Bicyclosubstituted azopyrazolone derivatives salts, method for preparing and using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable salts specified in a group consisting of sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, arginine salt, lysine salt, methanamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylaminte salt, triethylamine salt, ethanolamine salt, piperazine salt, dibenzylethylene diamine salt, methyl glucamine salt, tromethamine salt, quaternary tetramethylammonium salt, quaternary tetraethylammonium salt and choline salt, bicyclosubstituted azopyrazole derivatives of general formula

.

The invention also refers to a method for preparing them, a pharmaceutical composition containing them, and using them as a therapeutic agent, particularly as thrombopoietin (TPO) mimetics, using them as TPO agonists. In general formula (I), Het is specified in a group consisting of phenyl, furanyl and thienyl; each R1, R2, R3 and R4 are independently specified in a group consisting of hydrogen and alkyl; n is equal to 0, 1 or 2.

EFFECT: improving the pharmokinetic properties of the compound of formula (I) ensured by better solubility.

19 cl, 1 tbl, 25 ex

 

The SCOPE of the INVENTION

This invention relates to pharmaceutically acceptable salts of the new bicyclopentadiene derived aspiration, to methods for their preparation, pharmaceutical compositions containing them and to their use as a therapeutic agent, in particular as mimetics of thrombopoetin (TPO) and agonists thrombopoetin receptor.

PRIOR art

Thrombopoetin (TPO), also called a factor of growth and development of megakaryocytes (MGDF), incentive thrombocytopoiesis (TSF), a ligand with myeloproliferative leukemia (Mr1), the mpl ligand or megaplatinum, is a glycoprotein, which is described as producing platelets. Cm. Wendling, F., et. al., Biotherapy 10(4): 269-77 (1998); Kuter D. J. et al., The Oncologist, 1: 98-106 (1996); Metcalf, Nature 369: 519-520 (1994).

Under certain circumstances, TPO activity is the result of linking TVET with the TPO receptor (also called Mpl). The TPO receptor cloned, and its amino acid sequence is described. Cm. Vigon et al., Proc. Nat. Acad. Sci., 89: 5640-5644 (1992).

TPO is a 332-amino acid glycosylated polypeptide that plays a key role in the regulation of megakaryocytopoiesis and the process by which platelets are produced by megakaryocytes in the bone marrow. Cm. Kuter et al., Proc. Nat. Acad. Sci. USA 91: 11104-11108 (1994); Barley et al., Cell 77:1117-1124 (1994); Kaushansky et al., ature 369:568-571 (1994); Wendling et al., Nature 369: 571-574 (1994); and Sauvage et al., Nature 369: 533-538 (1994). TPO is produced in the liver, but operates mainly in the bone marrow, where it stimulates the differentiation of stem cells into precursors of megakaryocytes and stimulates proliferation of megakaryocytes, polyploidization and ultimately enters the circulation of platelets in the body. TPO is also a major regulator in situations involving thrombocytopenia, and a number of studies, which include an increased number of platelets, the size of the platelets and the inclusion of isotopes in platelets animals-recipients. Cm. Metcalf Nature 369: 519-520 (1994). Specifically believe that TPO affects megakaryocytopoiesis the following ways: (1) it causes an increase in the size and number of megakaryocytes; (2) it increases the amount of DNA in the form of polyploidy and the number of megakaryocytes; (3) it increases indomitus megakaryocytes; (4) it increases the number of Mature megakaryocytes; (5) it increases the percentage of progenitor cells, the number of small cells, positive for acetylcholinesterase, the number of bone marrow cells.

Platelets are necessary for blood clotting. When the platelet count is very low, the patient has a high risk of death in a catastrophic bleeding. Thus, the TPO used for both diagnosis and treatment of various hematological resstr ist, for example, disease, primarily caused by a defect in platelets. Similarly, the TPO may be useful for the treatment of thrombocytopenic States, in particular States, resulting from chemotherapy, radiation therapy or bone marrow transplantation for the treatment of cancer or lymphoma.

Slow recovery levels of platelets in patients suffering from thrombocytopenia is a serious problem, it is therefore desirable to obtain a connection for the treatment of thrombocytopenia through his actions as mimetica TPO. These peptides were designed to bind and activate the TPO receptor (TPO-R), but they do not have sequence homology with the natural TPO. In recent years, described the number of active low-molecular TPO mimetics, including derivatives of cyclic polyamines (WO 00/28987), thiazole-2-jbentley (WO 01/07423, WO 01/53267), derivatives of ataria (WO 00/35446, WO 01/17349), 2-arenaviridae (WO 01/39773, WO 01/53267) and derivatives semicarbazone (WO 01/34585). In systems based on cells all of these molecules can activate biochemical pathway of signal conversion, which are dependent on the presence of TPO receptor on the cell membrane. Certain types of compounds may act directly on the receptor for TPO. It was found that some of the most preferred compounds in this series and stimulate the proliferation and differentiation TPO-responsive human cell lines and TPO in cultures of human bone marrow at concentrations below 100 nm.

A few patents in the name of GlaxoSmithKline described similar thrombopoetin-eltrombopag (WO-2003098992/WO-01089457), with good activity.

In the present invention proposed a number of pharmaceutically acceptable salts bicyclopentadiene derived aspiration that are more effective TPO mimetics and agonist of the TPO receptor.

In the international application PCT/CN2009/000001 filed by the author of the present invention on January 4, 2009, describes the new bicyclopentadiene derivatives aspiration and their application as mimetics of thrombopoetin (TPO) and agonists of the receptor thrombopoetin. In the six examples (Example 1, Example 9, Example 15, Example 28, Example 43 and Example 52) described in this international application, as proposed, respectively, the following connections:

2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid,

5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid,

5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid,

4-(2-hydroxy-3-[N'-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene)-hydrazino]diphenylfuran-2-carboxylic acid,

5-(3-{N'-[1-(3,3-dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-GI is rasino}-2-hydroxyphenyl)-furan-2-carboxylic acid,

4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid,

and their esters.

These compounds were tested and showed good activity as an agonist of the TPO receptor. Therefore, this international application is fully incorporated into this application by reference. However, in international application no PCT/CN2009/000001 not described pharmaceutically acceptable salts of these compounds.

The inventor has discovered that the form of the free acid bicyclopentadiene derived aspiration of laboratorial in common solvents and, therefore, unfit to obtain the dosage form, because its limited bioavailability in vivo. It is necessary to develop new forms bicyclopentadiene derived aspiration that can be used in the conventional receiving dosage forms to improve their solubility and pharmacokinetic absorption.

SUMMARY of the INVENTION

In order to overcome the disadvantages of the prior art, the present invention proposed pharmaceutically acceptable salt new bicyclopentadiene derived aspiration, methods for their preparation, pharmaceutical compositions containing them and their use as a therapeutic agent, in particular as is mimetikov of thrombopoetin (TPO) and agonists thrombopoetin receptor. These salts have good activities for the treatment of thrombocytopenia, improved solubility, good activity in vivo, better bioavailability, low toxicity, being a good candidate for obtaining a medicinal product for the treatment of thrombocytopenia.

