Therapeutic agent for treating hepatitis, and method of treating hepatitis

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to drugs, and concerns a therapeutic agent for treating hepatitis containing 2-amino-2-[4-3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediole or its pharmaceutically acceptable salt, or hydrate as an active ingredient. Also, disclosed is a method of treating hepatitis by introducing to a patient an effective amount of the therapeutic agent 2-amino-2-[4-3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediole or its pharmaceutically acceptable salt, or hydrate as an active ingredient.

EFFECT: therapeutic agent shows a stronger effect in treating hepatitis as compared to the other analogues.

4 cl, 3 dwg, 1 tbl, 2 ex

 

The area of technical applications

The present invention relates to a new therapeutic tool for the treatment of liver diseases containing as active ingredient 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propandiol or its pharmaceutically acceptable salt or hydrate and acting as an agonist of the receptor for sphingosine-1-phosphate, which are used for the treatment of hepatitis.

Background of the present invention

One of the liver - hepatitis can be caused by viruses, alcohol, and drugs. Among hepatitis of various etiologies, the most common is viral hepatitis. Viral hepatitis causing viruses that infect the liver. In particular, it is known that hepatitis b and hepatitis C result in acute liver failure, but at much higher speeds - to cirrhosis and liver cancer (non-patent documents 1 and 2).

In Japan, more than 40,000 deaths each year are the result of liver cancer and hepatitis liver, approximately 70% are infected with hepatitis C virus and approximately 20% of the hepatitis b virus (non-patent document 3).

In recent years, intensively developed therapeutic agent for the treatment of hepatitis b and C. However, even lamivudine, one of the most promising therapeutic agents for petite, is not effective to the extent in which hepatitis b virus (HVB) destroyed all patients (non-patent document 4). Although interferon (IFN) has caused recent advances in the treatment of hepatitis C, combination therapy with interferon and ribavirin has not been sufficiently effective (non-patent document 5). Contrary to the normal development of therapeutics many people infected with these viruses for a long time, still need treatment because of persistent hepatitis can lead to cirrhosis and end-stage carcinoma of the liver cells.

Recently, viral hepatitis is considered as incomplete immunological interaction of the host with the virus without destroying virus (non-patent document 6). Currently, it is assumed that these viruses can damage the liver cells not only by direct damage, but also in the immune response, in which the immune cells of the host (type cytotoxic T cells) destroy and destroy infected liver cells. The ideal treatment of viral hepatitis, of course, is the elimination of the virus. When hepatitis b (as with the hepatitis C viral load is not necessarily a function of the severity of the inflammatory process.

Media asymptomatic viruses the hepatitis b despite high viral load, do not have an inflammatory process in the liver. If the destruction of the virus impossible, then choose another option, in which the patient being asymptomatic carrier of hepatitis b, the virus persists, but does not cause inflammation. The present invention provides compounds that, due to the suppression of activated T cells prevents the development of inflammatory process in the liver.

In the present description derivatives of 2-amino-1,3-propane diol are already described compounds (patent documents 1 and 2) and known as immunosuppressants. However, there are no studies or reports, demonstrate the use of these compounds in diseases of the liver or suggesting their effectiveness in suppressing the inflammatory process in the liver.

Non-patent document 1 - Annu. Rev. Biochem. 56:651 (1987).

Non-patent document 2 - Proc. Natl. Acad. Sci. USA, 87:6547(1990).

Non-patent document 3 - Sogo Rinsyo, 54:449 (2005).

Non-patent document 4 - N. Engl. J.Med., 348:848 (2003).

Non-patent document 5 - N. Engl. J.Med., 347:975 (2002).

Non-patent document 6 - J. Clin. Invest., 99:1472(1997).

Patent document 1 - WO 2003/029184 Avenue.

Patent document 2 - WO 2003/029205 Avenue.

The disclosure of the present invention

Tasks that should be solved by the present invention

Price is firm this invention is to provide a therapeutic agent for treating liver disease, in particular hepatitis. Specified therapeutic agent as an active ingredient contains agonist of the receptor for sphingosine-1-phosphate, in particular 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propandiol or its pharmaceutically acceptable salt or hydrate.

Means to solve these problems,

Applicants have developed the present invention based on the received data that 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propandiol or its pharmaceutically acceptable salt or hydrate, acting as an agonist of the receptor for sphingosine-1-phosphate, can be used as an effective therapeutic agent for treating liver disease, particularly hepatitis.

According to the present invention the goal is achieved that provides a therapeutic tool for the treatment of hepatitis, containing as active ingredient 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propandiol or its pharmaceutically acceptable salt or hydrate.

Therapeutic agent for the treatment of hepatitis preferably as an active ingredient contains hydrochloride 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propane diol or its hydrate.

