WO2019233473A1 - Prophylactic and therapeutic drugs for fatty liver disease and related diseases - Google Patents

Abstract

The present invention relates to a use of a compound YS000002, structural analogs thereof, and respective pharmaceutically acceptable isomers, salts, solvates, polymorphs in the prevention or treatment of fatty liver disease and related diseases (for example, nonalcoholic fatty liver disease, steatohepatitis, liver fibrosis, liver cirrhosis, etc.). The invention proves that the compound YS000002 is capable of significantly improving severity of fatty liver disease, liver fibrosis or liver cirrhosis, reducing liver damage, and has good safety and excellent clinical application prospects.

Description

Preventive and therapeutic drugs for fatty liver disease and related diseases

cross reference

This application claims the priority of the Chinese patent application 201810572794.7, filed on June 6, 2018 with the name of the invention "Prophylactic and therapeutic drugs for fatty liver disease and related diseases", the contents of which are incorporated by reference in their entirety. This article.

Technical field

The present invention relates to preventive and therapeutic drugs for fatty liver disease and related diseases. In particular, the present invention relates to the use of compound YS000002 and compounds having a structural similarity of more than 80% in the preparation and prevention of fatty liver, steatohepatitis, liver fibrosis or cirrhosis.

Background technique

Fatty liver refers to the pathological changes of excessive fat accumulation in liver cells caused by various reasons. It is a common liver pathological change, that is, fatty changes of the liver. Fatty liver disease is seriously threatening the health of people in China, becoming the second largest liver disease after viral hepatitis. The incidence is increasing and the age of onset is becoming younger. It is a new challenge in the field of liver disease in the 21st century.

At present, the US FDA has not approved any drug for non-alcoholic fatty liver disease. The existing phase III clinical drug obeticholic acid has very toxic side effects and has caused severe liver damage. The FDA has adopted a more cautious approach to this. . The use of the drug in Chinese patients is even more distant. Therefore, it is imminent to develop safe and effective drugs for fatty liver disease-related diseases in China.

Normal human liver tissue contains a small amount of fat, such as phospholipids, triglycerides, glycolipids, and cholesterol, and its weight is about 3% to 5% of liver weight. If too much fat is accumulated in the liver, it exceeds 5% of liver weight Or when more than 30% of liver cells have steatosis, it can be called fatty liver. In general, fatty liver is a reversible disease. Therefore, anti-fatty liver treatment can prevent the further deterioration of fatty liver and even improve the pathological characteristics of fatty liver, and can prevent the occurrence of fatty liver, so it has been highly valued.

Liver fibrosis is a pathophysiological process, which refers to abnormal proliferation of connective tissue in the liver caused by various pathogenic factors. Any liver injury has liver fibrosis in the process of liver repair and healing. If the damage factor cannot be removed for a long time, the fibrosis process will continue to develop into cirrhosis for a long time. There are many causes of liver fibrosis, and clinically, viral hepatitis, alcoholic liver, fatty liver, and autoimmune diseases are common. Anti-hepatic fibrosis treatment mainly includes the removal of pathogenic factors according to the primary disease, such as anti-hepatitis B, hepatitis C virus treatment, anti-schistosomiasis treatment, alcohol withdrawal, etc. Treatment for liver fibrosis itself, such as by inhibiting inflammation or lipid peroxidation, or inhibiting the proliferation of liver stellate cells, and promoting collagen degradation.

Cirrhosis is a clinically common chronic progressive liver disease. It is a diffuse liver damage caused by long-term or repeated effects of one or more causes. The causes of cirrhosis are divided into viral hepatitis cirrhosis, alcoholic cirrhosis, metabolic cirrhosis, cholestatic cirrhosis, hepatic venous obstruction, liver cirrhosis, autoimmune cirrhosis, toxic and drug-induced cirrhosis, Malnutrition cirrhosis, cryptogenic cirrhosis, etc. Histopathologically, there are extensive hepatic necrosis, nodular regeneration of residual hepatocytes, connective tissue hyperplasia and fibrous septum formation, leading to the destruction of hepatic lobular structure and the formation of pseudolobules. The liver gradually deforms and hardens to develop cirrhosis. In the early stage, there are no obvious symptoms due to strong liver compensatory function. In the later stage, liver function damage and portal hypertension are the main manifestations, and there are multiple system involvements. In the later stage, upper gastrointestinal bleeding, hepatic encephalopathy, secondary infection, and spleen are often present. Complications such as hyperfunction, ascites, canceration. Apart from liver transplantation, there is currently no cure for liver cirrhosis, mainly because of early detection and prevention of disease progression.