"Compounds of the present invention" and "the salt of the present invention" are used interchangeably, and both terms represent a pharmaceutically acceptable salt bicyclopentadiene derived aspiration formula (I)

where:

Het is selected from the group consisting of phenyl, purile and tanila;

R1, R2, R3and R4each independently selected from the group consisting of hydrogen atom and alkyl;

n is 0,1 or 2;

salts are salts of attaching the base.

In addition, the present invention relates to salts of compounds of formula (IA)

where:

Het is selected from the group consisting of phenyl, purile and tanila;

R1, R2, R3and R4each independently selected from the group consisting of hydrogen atom and alkyl;

M is selected from the group consisting of a metal ion, ammonium ion and basic amino acids;

m is 1 or 2;

n is 0,1 or 2;

salts are salts of attaching the base.

The term "free acid" refers to bizik samemanner derived aspiration formula (I).

The term "equivalent" applies to tautomers of compounds of formula (I), which are well known to specialists in this field of technology. The tautomers of the compounds of formula (I) include the compounds of formula (II) and formula (III), but are not limited to:

All tautomers of compounds of formula (I) is included in the scope of the present invention, and all of them are included in the definition of compounds of formula (I).

The term "pharmaceutically acceptable salt" in the present invention refers to a pharmaceutically non-toxic salts joining the Foundation. These salts are salts formed between compounds of formula (I) and a suitable base, such as alkali metal hydroxide, basic amino acid, amine or Quaternary ammonium, including sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, arginine salt, lysine salt, salt methanamine, dimethylamine salt, salt, trimethylamine salt of ethylamine salt of diethylamine, salt of triethylamine, ethanolamine salt, salt, piperazine salt of dibenziletilendiaminom, salt meglumine, tromethamine salt, Quaternary salt of Tetramethylammonium, Quaternary salt of tetraethylammonium and salt of choline, preferably the salt of diethylamine, ethanolamine salt, salt, choline chloride, salt, piperazine salt of meglumine and salt, tromethamine, more predpochtitel what about the salt ethanolamine, salt, choline chloride, salt meglumine and tromethamine salt, and most preferably ethanolamine salt.

Pharmaceutically acceptable salts of compounds of formula (I) of the present invention preferably include the following compounds, but are not limited to:

Example No.StructureName
1(Z)-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid bis-(ethanolamine)
2(Z)-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid bis-(diethylamine)
3(Z)-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid bis-(piperazine)
4(Z)-5-(3-{N'-[1-(3,3-dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-Hydra is Ino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(ethanolamine)

5(Z)-5-(3-{N'-[1-(3,3-dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(diethylamine)
6(2)-5-(3-{N'-[1-(3,3-dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(piperazine)
7(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(ethanolamine)
8(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(choline)
9(Z)-5-(2-hydroxy-3-{N'-[3-methyl-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(diethylamine)
10(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(meglumine)

11(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(piperazine)
12(Z)-5-(2-hydrox-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(trometamol)
13(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(dibenziletilendiaminom)
14(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol--ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid disodium salt
15(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(1-arginine)
16(Z)-5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid bis-(ethanolamine)

17(Z)-5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid bis-(diethylamine)
18(Z)-5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid bis-(piperazine)
19(Z)-4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid bis-(ethanolamine)
20(Z)-4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid bis-(diethylamine)
21(Z)-4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid bis-(piperazine)
22(Z)-4-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthyl-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(ethanolamine)

23(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid choline

The present invention relates to a method for producing pharmaceutically acceptable salts of compounds of formula (I), which includes stages:

(a) the dissolution or suspension of the free acid according to the present invention (the compounds of formula (I) in an organic solvent,where the organic solvent is selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and tetrahydrofuran, preferably tetrahydrofuran;

(b) adding a base to the mixture under stirring, where the base can be an organic or inorganic base, such as hydroxide of alkali metal or alkali earth metal hydroxide, basic amino acid, amine or Quaternary ammonium;

(c) obtaining the pharmaceutically acceptable salts of the compounds of formula (I),

where inorganic bases include hydroxides of alkali metals selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, basic amino acids selected from the group consisting of lysine and arginine; amines selected from the group consisting of methanamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenziletilendiaminom, meglumine and tromethamine; and Quaternary ammonium selected from the group consisting of Quaternary of Tetramethylammonium, the Quaternary of tetraethylammonium, choline hydroxide, preferably diethylamine, ethanolamine, choline hydroxide, piperazine, meglumine and tromethamine, more preferably ethanolamine, choline hydroxide, meglumine and tromethamine, most preferably ethanolamine.

At the stage (b) the ratio of EC is ivalent free acid and alkali metal hydroxide, basic amino acid, amine and Quaternary ammonium is preferably 1:5~5:1, more preferably 1:1~1:3 and most preferably 1:1~1:2.

At the stage (C) secretion of salts preferably includes direct filtration from the reaction mixture, concentration of the reaction mixture and recrystallization from an organic solvent. Salt can be dried in conditions, such as vacuum drying or high temperature air drying.

The salt formation reaction is usually carried out under conditions of cooling, room temperature or heating. However, it should be noted that the temperature of the reaction associated with the formation of the salt, which is well known to specialists in this field of technology.

The temperature range of the reaction according to the present invention is the range from room temperature to the boiling point of the solvent of the reaction mixture, preferably 0~40°C. the Specialist in the art can easily determine the most preferred reaction temperature for the reaction of formation of salts by standard methods.

The present invention relates to the use of pharmaceutically acceptable salts of compounds of formula (I) to obtain agonist thrombopoetin receptor.

The present invention relates to the use of pharmaceutically acceptable salts of compounds of formula (I) to obtain cartonnage for the treatment of thrombocytopenia, where the drug is administered together with a drug selected from the group consisting of a colony stimulating factor, cytokine, chemokine, agonist or antagonist of the receptor for interleukin or cytokine soluble receptor agonistic or antagonistic antibodies to the receptor or one or more peptide or low molecular weight compound that has the same mechanism with the drug.

The present invention relates to pharmaceutically acceptable salts of compounds of formula (I) for use as a drug for the treatment of thrombocytopenia where the drug is administered together with a drug selected from the group consisting of a colony stimulating factor, cytokine, chemokine, agonist or antagonist of the receptor for interleukin or cytokine soluble receptor agonistic or antagonistic antibodies to the receptor or one or more peptide or low molecular weight compound that has the same mechanism with the drug, where the drug is in the form of oral dosage forms, either the drug is in the form of parenteral dosage forms.

The present invention relates to a method of treatment of thrombocytopenia is, includes introduction to the subject in need, a therapeutically effective amount of pharmaceutically acceptable salts of the compounds of formula (I) where this pharmaceutically acceptable salt is administered together with a drug selected from the group consisting of a colony stimulating factor, cytokine, chemokine, agonist or antagonist of the receptor for interleukin or cytokine soluble receptor agonistic or antagonistic antibodies to the receptor or one or more peptide or low molecular weight compound that has the same mechanism of action drug, where the pharmaceutically acceptable salt is in the form of oral dosage forms, or pharmaceutically acceptable salt is in the form of parenteral dosage forms.