The invention is also a method of treatment of hepatitis, which according to the invention is that the patient is given EF is an objective quantity of a therapeutic agent, containing as active ingredient 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propandiol or its pharmaceutically acceptable salt or hydrate.

Most preferred is the use as an active ingredient hydrochloride 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propane diol.

Brief description of drawings

Figure 1. A graph showing the effect of suppression of the hydrochloride of 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propane diol (KRP-203) induced by concanavalin A (Con A) raising the level albinterferon (ALT) (p: PLSD test Fisher).

Figure 2. Micrograph showing the effect of suppression of KRP-203-induced concanavalin A (Con A) infiltration of inflammatory cells of the lesion in the liver and induced concanavalin A (Con A) necrosis of hepatocytes (staining with hematoxylin-eosin, X100) (A: control; B: KRP-203, introduced at a dose of 1 mg/kg).

3. Micrograph showing the effect of suppression of KRP-203-induced concanavalin A (Con A) infiltration of T cells CD4+in the liver and induced concanavalin A (Con A) necrosis of hepatocytes (staining using as immune label antibodies against CD4, h) (A: control; B: KRP-203, introduced at a dose of 1 mg/kg).

The best option is the implementation of the present invention

The claimed therapeutic with adsto as the active ingredient contains 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propandiol or its pharmaceutically acceptable salt or hydrate, representing new agonists of the receptor for sphingosine-1-phosphate.

Compounds of the present invention are disclosed, for example, in the avenues applications WO 2003/029184 and WO 2003/029205, and these compounds can be obtained according to methods described in these publications.

Compounds of the present invention, and their pharmaceutically acceptable salts and hydrates effective in the treatment of liver, including hepatitis. A therapeutic agent of the present invention can be entered either systemically or topically, and orally or parenterally. While the dosage form of the compounds may vary depending on the nature of the compounds, usually these compounds are used in the formulation of oral or parenteral dosage forms. In particular, in order to prepare granules, powders, tablets, capsules, syrups, suppositories, suspensions or solutions, the active ingredients can be mixed with pharmaceutically acceptable carriers, fillers, binders or diluents.

While the clinical dose of the compounds of the present invention may vary depending on the destination or depending on body weight, age and condition of patients receiving treatment, usually these compounds is administered in a single dose, which ranges from 0.01 to 100 mg/patient preferred a single is CNA dose, component of from 0.1 to 5 mg/patient), the ratio of the daily injection is from 1 to 3 times.

Examples

Hereinafter the present invention will be discussed in detail with reference to examples. Although the following examples will describe the connection, which is the hydrochloride of 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propane diol (which hereinafter will be called KRP-203), but the examples are not intended to limit the scope of the present invention.

Example 1. The effect of suppressing the inflammation caused by concanavalin A.

Male BALB/C mice aged 8-12 weeks were obtained from Charles River, Japan. In phosphate-buffered saline (FSB) opened concanavalin A (Con A). 0.2 ml of the obtained solution was administered intravenously to animals to obtain Con And 40 mg/kg Suspended in distilled water KRP-203 was administered orally at a dose comprising 0.1 mg/ 10 g of body weight, the process is carried out for 24 h prior to the introduction of animal Con A. After 24 h after injection And Con animals killed and measured the activity of serum transaminases. For collection of liver infiltration was also conducted perfusion of the liver, we used 30 ml of 0.1% solution containing add-FSB (Eur. J. Immunol., 17:37, 1987). The first 2.5 ml of the collected solution was discarded in order to eliminate contamination by peripheral blood lymphocytes. Spent krasivaya collected cells using as labels antibody against CD4 antibody against CD8, antibody against CD45/B220, antibody against CD11b, antibody against Ly-49C, the counting of cells was performed using the excited fluorescence.

Samples for histological analysis were prepared as follows. The liver was fixed in 10% formalin, introduced in paraffin and prepared slices. The obtained sections were stained with hematoxylin-eosin, then followed by infiltration of cells. Tissue was frozen in liquid nitrogen (used Tissue So), the cryostat was prepared slices and recorded them in acetone. The color of cooked slices conducted using immune labels, was used for this antibody mouse in relation to CD4 treated with Biotin antibody (rat IgG and streptavidin-Alexa 488, and then followed by the infiltration of T cells CD4+.

Results

A measurement was performed activity albinterferon in the model of hepatitis induced concanavalin A. the results are shown in the table. Figure 1 shows the serum concentration of albinterferon measured after 24 h after injection of concanavalin A. For 24 h prior to the introduction of concanavalin And animals orally introduced hydrochloride 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propane diol (KRP-203). If the inflammation in the liver was the Indus is verified by concanavalin And, level albinterferon increased, which indicate liver damage. The preliminary introduction of KRP-203 in doses of 0.1 mg/kg and 1 mg/kg significantly reduces the increase of the level albinterferon. The tendency to reduce this level was also observed in the group of animals that were administered a low dose of KRP-203, a component of 0.01 mg/kg

The table below shows the types and number of cells that are filtered by the liver. The total number of these cells was reduced by approximately 50% in the group of animals treated KRP-203. In this group, in particular, the suppression of the infiltration of T cells CD3+and CD4+and b cells B220+there was significant suppression of the infiltration of T cells CD8+and NK-T cells was negligible. Infiltration of NK-cells and monocytes influence was weak.