YS000002 is a thrombin receptor PAR-1 antagonist and has been marketed for the treatment of cardiovascular diseases. However, this molecule or its structural analog has not been found to have a preventive or reversible effect on fatty liver disease. And the role of PAR-1 in fatty liver disease is not clear, and there is no evidence that inhibiting the activity or function of PAR-1 must be able to alleviate or reverse fatty liver disease.

Summary of the Invention

The molecular formula of YS000002 of the present invention is C ₂₉ H ₃₃ FN ₂ O ₄ .

The technical problem to be solved by the present invention is to provide a medicine for preventing and treating fatty liver disease, such as fatty liver, liver fibrosis or cirrhosis. The inventors unexpectedly found that the compound YS000002 or a compound having a structural similarity of more than 80% can obviously alleviate the symptoms of fatty liver disease, steatohepatitis, and liver fibrosis, thereby preventing the occurrence of cirrhosis. Therefore, the drug or drug combination using YS000002 or its structural analog as the main active ingredient is an ideal drug for the prevention and treatment of fatty liver disease, liver fibrosis or cirrhosis. This compound has the following molecular structure:

It should be emphasized that the method for measuring the structural similarity of a compound in the present invention includes, but is not limited to, the following: The Tanimoto similarity index of a two-dimensional molecular fingerprint is used to calculate the similarity of a compound.

An object of the present invention is to provide YS000002 or a molecule with a structural similarity of more than 80%, such as a himbacine analog), a pharmaceutically acceptable isomer, salt, solvate, polymorph, Use of an intermediate compound or an intermediate compound thereof in the manufacture of a medicament for preventing or treating fatty liver disease and related diseases. The fatty liver disease is selected from fatty liver, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, liver fibrosis or cirrhosis.

The compounds of the present invention have asymmetric carbon atoms. The carbon-carbon bond of the compound of the present invention may use a solid line

Solid wedge

Point wedge

Means. A solid line is used to indicate all possible stereoisomers (ie, specific enantiomers, racemic mixtures, etc.) that are bonded to an asymmetric carbon atom, including that carbon atom. Use of a solid wedge or a point wedge indicates that only the stereoisomers shown are bonded to the asymmetric carbon atom. YS000002 contains more than one asymmetric carbon atom. For these compounds, a solid line is used to indicate all possible stereoisomers that are bonded to an asymmetric carbon atom. For example, unless otherwise specified, YS000002 compounds may exist as mirror and non-mirro isomers or racemates and other mixtures. The use of solid lines in YS000002 compounds indicates a mixture of one or more asymmetric carbon atoms and the use of solid wedges or point wedges in the same compound indicates a mixture of non-image isomers that are bonded to other asymmetric carbon atoms .

As used herein, "YS000002" may be referred to as "the compound of the present invention", "the present invention", and "the compound of YS000002". These compounds are defined to include all forms of the YS000002 compound, including its hydrates, solvates, isomers, crystalline and amorphous forms, isomorphs, polymorphs, tautomers and metabolites. For example, the compound of the invention or its pharmaceutically acceptable salt may exist in unsolvated and solvated forms. When intimately connected to a solvent or water, the composite will have a well-defined stoichiometry that is independent of humidity. However, when bonded to solvents or water with weak bonds, such as channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In these cases, non-stoichiometry will be the benchmark.

The stereoisomers of YS000002 include cis and trans isomers, optical isomers (such as R and S mirror image isomers), non-image mirror isomers, geometric isomers, and rotational isomers of the compounds of the present invention. Compounds, conformational isomers and tautomers, including compounds with more than one isomeric form and other mixtures (such as racemates and non-mirror isomer pairs). Also included are acid addition salts or base addition salts, in which the counter ion is optically active, such as D-lactate or L-lysine, or a racemate, such as DL-tartrate or DL-arginine.