The present invention relates to pharmaceutical compositions containing a therapeutically effective amount of pharmaceutically acceptable salts of compounds of formula (I) and pharmaceutically acceptable carriers or diluents, where the composition is administered together with a drug selected from the group consisting of a colony stimulating factor, cytokine, chemokine, interleukin, and agonist of the receptor of the cytokine. The present invention also relates to the use of these compositions for the preparation of Lech the only means for the treatment of thrombocytopenia, where co-administration includes administration of the drugs in the present invention simultaneously or sequentially.

The present invention relates to a method for producing pharmaceutical compositions containing a therapeutically effective amount of pharmaceutically acceptable salts of compounds of formula (I) and pharmaceutically acceptable carriers or diluents, where the method includes a step of combining compounds of the formula (I) with pharmaceutically acceptable carriers or diluents.

In a method of producing pharmaceutical compositions, it is important to get the drug in an appropriate form, easy to use and in circulation, not only in terms of commercially available drug, but also in terms of pharmaceutical dosage forms containing the active connection.

In another aspect in a method of producing pharmaceutical compositions, it is important to ensure reliable, repeatable and constant curve the concentration of drug in plasma after administration to a subject.

Other important factors include chemical resistance, stability in the solid state and the retention of the active ingredient. Medicines containing these compositions can preferably be stored for a relatively long time without any visible change in the physical and chemical properties of them as the active ingredients, such as chemical composition, density, hygroscopicity and solubility.

It is also important to provide chemically pure drug.

In a typical case, the drug can provide the following advantages: easy handling, obtain a suitable dosage forms and reliable solubility, if this drug can be obtained in a stable form, such as a stable crystalline form, which is well known to specialists in this field of technology.

An effective amount of the active ingredient into standard pharmaceutical dosage form, as described above, should be non-toxic, preferably selected in the range of 0.001-100 mg/kg of the total mass, more preferably 0.001 to 50 mg/kg In the treatment of a subject in need of TPO mimetics, the selected dose is preferably administered orally or parenterally. Preferred parenteral forms include forms of local, rectal, percutaneous injection, injections and continuous infusions. Oral standard dosage forms for administration to man preferably contain from 0.05 to 3500 mg of active ingredient, most preferably from 0.5 to 1000 mg of active ingredient. Preferably oral administration, in which they use a lower dosage. Parenteral the first introduction at high dosages, however, you can also apply when it is safe and acceptable to the patient. The above dosages are preferred to the amount of the active ingredient, in terms of free acid.

Specialists in the art it is clear that the optimal quantity and spacing of individual dosages of the active ingredient depends on the nature and extent of the condition to be treated, the form, route and site of administration and the specific patient to be treated, and that such optimums can be determined by standard methods. Specialists in the art will also understand that the optimal course of treatment, that is, the number of doses of the active ingredient, given per day for a certain number of days, can be determined by a specialist in the art using conventional tests determine the course of treatment.

Compounds of the present invention can be administered orally or parenterally, and these compounds can be prepared in the form of tablets, pills, powders and granules, used for different routes of administration. In the above-described solid dosage forms, the active ingredients are mixed with at least one inert diluent. In accordance with generally accepted actions, in addition to the inert diluent, in oral dosage forms are also on the look to another substance, such as lubricants, glidant and antioxidants. Prepared in the form of capsules, tablets and pills, the dosage forms contain buffering agents. Tablets and pills can be prepared in dosage form extended release.

Although you can use non-aqueous emulsion, for parenteral dosage forms of the present invention contain a sterile aqueous solution, and these dosage forms can also contain adjuvants, such as antiseptics, moistening agents, agents that promote permeability, buffering agents, emulsifying agents and dispersing agents. In the sterilization process, you can use the filter traps bacteria, and in compositions which have been subjected to irradiation or heating for sterilization, you can add sterilizing agents.

Compared with the free acid salts of the present invention have the following advantages:

(1) Salt of the present invention is easily dissolved in common solvents such as water, methanol, 0.1% of hydrochloric acid, and are adapted to receive conventional dosage forms, where the solubility of salts of ethanolamine significantly better in 0.1% hydrochloric acid.

(2) Salts of the present invention have improved stability.

(3) Salts of the present invention have better biological the activity in vitro.

(4) Salts of the present invention have better pharmacokinetic properties in vivo, the best absorption, higher bioavailability and the best curve pharmacokinetics where ethanolamine salt, salt, choline chloride, salt, piperazine salt of meglumine and tromethamine salt, preferably a salt of ethanolamine, have better pharmacokinetic properties.

(5) the Method of obtaining salts of the present invention has the advantages of high yield, high purity, speed, convenience and low cost, and in ways more preferred the salts of ethanolamine, salt, choline, salts diethylamine and salts of piperazine, which can crystallize directly.

Compared with the free acid salts of the present invention, preferably the salt of diethylamine, ethanolamine salt, salt, choline chloride, salt, piperazine salt of meglumine and tromethamine salt, more preferably ethanolamine salt, salt, choline chloride, salt meglumine and tromethamine salt, most preferably ethanolamine salt, possess the best properties of solubility, stability, biological activity in vitro and pharmacokinetics.

DETAILED description of the INVENTION

Unless otherwise stated, the following terms used in the description and claims have the meanings described below.

The term "ethanolamine" refers to 2-amino is tanoli".

The term "choline" refers to "(2-hydroxyethyl)trimethylamine".

The term "meglumine" refers to N-methyl-D-meglumine".

The term "pharmaceutical composition" refers to a mixture of one or more pharmaceutically acceptable salts of the compounds described in this application, or its prodrugs with other chemical components, such as physiologically/pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate the introduction of compounds into the body.

The term "stability" refers to the chemical stability and the stability of the solid state.

The term "chemical stability" refers to the storage of the compounds of the present invention, including isolated form or dosage form, mixed with pharmaceutically acceptable carriers or diluents (e.g., oral dosage forms such as tablets, capsules, and so on), under standard conditions with a slight chemical decomposition or chemical disintegration.

The term "stability solid state" refers to the storage of the compounds of the present invention, including isolated solid form or dosage form, mixed with pharmaceutically acceptable carriers or diluents (e.g., oral dosage forms such as tablets, capsules, and so on), under standard conditions with esnecially polymorphic transformation (for example, crystallization, recrystallization, phase change status, hydration, dehydration, solvation or removal of solvent).

Examples of the term "stored in standard conditions include a temperature range from -80°C to +50°C (preferably from 0°C to 40°C, more preferably at room temperature, such as 15°C~30°C), pressure range from 0.1 PA to 2 PA, preferably at atmospheric pressure), the range of relative humidity from 5% to 95% (preferably 10%~60%) and/or effects Suite 460 UV/visible light for a long time (longer or equal to six months).

The term "parenteral administration includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration, preferably oral administration.

The term "absorption" refers to the property of the ability or extent to which a substance can absorb water at a certain temperature and humidity. Test samples are solid ingredients that meet the standard of quality control of medicines. Drug packaging and storage conditions may relate to the results of the above tests.