The types and number of cells that are filtered by the liver
The number of cells (× 105)ControlKRP-203 1 mg/kg
The total number of cellsof 31.8±8,416,3±3,5*
CD4+2,97±0,990,93±0,33*
CD8+2,53±0,64
CD3+NK-8,24±2,30to 2.29±0,53*
NK+CD3-0,51±0,240,40±0,24
B220+6,24±2.06 toof 2.06±0,21*
CD11b+of 10.72±4,36of 8.47±2,75

Figure 2 and 3 shows the histologic findings of the liver. In the liver of animals that have not undergone processing, along with clusters of areas of necrosis were observed infiltration of monocytes and polymorphonuclear leukocytes caused by concanavalin A. In this group was also observed the formation of vacuoles in hepatocytes (figa). In the group of mice treated with KRP-203, no significant infiltration of monocytes or necrotic changes were observed (pigv). In the control group painting using immune labels showed significant infiltration of T cells CD4+(figa), however, in the group treated with the KRP-203, no infiltration is not marked (pigv).

These observations suggest that the KRP-203, suppressing the infiltration of T cells in the liver, prevent the start and spread of the inflammatory process; therefore, this connection can IP alsowhat to prevent hepatitis, as well as for its treatment.

Example 2. The example formulations. The composition of the capsules (one capsule):

Connection (KRP-203)0.1 mg
D-Mannitolof 247.5 mg
Magnesium stearate2.5 mg

In particular, KRP-203 is mixed with D-mannitol. Then, the resulting mixture was mixed with magnesium stearate to obtain a mixed powder. After that the prepared powder is placed in a capsule.

Industrial applicability

As mentioned above, it is shown that in the model of hepatitis caused by concanavalin And the connection of the present invention (KRP-203) prevent initiation and propagation of the inflammatory process, this is done by suppressing the infiltration and accumulation of T cells in the liver. Thus, the claimed according to the present invention, the substances are useful as therapeutic agents for the treatment of hepatitis.

1. Therapeutic agent for the treatment of hepatitis, containing as active ingredient 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propandiol or its pharmaceutically acceptable salt or hydrate.

2. Therapeutic agent for hepatitis according to claim 1, characterized in that the active is ngredient contains hydrochloride 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propane diol or its hydrate.

3. A method of treating hepatitis by introducing the patient an effective amount of a therapeutic agent containing as active ingredient 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propandiol or its pharmaceutically acceptable salt or hydrate.

4. The method according to claim 3, characterized in that the active ingredient used hydrochloride 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]ethyl-1,3-propane diol.



 

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19 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: described is stable pharmaceutical preparation of absorption type for transcutaneous introduction, which includes bottom layer and adhesive layer, containing metal chloride, adhesive and at least one composition from (-)-(R)-N, α-dimethyl-N-2-propinylphenethylamine and its hydrochloride, where adhesive layer is subjected to crosslinking.

EFFECT: pharmaceutical preparation of absorption type for transcutaneous introduction of selegiline or selegiline hydrochloride does not suffer reduction of cohesive strength of adhesive layer even in presence of sweat components caused by excretion of sweat during wearing, and is free of cohesive destruction and remains of adhesive when preparation is removed.

4 cl, 2 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula I: or its pharmaceutically acceptable salt, where R2 represents (CR3R4)n-NR5R6 and m, p, q, Ar, R1, R3, R4, R5 and R6 are those as specified in the patent claim and defined as selective 5-NT6 and/or 5-NT2A antagonists. There is also described a pharmaceutical composition containing this compound, and application thereof in preparing drugs for treating diseased conditions of central nervous system chosen from psychoses, schizophrenia, manic depressions, neural disorders, memory impairment, attention deficient syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, malnutrition and Huntington's disease.

EFFECT: preparation of the compounds which can find application in treatment of a diseased condition of central nervous system.

27 cl, 1 tbl, 29 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to otolaryngology, and can be applied for treatment of chronic pharyngitis. For this purpose intranasallly solution, which contains novocaine and lazolvan, is introduced.

EFFECT: invention ensures efficient treatment of said diseases due to stimulation of local antivirus protection, suppression of non-residential microflora vegetation on mucous tunic of gullet, anti-edematous and anti-inflammatory action.

4 cl, 4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

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