The compound YS000002 contained in the medicine of the present invention may be the compound itself or a pharmaceutically acceptable derivative thereof, such as a pharmaceutically acceptable salt or ester.

The pharmaceutically acceptable salts of the compounds of the invention for therapeutic use include conventional non-toxic salts of the compounds of the invention, such as those formed from organic or inorganic acids. As examples, mention may be made of salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, malic acid, tartaric acid, Salts of citric acid, ascorbic acid, maleic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, methanesulfonic acid, stearic acid, lactic acid.

The invention provides the application of the compound YS000002 or a molecule with a structural similarity of more than 80% in the preparation of a medicament for preventing or treating fatty liver disease, liver fibrosis or cirrhosis. In particular, the mass-volume ratio of the compound YS000002 or a compound having a structural similarity of 80% or more in the medicine according to the present invention is 0.1% to 99%, and the mass-volume of the pharmaceutically acceptable carrier contained in the medicine The ratio is 0.1% to 99%.

The compound YS000002 of the present invention or a molecule whose structural similarity is above 80% can also be combined with one or more therapeutic drugs for diabetes or fatty liver disease to prepare a pharmaceutical composition for preventing or treating fatty liver disease. Either a fixed dose or a non-fixed dose. The medicine for treating diabetes or fatty liver disease includes, but is not limited to, one or more of Pioglitazone, Vitamin E, Obeticholic acid, Elafibranor, Aramchol, Emricasan, or Simtuzumab. The ratio of various active ingredients is adjustable.

The dosage form of the drug or pharmaceutical composition prepared by the present invention is any dosage form that is pharmaceutically acceptable. Including but not limited to tablets (including dispersible tablets, enteric tablets, chewable tablets, orally disintegrating tablets, effervescent tablets, etc.), hard capsules (including enteric capsules), soft capsules, granules, pills, pellets , Pills, dry suspensions, oral solutions, dry syrups, powders, oral suspensions, and oral immediate or slow release or controlled release and other dosage forms, injections (including powder injections (including Bacteria filling powder, lyophilized powder injection), aqueous solution injection), ointment, gel, emulsion, latex, patch, suppository and so on.

In the present invention, the term "pharmaceutically acceptable" (or "pharmaceutically acceptable") refers to molecular entities and compositions that do not produce any adverse, allergic effects or other adverse reactions when administered to a human .

The medicament or pharmaceutical composition of the present invention can be administered by the oral route, or by intravenous, intramuscular, flesh or subcutaneous injection, intravenous drip, intraperitoneal administration, intrathoracic administration, inhalation, eye drops, and nasal route.

The invention provides the use of compound YS000002 or a compound having a structural similarity of more than 80% to a subject in a therapeutically effective amount to prevent or treat fatty liver disease.

The "subject", "patient" or "individual" of the present invention refers to a warm-blooded animal, which can be a rodent (eg, guinea pig, hamster, rat, mouse), a mammal, such as a rabbit (eg, rabbit), canine Animal (e.g. dog), feline (e.g. cat), equine (e.g. horse), pig (e.g. pig), sheep (e.g. sheep), cattle (e.g. cows), primates, apes (e.g. Such as monkeys or apes), monkeys (such as marmoset, baboon), apes (such as gorillas, chimpanzees, orangutans, gibbon), or humans.

A "therapeutically effective amount" means the amount of a compound of the invention that (1) treats or prevents a particular disease, symptom, or disorder, and (2) reduces, alleviates, or removes one or more of the particular disease, symptom, or disorder. Signs, or (3) prevent or delay the onset of one or more signs of that particular disease, symptom, or disorder.

As used herein, unless indicated otherwise, "treatment" means reversing, alleviating, or inhibiting the progress of one or more symptoms or one or more symptoms of the treatment to which it is administered, or delaying the disease or symptom or one or more of its symptoms. Progress, delay the onset of the disease or symptom or one or more of its symptoms or prevent the disease or symptom or one or more of its symptoms. Unless otherwise specified, "treatment" as used herein refers to the treatment effect of the above treatment. The "treatment" also includes pre- and non-pre-treatment of the individual. For the avoidance of doubt, "treatment" as used herein includes therapeutic, soothing, and prophylactic treatments and administration of drugs for the treatment. Further, the "treatment" in the present invention mainly refers to reducing the degree of fatty liver, liver fibrosis, or cirrhosis; or curing fatty liver, liver fibrosis, or cirrhosis to normalize it; or slowing fatty liver, liver fibrosis Or the process of cirrhosis.