The METHOD of SYNTHESIS of the COMPOUNDS ACCORDING to the INVENTION

In order to achieve the objectives of the invention the invention ispolzovanie below solutions:

The method of synthesis of compounds of formula (I) disclosed in examples 1, 9,15, 28, 43 and 52 of the international application PCT/CN2009/000001, filed January 4, 2009. This application is fully incorporated into this application by reference.

The way to obtain pharmaceutically acceptable salts of compounds of formula (I) includes the following stages:

(a) the dissolution or suspension of the free acid according to the present invention (the compounds of formula (I) in an organic solvent, where the organic solvent is selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and tetrahydrofuran, preferably tetrahydrofuran;

(b) adding to the mixture of the base with stirring, where the base can be an organic or inorganic base, such as hydroxide of alkali metal or alkali earth metal hydroxide, basic amino acid, amine or Quaternary ammonium;

(c) obtaining the pharmaceutically acceptable salts of the compounds of formula (I), where inorganic bases include hydroxides of alkali metals selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide; amines and Quaternary ammonium selected from the group consisting of Quaternary of Tetramethylammonium, the Quaternary of tetraethylammonium, ethanolamine, choline, lysine, arginine, m is takamina, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, dibenziletilendiaminom, meglumine, piperazine or tromethamine; preferably diethylamine, ethanolamine, piperazine, choline hydroxide, meglumine and tromethamine, more preferably ethanolamine, choline hydroxide, meglumine and tromethamine, most preferably ethanolamine.

At the stage (b) the ratio of equivalents of the free acid and the base is preferably 1:5~5:1, more preferably 1:1~1:3 and most preferably 1:1~1:2.

At the stage (C) secretion of salts preferably includes direct filtration from the reaction mixture, concentrated from the reaction mixture and recrystallization from an organic solvent. Salt can be dried under conditions, such as vacuum drying or high temperature air drying.

Above the salt formation reaction is usually carried out under conditions of cooling, room temperature or heating. However, it should be noted that the reaction temperature has an influence on the reaction of the salt, which is well known to specialists in this field of technology. The range of reaction temperature of the present invention ranges from room temperature to the boiling point of the solvent of the reaction mixture, preferably 0~40°C. the Specialist in the art can easily ODA is to share the most preferred reaction temperature of the reaction of formation of salts by standard methods.

The present invention is further described in the following Examples, which are not intended to limit the scope of the invention.

EXAMPLES

Structures of all compounds were identified by nuclear magnetic resonance (1H NMR) or mass spectrometry (MS).

NMR was performed on a spectrometer Bruker AVANCE-400. Appropriate solvents include deuterated methanol (CD3OD), deuterated chloroform (CDCl3) and deuterated dimethylsulfoxide (DMSO-d6) with tetramethylsilane was (TMS) as internal standard, and chemical shifts were recorded in the form of mn-1(10-6).

MS was determined by mass spectrometer FINNIGAN LCQ Ad (ESI) (Thermo, Model: Finnigan LCQ advanced MAX).

EC50was determined on NovoStar ELIASA (BMG Co. German).

The concept of "thin-layer gel" refers to a plate of silica gel Yantai Huanghai HSGF254 or Qingdao GF254. The size of the plates used in TLC is from 0.15 mm~0.2 mm, and the size of the plates used in the purification of the drug, were 0.4 mm~0.5 mm

When column chromatography is usually used silica gel Yantai Huanghai 200-300 mesh as a carrier.

HPLC for high performance liquid chromatograph Agilent 1200DAD (chromatographic column Sunfire C18 150×4.6 mm) and high performance liquid chromatograph Waters 2695-2996 (chromatographic column Gimini C18 150×4.6 mm).

Reacts and hydrogenation under pressure was performed using hydrogenator Parr 3916EKX and hydrogen generator QL. Microwave reactions were performed using a microwave reactor CEM Discover S 908860.

When the reactions of hydrogenation reaction system is usually placed in a vacuum and filled with hydrogen, repeating the operation three times.

Known source material according to the invention can be obtained by a method conventional in the art, or purchased from the company ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari chemical Company, etc.

Unless otherwise noted, the following reactions were carried out in nitrogen atmosphere.

The term "nitrogen" refers to the fact that reaction flask equipped with a 1 l cylinder of nitrogen.

The term "atmosphere of hydrogen" refers to the fact that reaction flask equipped with a 1 liter bottle of hydrogen.

Unless otherwise stated, the solution used in the following reaction, refers to aqueous solution.

The term "TLC" refers to thin layer chromatography.

The term "HPLC" refers to high performance liquid chromatography.

Experimental conditions HPLC: running time: 30 min, column temperature: 30°C PDM: 230 nm, mobile phase: acetonitrile: water (0.1% of triperoxonane acid)=25:75, flow rate: 1.0 ml/min.

Chromatographic column: C18,150*4.6 mm Gemini.

Example 1

(Z)-2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid bis-(ethanolamine)

Stage 1

2-Bromo-6-NITROPHENOL

A solution of 60 ml of concentrated sulfuric acid, diluted 186 ml of water, cooled to room temperature. To this solution was added sodium nitrate (to 79.2 g of 0.93 mol). 2-Bromphenol 1A (60 ml, 0.52 mol) was added dropwise with such a rate as to maintain the reaction temperature below 25°C. the Reaction mixture was stirred at room temperature for 2 hours. The residue was dissolved in 320 ml of ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel with getting the connection specified in the header, 2-bromo-6-NITROPHENOL 1b (48,2 g, yield 42,8%) as a yellow solid.

MS m/z (IER):218[M+1]

1H NMR (400 MHz, CDCl3): δ 11.18 (s, 1H), 8.12-8.15 (m, 1H), 7.89-7.91 (m, 1H), 6.88-7.02 (m, 1H)

Stage 2

1-Bromo-2-methoxy-3-nitrobenzene

2-Bromo-6-NITROPHENOL 1b (46,55 g, 0,214 mol) was dissolved in 500 ml of acetone followed by the addition of potassium carbonate (up RUB 35.36 g, 0.26 mol) and iodomethane (20,1 ml, 0.32 mol). The reaction mixture is boiled under reflux at 70°C for 40 hours. The reaction mixture was concentrated under reduced pressure and diluted with 1300 ml of ethyl acetate and 500 ml of water. Water was kolektyviniai with ethyl acetate (300 ml×2). The combined organic extracts were washed with 4 M hydrochloric acid and saturated sodium bicarbonate solution, and then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel with getting the connection specified in the header, 1-bromo-2-methoxy-3-nitrobenzene 1 (44,59 g, yield of 90.0%) as a brown solid.

