates thereof which may be prepared therefrom. The solvates and hydrates of the compounds of Formula 1 may be prepared from the compounds of Formula 1 using conventional methods.

Further, the compound of formula (I) according to the present invention may be prepared in a crystalline form or an amorphous form, and when the compound of formula (1) is prepared in a crystalline form, it may optionally be hydrated or solvated. In the present invention, compounds containing various amounts of water as well as stoichiometric hydrates of the compound of formula (1) may be included. Solvates of compounds of formula 1 according to the present invention include both stoichiometric and non stoichiometric solvates.

The pharmaceutical composition comprising an active ingredient of bernine and bernine derivatives according to the present invention may not only have a therapeutic effect of drugs and psychotropic drugs, but also have fewer side effects, and thus may be usefully used as a drug for treating drug addiction.

1 is a drug poisoning inhibitory effect of reducing the number of jumps measured after administering naloxone to a morphine-addicted mouse by administering a compound Bergenin or penta-O-acetylbergenin (Com 1) according to an embodiment of the present invention It is shown.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided to further understand the present invention, and the present invention is not limited by the examples.

Bergenin used in the experiment was purchased from Sigma-Aldrich (USA).

Example Synthesis of Penta-O-Acetyl Bergenin

(2R, 3S, 4S) -3,4,8,10-tetrahydroxy-2- (hydroxymethyl) -9-methoxy-2,3,4,4a-tetrahydropyrano [3,2-c] isochromen-6 (10bH) -one compound (1 g, 3.05 mmol, bergenin, Sigma Chem. Co., USA) was dissolved in pyridine (10 mL), and acetyl chloride (16.0 mmol) was added at 0 ° C. and stirred at room temperature for 16 hours. After cooling water (20 mL) was added to the reaction solution, ethyl acetate (20 mL) was added to separate the organic layer, which was washed with brine (20 mL), the organic layer was separated, dried, and the solvent under reduced pressure. After the removal of the residue, the residue was purified by column chromatography to obtain the title compound (yield: 71%).

IR v _max (KBr) 3024, 2950, 1755, 1748, 1732, 1609, 1486, 1455, 1428, 1372, 1328, 1196, 1091, 1032, 962, 892 cm ⁻¹ ; ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 5.48 (t, J = 9.48 Hz, 1H), 5.13 (t, J = 9.64 Hz, 1H), 4.82 (d, J = 10.74 Hz, 1H), 4.40-4.29 (m, 2H), 4.14 (dd, J = 12.64, J = 3.79 Hz, 1H), 3.91 (s, 3H), 3.85-3.79 (m, 1H), 2.34 (d, J = 2.53 Hz, 6H), 2.11-2.07 (m, 9H); ¹³ C NMR (63 MHz, CDCl ₃ ) δ 170.5, 170.0, 169.7, 168.3, 167.7, 161.7, 150.2, 144.4, 141.5, 129.7, 124.1, 118.8, 77.7, 77.2, 76.8, 76.7, 73.0, 72.3, 68.5, 62.0 , 61.6, 20.8, 20.7; MALDI-Toff-MS calcd. for C ₂₄ H ₂₆ O ₁₄ 561.1215 [M + Na] ⁺ , found: 561.3566

Experimental Example : Determination of drug addiction inhibition

Step 1) Preparation of experimental animals and medication

All behavioral experiments were conducted with male mice at 8 weeks of age C57BL / 6. 10 mg / kg morphine was administered intraperitoneally daily for 7 days to induce morphine intoxication (each experimental group was 10). As a comparative control group, the normal group injected with physiological saline only and the group administered with morphine only were used.

The compound prepared in Example was administered by intraperitoneal injection method at 10 mg / kg or 20 mg / kg, and the group administered with morphine was previously administered 30 minutes before morphine treatment.

Step 2) Animal Behavior

To induce morphine withdrawal symptoms, mice administered morphine and the compounds of the present invention for 7 days daily were administered naloxone 5 mg / kg by intraperitoneal injection. Naloxone is a μ-opioid receptor antagonist that is primarily involved in morphine poisoning.

On the seventh day, morphine and the compound of the present invention were administered and naloxone after 6 hours, the number of mouse jumping reactions in the clear cylinder caused by withdrawal symptoms was measured for 30 minutes. The higher the number of jumps, the more severe the drug addiction.

The number of mouse jumping reactions for each compound is shown in FIG. 1. As shown in FIG. 1, it was confirmed that a very good morphine poisoning inhibitory effect was obtained when the vergenin or penta-O-acetyl berninine compound was administered with morphine.

Claims (5)

A pharmaceutical composition for treating narcotic and psychoactive drug addiction, comprising a compound represented by the following Chemical Formula 2, or a pharmaceutically acceptable salt thereof:
(2)

The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable carrier.





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