The "prevention" in the present invention mainly refers to preventing or reducing the occurrence of fatty liver, liver fibrosis or cirrhosis after use in the presence of possible risk factors for fatty liver, liver fibrosis or cirrhosis.

The therapeutic dose can be adjusted according to a variety of parameters, such as weight, condition, etc., and the administered dose is, for example, about 1 mg to 10 mg per day, twice a day to once a day to several days.

"About" is a relative term that represents ± 10% of the approximate nominal value (± 5% in one embodiment and ± 2% in another embodiment). For the purposes of this disclosure, unless a more stringent range is specifically noted for this value, the degree of approximation is approximate.

The fatty liver disease in the present invention refers to fatty liver, steatosis of liver cells, steatohepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, non-alcoholic steatohepatitis Liver fibrosis, cirrhosis, etc. The indicators of disease improvement are mainly examined and analyzed through tissue sections, which include, but are not limited to, the following main aspects: anti-steatosis, cell hypertrophy, apoptosis, inflammation and fibrosis. The fatty liver disease scoring system (NAS for short) includes three parts: Steatosis, Lobular Inflammation, and Hepatocyte Ballooning.

Advantages and beneficial effects of the present invention :

At present, the US FDA has not approved any drug for non-alcoholic fatty liver disease. The existing phase III clinical drug obeticholic acid has very toxic side effects and has caused severe liver damage. The FDA has adopted a more cautious approach to this. . The use of the drug in Chinese patients is even more distant. Therefore, it is imminent to develop safe and effective drugs for fatty liver disease-related diseases in China.

The present invention provides a new drug for the treatment or prevention of fatty liver disease, compound YS000002 (the original drug molecule of the cardiovascular drug marketed, trade name Zontivity) or a compound with a structural similarity of more than 80%. The drug has the advantages of treating fatty liver disease, having good curative effect, rapid onset of action, marked improvement of the disease, and low toxic and side effects. Because it is an old medicine, it can be marketed at a relatively rapid rate, and it can quickly help patients with fatty liver disease in China to get rid of their pain. It has broad application prospects and good social and economic benefits.

Unless otherwise specified herein, the scientific and technical terms used in the present invention have meanings generally understood by those of ordinary skill in the art. Unless specifically stated otherwise herein, the singular terms "a" and "the" are used in the specification and appendixes in the plural.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Difference in scores of fatty liver disease severity among three groups of animals (YS000002 experiment)

Figure 2. Fibrosis area percentage difference between the three groups (YS000002 experiment)

Figure 3. Changes in relative fibrosis area between the three groups (YS000002 experiment)

Figure 4. Fibrosis area percentage difference between three groups of experiments (YS000005 experiment)

Detailed ways

The content of the present invention can be more easily understood by referring to the following examples, which are only for further explaining the present invention and are not meant to limit the scope of the present invention.

Example 1: Therapeutic or preventive effect of compound YS000002 on mice with fatty liver, liver fibrosis or cirrhosis

Experimental material

MCD model rat. Healthy adult mice are half male and half female; YS000002 molecule is dissolved in water; control group is water.

2. Experimental method

2.1 Establishment of a score system for the severity of fatty liver

The fatty liver disease severity scoring system (NAS for short) commonly used by humans and animals internationally includes three parts: steatosis, Lobular Inflammation, and hepatocyte ballooning. In this example, the significance of the treatment effect is determined by comparing the score of fatty liver disease severity scores after imaging of liver tissue sections between the medication group and the control group (Kleiner DE. Et al., 2005).

2.2 The establishment of MCD model

According to the reference (Rinella M. et al., 2008), mice were fed methionine and choline-deficient diet (MCD). From the beginning of feeding, liver cells became fatty and hypertrophic. Apoptosis occurred; fibrosis began to occur at the 6th week; inflammation occurred; severe fibrosis began to occur at the 12th week and liver cirrhosis occurred; the experiment proceeded to the end of the 18th week. It needs to be stated that the MCD model is recognized by mainstream international academic journals to simulate the disease process of human fatty liver, steatohepatitis, liver fibrosis and cirrhosis.