MS m/z (IER):234[M+1]

Stage 3

2'-Methoxy-3'-nitrobiphenyl-3-carboxylic acid

1-Bromo-2-methoxy-3-nitrobenzene 1C (23,25 g, 0.10 mol), 3-carboxybenzeneboronic acid (19.5 g, 117 mmol) and tetrakis(triphenylphosphine)palladium (8,86 g, 7.7 mol) was dissolved in a solvent mixture of 100 ml of 2 M sodium carbonate solution and 500 ml of 1,4-dioxane. The reaction mixture is boiled under reflux at 105°C for 43 hours. The mixture was concentrated under reduced pressure, and then added 300 ml of 6 N. hydrochloric acid and 400 ml of ethyl acetate. The aqueous layer was extracted with ethyl acetate (200 ml×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to get the connection specified in the header, 2'-methoxy-3'-nitrobiphenyl-3-carboxylic acid 1d (53,93 g) as a pale yellow solid.

MC m/z (IER): 272 [M]

1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.90-7.92 (m, 1H), 7.82-7.84 (m, 1H), 7.21-7.75 (m, 1H), 7.63-7.67 (m, 1H), 7.42-7.46 (m, 1H), 3.45 (s, 3H)

Stage 4

2'-Methoxy-3'-aminobiphenyl-3-carboxylic acid

2'-Methoxy-3'-nitrobiphenyl-3-carboxylic acid 1d (0,48 g of 1.74 mmol) was dissolved in 60 ml of ethanol, followed by addition of 0.5 g of palladium on carbon (10%) and ammonium formate (1.1 g, to 17.4 mmol). The reaction mixture is boiled under reflux at 80°C for 20 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure and dried to obtain the connection specified in the header, 2'-methoxy-3'-aminobiphenyl-3-carboxylic acid 1E (0,42 g, yield of 93.3%) as a white solid.

MS m/z (IER): 242[M-1]

Stage 5

3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide

Using the known method described in the patent application WO 0189457: 2'-methoxy-3'-aminobiphenyl-3-carboxylic acid 1 (2.5 g, or 10.3 mmol) was dissolved in 100 ml of Hydrobromic acid (40%). The reaction mixture is boiled under reflux at 120°C during the night. The mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with getting the connection specified in the header, 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (2.4 g, 88,8%) as a solid khaki./p>

MS m/z (IER): 230 [M+1]

Stage 6

Indan-5-ilkerin

Indan-5-ylamine 1g (3,59 g of 27.0 mmol) was dissolved in 20 ml of concentrated hydrochloric acid while cooling in a bath of ice-water and the mixture was stirred for 10 minutes. Was added dropwise 10 ml of a solution of sodium nitrite (1.86 g, of 27.0 mmol) and the mixture was stirred for 15 minutes and used in subsequent reactions.

While cooling in ice bath-salt dihydrate tin chloride (24.4 g, 108,0 mmol) was dissolved in 10 ml of concentrated hydrochloric acid followed by the addition of the above-mentioned stored mixture. The reaction mixture was heated to room temperature and subjected to interaction within 1.5 hours. The mixture is then brought to pH 9 with 40% sodium hydroxide solution while cooling in a bath of ice-water. The mixture was extracted with 400 ml of ethyl acetate, the combined organic extracts were concentrated under reduced pressure and dried to obtain the connection specified in the header, indan-5-Algeria 1h (2,05 g, yield 51,3%) as a reddish brown solid.

MS m/z (IER): 149 [M+1]

Stage 7

2-Indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one

Indan-5-ilkerin 1h (2,05 g of 13.8 mmol) was dissolved in 50 ml of acetic acid followed by the addition of ethylacetoacetate (1,76 ml of 13.8 mmol). The reaction mixture was heated at 100°C during the night. The mixture was concentrated under reduced giving the situation and the resulting residue was purified column chromatography on silica gel to obtain compound, specified in the header, 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (1.84 g, yield of 62.3%) as a yellow solid.

MS m/z (IER): 215 [M+1]

1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 3.44 (s, 2H), 2.90-2.97 (m, 4H), 3.21 (s, 3H), 2.07-2.14 (m, 2H)

Stage 8

(Z)-2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid

When cooled in a bath of ice-water 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid hydrobromide 1f (267 mg, of 1.16 mmol) was dissolved in 10 ml of 1 M hydrochloric acid, followed by adding dropwise 10 ml of a solution of sodium nitrite (88 mg, 1.28 mmol) and 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (249 mg, of 1.16 mmol). The mixture was brought to pH 8 with saturated sodium bicarbonate solution, followed by adding 10 ml of ethanol. The reaction mixture was heated to room temperature over night. The mixture was filtered, dried and recrystallize from methanol to obtain the connection specified in the header, (Z)-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid 1j (60 mg, yield of 11.4%) as a yellow solid.

MS m/z (IER): 453 [M-1]

1H NMR (400 MHz, DMSO-d6): δ 13.76 (br. s, 1H), 13.03 (br.s, 1H), 9.66 (br.s, 1H), 8.13 (s, 1H), 7.96-7.98 (d, J=8.1 Hz, 1H), 7.60-7.82 (m, 5H), 7.28-7.30 (d, J=8.1 Hz, 1H), 7.13-7.17 (m, 2H), 2.86-2.93 (m, 4H), 2.34 (s, 3H), 2.03-2.10 (m, 2H)

Stage 9

(Z)-2'-is hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid bis-(ethanolamine)

(Z)-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydropyrazol-4-yl Eden)-hydrazino]-diphenyl-3-carboxylic acid 1j (454 mg, 1.0 mmol) was dissolved in 16 ml of tetrahydrofuran. To the reaction mixture was added ethanolamine (143 mg, 2,35 mmol) and was stirred for 3 hours. The mixture was filtered, the filter cake was washed with tetrahydrofuran (2 ml×3) and the solid was dried in vacuum to obtain the connection specified in the header, (Z)-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid bis-(ethanolamine) 1 (553 mg, yield:

96,0%) as a dark red solid.

MC m/z (IER): 453 [M-1]

1H NMR (400 MHz, CD3OD): δ 8.13 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.69 (m, 3H), 7.61 (d, J=8.0 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 3.65 (t, J=5.2 Hz, 4H), 2.95 (m, 4H), 2.86 (t, J=5.2 Hz, 4H), 2.41 (s, 3H),2.12 (m, 2H).

Example 2

(Z)-2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino-diphenyl-3-carboxylic acid bis-(diethylamine)

(Z)-2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydropyrazol-4-yl Eden)-hydrazino]-diphenyl-3-carboxylic acid 1j (150 mg, 0.33 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red solution. To this solution was added dropwise diethylamine (48 mg, 0.66 mmol) to form a purple solution and re is shivali within 2 hours. The solid was besieged from the solution. The mixture was filtered, the filter cake was washed with tetrahydrofuran (1 ml×3) and the solid was dried in vacuum to obtain the connection specified in the header

(Z)-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid bis-(diethylamine) 2 (132 mg, yield: 66,7%) as a red solid.

HPLC: 99.2% of

MS m/z (IER): 452,9 [M-1]

1H NMR (400 MHz, CD3OD): δ 8.08 (m, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.72 (m, 2H), 7.62 (m, 2H), 7.55 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.07 (m, 1H), 2.89-2.98 (m, N), 2.38 (s, 3H), 2.09-2.14 (m, 2H), 1.34 (m, N).

Example 3

(Z)-2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino-diphenyl-3-carboxylic acid bis-(piperazine)

(Z)-2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid, 1] (150 mg, 0.33 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added piperazine (57 mg, 0.66 mmol) to form a purple solution and stirred at room temperature for 2 hours. The solid was besieged from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml×3) and dried under vacuum to obtain the connection specified in the header, (Z)-2'-Ki-the Roxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid bis-(piperazine) 3 (130 mg, output:

62,8%) as a dark red solid.

HPLC: 98.5% of

MS m/z (IER): 452,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 8.10 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.68 (m, 3H), 7.61 (m, 1H), 7.43 (m, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.15 (m, 1H), 7.00 (m, 1H), 2.89-2.95(m, 4H), 2.84 (s, 16H), 2.39 (s, 3H), 2.09-2.12 (m, 2N)

Example 4

(Z)-5-(3-(N'-[1-(3,3-Dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(ethanolamine)

Stage 1 Di-tert-butyl-1-(3,3-dimethylene-5-yl)hydrazine-1,2 -, in primary forms

6-Bromo-1,1-dietlinde (obtained by using well-known methods: the patent application WO 2005066115) 4A (4,32 g, 19,27 mmol) was dissolved in 40 ml of tetrahydrofuran, and then added dropwise utility (15,67 ml, 1.6 M, 25,05 mmol) at -78°C. After interaction of the reaction mixture for 40 minutes, then was added a solution of di-tert-utilization.bacteria (5.32 g, 23,12 mmol) in 30 ml of tetrahydrofuran. The reaction mixture was subjected to interaction for another 3 hours at -78°C. To the reaction mixture were added 5 ml of methanol, then heated to room temperature and filtered on silica gel. The filtrate was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with getting the connection specified in the header, di-tert-BU the Il-1-(3,3-dimethyl-1H-inden-5-yl)hydrazine-1,2-in primary forms 4b (2.70 g, output 37,2%) as a yellow solid.

Stage 2

2-(3,3-Dietlinde-5-yl)-5-methyl-2,4-dihydropyrazol-3-one

Di-tert-butyl-1-(3,3-dimethyl-1H-inden-5-yl)hydrazine-1,2 -, in primary forms 4b (2.70 g, 7,18 mmol) was dissolved in 100 ml of acetic acid and then adding 20 ml triperoxonane acid. After interaction of the mixture at room temperature for 2 hours was added ethylacetoacetate (0,98 g, rate of 7.54 mmol). Then the mixture was heated to 100°C and subjected to interaction within 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The reaction mixture was neutralized with a saturated solution of sodium bicarbonate, and then extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel with getting the connection specified in the header, 2-(3,3-dietlinde-5-yl)-5-methyl-2,4-dihydropyrazol-3-one 4 (1.0 g, yield 47,7%) as a light brown solid.

MS m/z (IER):243[M+1]

Stage 3

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan

1-Bromo-2-methoxy-3-nitrobenzene 1C (67 g, 289 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxanone is an (110 g, 433 mmol), tetrakis(triphenylphosphine)palladium (11,80 g, 14,44 mmol) and potassium acetate (71 g, 724 mmol) was dissolved in 600 ml of oxalic acid dimethyl ester. The mixture was boiled under reflux for 17 hours. The mixture was concentrated under reduced pressure, the resulting residue was purified column chromatography on silica gel with getting the connection specified in the header, 2-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 4d (50.5 g, 61.9%) in the form of yellow crystals.

Stage 4

5-(2-Methoxy-3-nitrophenyl)furan-2-carboxylic acid

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan 4d (10 g, 35,85 mmol), 5-bromofuran-2-carboxylic acid (5,47 g, 28,66 mmol), tetrakis(triphenylphosphine)palladium (2,07 g, to 1.79 mmol) and sodium carbonate (7,60 g, 71,66 mmol) was dissolved in a solvent mixture of 200 ml of 1,4-dioxane and 30 ml of water. The reaction mixture is boiled under reflux for 2.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 ml of water and brought to pH 3 1 M hydrochloric acid. Then the mixture was filtered and the filter cake washed with 50 ml of a mixture solvent of n-hexane/ethyl acetate (V/V=1:1). The residue was dried to obtain the connection specified in the header, 5-(2-methoxy-3-nitrophenyl) furan-2-carboxylic acid 4F (to 4.23 g, yield 56,1%) as a gray solid./p>

MS m/z (IER): 262[M-1]

Stage 5

5-(3-Amino-2-methoxyphenyl)-furan-2-carboxylic acid

5-(2-Methoxy-3-nitrophenyl)furan-2-carboxylic acid 4F (to 4.23 g, 16,09 mmol) was dissolved in 125 ml of ethyl acetate followed by the addition 423 mg of palladium on carbon (10%) and ammonium formate (field are estimated at 4.054 g, 64,35 mmol). The reaction mixture is boiled under reflux for 3.5 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-(3-amino-2-methoxyphenyl)-furan-2-carboxylic acid 4f (2,79 g, yield of 74.4%) as a pale green solid.

MS m/z(IER):232[M-1]

Stage 6

5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide

5-(3-Amino-2-methoxyphenyl)-furan-2-carboxylic acid 4f (2,79 g, of $ 11.97 mmol) was dissolved in 25 ml of dichloromethane followed by the addition dropwise of tribromide boron (23.9 ml, 2.0 M). The reaction mixture was subjected to interaction at room temperature for 1 hour. The mixture was concentrated under reduced pressure after addition of 5 ml of methanol. The residue was diluted with 100 ml ethyl acetate and stirred for 1 hour. Then the mixture was filtered and the filter cake was dried to obtain the connection specified in the header, 5-(3-amino-2-hydroxyphenyl)-furan-2-carboxylic acid Hydra is bromide 4D (1.24 g, output 47,2%) as a yellow solid.

MC m/z (IER): 218[M-1]

Stage 7

(Z)-5-(3-{N'-[1-(3,3-Dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid

(Z)-5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 4g (333 mg, 1.1 mmol) was dissolved in hydrochloric acid (3,7 ml, 1 M) under cooling in a bath of ice-water, followed by adding dropwise 1.5 ml of a solution of sodium nitrite (85 mg, 1,22 mmol). After the mixture was subjected to interaction within 20 minutes, was sequentially added 2-(3,3-dietlinde-5-yl)-5-methyl-2,4-dihydropyrazol-3-he 4 (242 mg, 1.0 mmol), sodium bicarbonate (1.4 g, 16,67 mmol) and 3 ml of ethanol. The reaction mixture was subjected to interaction overnight at room temperature. The mixture was filtered and the filtration cake was added 20 ml of water. The mixture was brought to pH 3-4 with concentrated hydrochloric acid. The mixture was filtered and the filter cake was dried and purified column chromatography on silica gel with getting the connection specified in the header, (Z)-5-(3-{N'-[1-(3,3-dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid 4h (190 mg, yield of 40.3%) as a red solid.