The present invention uses the following animal experiments to show the therapeutic or preventive effect of YS000002 on fatty liver, steatohepatitis, and liver fibrosis:

I Anti-stearosis, cell hypertrophy and apoptosis experiments to represent the therapeutic effect of molecules on fatty liver and steatohepatitis: oral administration from the third week of MCD diet for five weeks; divided into two doses Groups (5 mg / kg, orally and 10 mg / kg, orally) and a control group of 20 rats each. At the end of five weeks, the animals were sacrificed and liver sections were quickly taken for NAS score analysis.

II Blocking experiment on fibrosis and inflammation: Dosing was started from the eighth week of the MCD diet for five weeks; divided into two dose groups (5 mg / kg, po and 10 mg / kg, po) and a control group. 20 rats per group. Animals were sacrificed after the end of five weeks, and liver sections were quickly taken for percentage analysis of fibrotic area;

3. Experimental results

3.1 Animal experiment I--YS000002 for the treatment or prevention of fatty liver and steatohepatitis

Both dose groups treated with YS000002 showed significantly lower NAS scores compared to the control group (Figure 1, p <0.0001, statistical method One-way ANOVA, Tukeys multiple comparison post hoc analysis). As mentioned earlier, NAS reflects the severity of fatty liver disease. Taking YS000002 before fibrosis can significantly alleviate the severity of fatty liver and fatty liver disease.

3.2 Animal Experiment II--YS000002 for the treatment or prevention of liver fibrosis

Both dose groups treated with YS000002 showed a significantly reduced percentage of hepatic fibrosis compared to the control group (Fig. 2, p <0.01, statistical method One-way ANOVA, Tukeys multiple comparison post hoc analysis). If the fibrosis area of the control group is taken as 100 and the relative fibrosis area of the two treatment groups is calculated, it can be found that the percentages of fibrosis area of the 5 mg / kg group and the 10 mg / kg group are about 22% and 38%, respectively. (image 3). It shows that taking YS000002 after the occurrence of fibrosis can significantly alleviate the severity of fibrosis and prevent the progress of the disease to cirrhosis.

Further, the therapeutic effect shows a dose-effect correlation-the effect of the high-dose group is better than that of the low-dose group, which further proves that the efficacy is unlikely to come from other interference factors, but from YS000002.

Example 2: Therapeutic or preventive effect of hibasin-derived compound YS000005 on mice with fatty liver, liver fibrosis or cirrhosis

Experimental material

A molecule with a two-dimensional structural fingerprint and a Tanimoto similarity of YS000002 (YS000005) with more than 80% similarity was selected as the research object. The molecule is a derivative of hibasin, Pubchem accession number CID 984049. MCD model mice were also used. Healthy adult mice are half male and half female; YS000005 molecule is dissolved in water; control group is water.

2. Experimental method

For the method of establishing the MCD model, see Example 1.

The present invention uses the following animal experiments to block fibrosis and inflammation to show the therapeutic or preventive effect of YS000005 on liver fibrosis:

Dosing was started from the second week of MCD diet for five weeks; divided into two dose groups (5 mg / kg, po and 10 mg / kg, po) and a control group. 20 rats per group. Animals were sacrificed after the end of five weeks, and liver sections were quickly taken for percentage analysis of fibrotic area;

3. Experimental results

YS000005 for the treatment or prevention of liver fibrosis.

Both dose groups treated with YS000005 showed a significantly reduced percentage of liver fibrosis compared with the control group (Figure 4, p <0.01, statistical method One-way ANOVA, Tukeys multiple comparison post hoc analysis). It shows that taking YS000005 after the occurrence of fibrosis can significantly alleviate the severity of fibrosis and prevent the progress of the disease to cirrhosis.

Further, the therapeutic effect shows a dose-effect correlation-the effect of the high-dose group is better than that of the low-dose group, which further proves that the efficacy is unlikely to come from other interference factors, but from YS000005.

Although the embodiments of the present invention have been shown and described, those of ordinary skill in the art can understand that various changes, modifications, replacements and variations can be made to these embodiments without departing from the principles and spirit of the present invention, The scope of the invention is defined by the claims.