MS m/z (IER): 470,9 [M-1]

1H NMR (400 MHz, DMSO-d6): δ 13.74 (br. s, 1H), 13.15 (br. s, 1H), 9.99 (br. s, 1H), 7.71 (t, 3H), 7.55 (d, J=6.8 Hz, 1H), 7.37 (d, J=.6 Hz, 1H), 7.20 (m, 2H), 7.15 (m, 1H), 2.86 (t, J=7.2 Hz, 2H), 2.33 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 1.26 (s, 6H)

Stage 8

(Z)-5-(3-{N'-[1-(3,3-Dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(ethanolamine)

(Z)-5-(3-{N'-[1-(3,3-Dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-or den]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid 4h (2.3 g, to 4.87 mmol) was dissolved in 20 ml of tetrahydrofuran. To the solution was added ethanolamine (594 mg, of 9.75 mmol) and was stirred for 1 hour at room temperature. The mixture was filtered, the filter cake was washed with tetrahydrofuran (1 ml×3) and dried under vacuum to obtain the connection specified in the header, (Z)-5-(3-{N'-[1-(3,3-dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(ethanolamine) 4 (2.5 g, yield: 86.4 per cent) as a black solid.

MC m/z (IER): 470,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.57 (m, 4H), 7.19 (m, 1H), 7.03 (d, J=3.6 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H), 6.71 (t, J=8.0 Hz, 1H), 3.73 (t, J=5.2 Hz, 4H), 2.98 (m, 4H), 2.88 (t, J=7.2 Hz, 2H), 2.36 (s, 3H), 1.96 (t, J=7.2 Hz, 2H), 1.29 (s, 6H)

Example 5

(Z)-5-(3-{N'-[1-(3,3-Dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-Illidan-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(diethylamine)

(Z)-5-(3-{N'-[1-(3,3-Dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-or den]-hydrazino}-2-hydroc fenil)-furan-2-carboxylic acid 4h (150 mg, 0.32 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added diethylamine (46 mg, 0,63 mmol) forming a purple solution and stirred at room temperature overnight. The solution was concentrated under reduced pressure, the resulting residue was purified column chromatography on silica gel (hexane: ethyl acetate=10:1) and the solid was dried in vacuum to obtain the connection specified in the header, (Z)-5-(3-{N'-[1-(3,3-dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(diethylamine) 5 (170 mg, yield: 86,7%) as a dark red solid.

HPLC: 94,6%

MS m/z (IER): 471,9 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.60 (m, 4H), 7.19 (m, 1H), 7.04 (m, 1H), 6.87 (m, 2H), 2.98 (q, J=7.2 Hz, 8H), 2.89 (t, J=7.2 Hz, 2H), 2.36 (s, 3H), 1.96 (t, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, N), 1.25 (s, 6N)

Example 6

(Z)-5-(3-[N'-[1-(3,3-Dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-Illidan-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(piperazine)

(Z)-5-(3-{N'-[1-(3,3-Dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-or den]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid 4h (150 mg, 0.32 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added piperazine (55 mg,0,64 mmol) forming a purple solution and stirred at room temperature overnight. The mixture was filtered, the filter cake was washed with tetrahydrofuran (1 ml×3) and the solid was dried in vacuum to obtain the connection specified in the header, (Z)-5-(3-{N'-[1-(3,3-dietlinde-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid bis-(piperazine) 6 (158 mg, yield: 77.1 percent) as a red solid.

HPLC: 99,28%

MC m/z (IER): and 471.8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.64-7.66 (m, 3H), 7.55 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.04 (m, 1H), 6.87-6.88 (m, 2H), 3.01 (s, 16H), 2.90 (t, J=7.2 Hz, 2H), 2.38 (s, 3H), 1.97 (t, J=7.2 Hz, 2H), 1.29 (s, 6H)

Example 7

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(ethanolamine)

Stage 1

(5,6,7,8-Tetrahydronaphthalen-2-yl)-hydrazine

5,6,7,8-Tetrahydronaphthalen-2-ylamine 7a (3,68 g 25,0 mmol) was dissolved in 20 ml of concentrated hydrochloric acid and the mixture was stirred for 10 minutes under cooling in a bath of ice-water. Was added dropwise 10 ml of a solution of sodium nitrite (1,72 g 25,0 mmol), the mixture was stirred for 15 minutes and used in the next reaction.

When cooled in a bath of ice and salt, the chloride dihydrate tin (22,6 g, 100 mmol) was dissolved in 10 ml of concentrated hydrochloric acid and then adding the above is saved mixture. The reaction mixture was heated to room temperature and subjected to interaction within 1.5 hours. The mixture is then brought to pH 9 with 40% sodium hydroxide solution. The mixture was extracted with 400 ml of ethyl acetate, then the combined organic extracts were concentrated under reduced pressure and dried to obtain the connection specified in the header (5,6,7,8-tetrahydronaphthalen-2-yl)-hydrazine 7b (2,19 g, yield of 53.7%) as a yellow oil.

MS m/z (IER): 163[M+1]

Stage 2

5-Methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one

(5,6,7,8-Tetrahydronaphthalen-2-yl)-hydrazine 7b (2.0 g, 12.3 mmol) was dissolved in 50 ml of acetic acid followed by the addition of ethylacetoacetate (of 1.57 ml, 12.3 mmol). The reaction mixture was heated to 100°C during the night. The mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-she 7C (1,58 g, yield of 56.2%) as a colourless oil.

MS m/z (IER): 457 [2M+1]

1H NMR (CDCl3): δ 7.54-7.58 (m, 2H), 7.09 (d, J=8 Hz, 1H), 3.43 (s, 2H), 2.77-2.81 (m, 4H), 2.21 (s, 3H), 1.80-1.83 (m, 4H).

Stage 3

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid

5-(3-Amino-2-hydroxyphenyl)-furan-karbonovoi acid hydrobromide 4g (292 mg, 0.98 mmol) was dissolved in 3.3 ml of 1 M hydrochloric acid while cooling in a bath of ice-water, followed by adding dropwise 1.3 ml of a solution of sodium nitrite (74 mg, 1.07 mmol). After the mixture was stirred for 20 minutes, was added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 7C (200 mg, 0.88 mmol). The mixture was brought to pH 8~9 by adding portions of sodium bicarbonate solution (1,226 g, 14.6 mmol). The formed bubbles extinguished 2 ml of ethanol. The reaction mixture was heated to room temperature and subjected to interaction during the night. The mixture was filtered and the filter cake was dissolved in 20 ml of water. After a good stirring of the mixture was brought to pH 3-4 with concentrated hydrochloric acid, filtered and dried. The crude product was purified HPLC with getting the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (160 mg, yield of 39.8%) as a red solid.

MS m/z (IER): 457 [M-1]

1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=8.4 Hz, 1 H), 7.63 (m, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.37 (d, J=3.2 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.13 (m, 2H), 2.75 (m, 4H), 2.33 (s, 3H), 1.76 (m, 4H)

Stage 4

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(ethanolamine)

(Z)-5-(2-Ki-the Roxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (3.3 grams, 7.2 mmol) was dissolved in 15 ml of tetrahydrofuran. To the reaction solution was slowly added dropwise ethanolamine (0.88 g, 13 mmol) and was stirred for 1.5 hours at 15~20°C. Of the solution was deposited a large amount of solid substance was filtered, then the filter cake was washed with tetrahydrofuran (10 MLH) and dried under vacuum to obtain the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(ethanolamine) 7 (3 g, yield: 74%) as a dark red solid.