【references】

Kleiner DE. Et al., Design and Validation of Histological Scoring System for Nonalcoholic Fatty Liver Disease. Hepatology, 2005; 41: 1313

Rinella ME.et al., Mechanisms of Hepatic, Steatosis, Mice, Fed, Lipogenic, Methionine, Choline-deficient diet. Journal of Lipid Research, 2008; 49: 1068

Claims (10)

1. Compound YS000002 or a compound having a structural similarity of more than 80%, or a pharmaceutically acceptable prodrug, isomer, salt, solvate, polymorph thereof is used for the preparation or prevention of fatty liver disease and related diseases. Use in medicine.
2. The use according to claim 1, characterized in that the fatty liver disease is selected from fatty liver, hepatocyte steatosis, steatohepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, Liver fibrosis and cirrhosis caused by non-alcoholic steatohepatitis.
3. The use according to claim 2, characterized in that the fatty liver is selected from fatty liver caused by excessive alcohol intake, fatty liver caused by insulin resistance, fatty liver caused by obesity, fatty liver caused by rapid weight loss, nutrition Fatty liver caused by malady, fatty liver caused by diabetes, fatty liver caused by hyperlipidemia, fatty liver caused by exposure to substances that are toxic to the liver, fatty liver caused by viral hepatitis, simple fatty liver, fatty hepatitis, Fatty liver fibrosis, fatty liver cirrhosis; or said liver fibrosis includes liver fibrosis caused by viral hepatitis, liver fibrosis caused by alcohol, liver fibrosis caused by fatty liver, liver caused by autoimmune disease Fibrosis, mild liver fibrosis, moderate liver fibrosis, and severe liver fibrosis; or the cirrhosis is selected from the group consisting of cirrhosis caused by viral hepatitis, cirrhosis caused by alcohol, cirrhosis caused by metabolic disorders, and cholestasis Cirrhosis due to cirrhosis, Cirrhosis due to circulatory disorders, Cirrhosis due to autoimmune diseases, Cirrhosis due to industrial poisons and drugs, Cirrhosis due to malnutrition, cirrhosis due to schistosomiasis, cirrhosis in the early stage of ascites, cirrhosis in the reactive ascites stage, cirrhosis in the refractory ascites stage, and cirrhosis in the liver and kidney syndrome.
4. The use according to any one of claims 1 to 3, characterized in that YS000002 or a compound having a structural similarity of more than 80% thereof is combined with a therapeutic drug for diabetes or steatohepatitis to prepare or prevent fat Composition for sexual liver disease and related diseases.
5. The use according to claim 4, characterized in that the therapeutic drug for diabetes or steatohepatitis comprises one or more of Pioglitazone, vitamin E, metformin, obeticholic acid, Elafibranor, Aramchol, Emricasan, or Simtuzumab Species.
6. The use according to claim 1 or 4, wherein the dosage form of the drug or pharmaceutical composition is selected from tablets (such as dispersible tablets, enteric tablets, chewable tablets, orally disintegrating tablets or effervescent tablets) , Hard capsules (such as enteric capsules), soft capsules, granules, pills, pellets, drops, dry suspensions, oral solutions, dry syrups, powders, oral suspensions, oral immediate release Or slow-release or controlled-release dosage forms, injections (including powder injections for injections, sterile filling powders for injection and lyophilized powder injections, aqueous injections), ointments, gels, emulsions, emulsions, patches, or Suppository.
7. The use according to claim 1 or 4, wherein the route of administration of the drug or pharmaceutical composition comprises transdermal, oral, injection, intravenous drip, intraperitoneal, anorectal, thoracic, Inhalation, eye drops, nose drops.
8. The use according to claim 1 or 4, characterized in that at least one hydrogen atom in the compound is replaced by a deuterium atom or at least one carbon atom or other atom is replaced by a corresponding isotope.
9. The use according to claim 1 or 4, wherein the medicament or pharmaceutical composition comprises a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier, wherein the medicament or pharmaceutical composition is about 1 mg- 10 mg / day, administered to humans twice a day to once a day to several days.
10. The compound according to claim 1, characterized in that the compound having a structural similarity to YS000002 of 80% or more is a himbacine derivative.

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