HPLC: 99.3% of the

MS m/z (IER): 456,8 [M-1]

1H NMR (400 MHz, CH3OD): δ 7.51 (d, J=8.0 Hz, 1H), 7.44-7.46 (m, 3H), 6.93-6.98 (m, 2H), 6.88 (d, J=3.6 Hz, 1 H), 6.67 (t, J=8.0 Hz, 1 H), 3.61 (t, J=5.2 Hz, 4H), 2.86 (t, J=5.2 Hz, 4H), 2.65-2.70 (m, 4H), 2.24 (s, 3H), 1.70-1.72 (s, 3H)

Example 8

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5.6.7.8-tetrahydronaphthalen-2-yl)-1.5-dihydropyrazol-4-Illidan-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(choline)

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added 45% solution of choline hydroxide in methanol (45 mg, 0.44 mmol) with the formation of purpu the aqueous solution and was stirred for 1 hour at room temperature. The solid was besieged from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml×3) and dried under vacuum to obtain the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(choline) 8 (140 mg, output: 96,6%) as a dark red solid.

HPLC: 98,82%

MS m/z (IER): 457,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.74 (d, J=8.0 Hz, 1H), 7.60 (m, 3H), 7.08 (m, 3H), 6.91 (t, J=8.0 Hz, 1H), 3.96 (m, 4H), 3.45 (t, J=4.8 Hz, 4H), 3.18 (s, 18H), 2.80 (m, 4H), 2.38 (s, 3H), 1.84 (m, 4H)

Example 9

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(diethylamine)

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added dropwise diethylamine (32 mg, 0.44 mmol) to form a purple solution and stirred at room temperature overnight. The solid was besieged from the solution, was filtered and the filter cake was washed with tetrahydrofuran (1 MLH), the solid was dried in vacuum to obtain the soedineniya, specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(diethylamine) 9 (77 mg, yield: 58,3%) as a dark red solid. HPLC:99,1% MS m/z (IER): 457,9 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.59 (t, 4H), 7.08 (d, J=8.0 Hz, 1H), 7.04 (d, J=3.6 Hz, 1 H), 6.94 (d, J=3.6 Hz, 1 H), 6.82 (t, J=8.0 Hz, 1 H), 2.99 (q, J=7.2 Hz, 8H), 2.79 (t, 4H), 2.36 (s, 3H), 1.82 (t, J=3.2 Hz, 4H), 1.27 (t, J=7.2 Hz, N)

Example 10

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(meglumine)

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) suspended in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture were added meglumin (85 mg, 0.44 mmol) and stirred at room temperature overnight. To the resulting solution were added 4 ml of methanol and concentrated under reduced pressure to get the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(meglumine) 10 (168 mg, yield: 90,8%) in the form of dark red firm is about substance.

HPLC: 97,7%

MC m/z (IER): 457,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.56 (m, 4H), 7.06 (m, 2H), 6.98 (d, J=3.2 Hz, 1H), 6.75 (t, J=7.6 Hz, 1H), 4.08 (m, 2H), 3.81 (m, 2H), 3.77 (m, 2H), 3.63 (m, 6N), 3.11 (m, 4H), 2.76 (m, 4H), 2.64 (s, 6N), 2.33 (s, 3H), 1.79 (m, 4H)

Example 11

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-Illidan-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(piperazine)

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added piperazine (37 mg, 0.44 mmol) to form a purple solution was stirred for 2 hours at room temperature. The solid was besieged from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml×3) and dried under vacuum to obtain the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(piperazine) 11 (120 mg, output: 87,6%) as a dark red solid.

HPLC: 98.8% of the

MS m/z (IER): 457,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.59 (m, 4H), 7.08 (d, J=8.0 Hz, 1H), 7.04 (d, J=3.2 Hz, 1H), 6.87 (d, J=3.2 Hz, 1H), 6.82 (t, J=8.0 Hz, 1H), 3.00 (s, 16H), 2.78 (m, 4H), 2.36 (s, 3H), 1.81 (m, 4H)

Example 12

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(trometamol)

(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture were added trometamol (53 mg, 0.44 mmol) with formation of a brown solution and stirred at room temperature overnight. The solid was besieged from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml×3) and dried under vacuum to obtain the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(trometamol) 12 (142 mg, output: 92,8%) as a dark solid. HPLC: 94,0% MS m/z (IER): 457,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.58 (m, 4H), 7.05 (m, 2H), 6.96 (d, J=3.6 Hz, 1H), 6.90 (t, J=8.0 Hz, 1H), 3.65 (s, 12H), 2.76 (m, 4H), 2.33 (s, 3H), 1.80 (m, 4H)

Example 13

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(dibenziletilendiaminom)

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added dibenziletilendiaminom (104 mg, 0.44 mmol) with formation of a brown solution and was stirred for 2 hours at room temperature. To the resulting solution were added 4 ml of methanol and concentrated under reduced pressure to get the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(dibenziletilendiaminom) 13 (167 mg, yield: 81.8 percent) as a dark solid.

HPLC: 96.8% of the

MS m/z (IER): 457,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.52-7.54 (m, 3H), 7.39 (d, J=7.2 Hz, 1H), 7.24-7.28 (m, 20N), 7.01-7.04 (m, 2H), 6.65-6.72 (m, 1H), 3.89 (s, 8H), 3.01 (s, 8H), 2.73 (m, 4H), 2.32 (s, 3H), 1.78 (m, 4H)

Example 14

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid disodium salt

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (110 mg, 0.24 mmol) was dissolved in 4 ml of tetrahydro the uranium with the formation of a dark red suspension. To the reaction mixture was added dropwise a 1 M solution of sodium hydroxide (0.4 ml, 0.44 mmol), was stirred for 2 hours at room temperature. The reaction mixture was filtered, then the filtrate was added 4 ml of methanol and concentrated under reduced pressure. The resulting solid was washed with hexane to obtain the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid disodium salt 14 (115 mg, yield: 81.8 percent) as a dark solid. HPLC: 96.8% of MS m/z (IER): 457,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.79 (dd, J1=7.6 Hz, J2=1.2 Hz, 1H), 7.52 (m, 3H), 7.18 (d, J=3.6 Hz, 1H), 7.05 (m, 2H), 6.70 (m, 1H), 2.78 (m, 4H), 2.41 (s, 3H), 1.82 (m, 4H)

Example 15

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-Illidan-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(L-arginine)

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added L-arginine (76 mg, 0.44 mmol) and 2 ml of water, was stirred for 2 hours at room temperature. The reaction solution of Koh which was interaval under reduced pressure, added 5 ml of ethyl acetate. The solid was besieged from solution, filtered, then the filter cake was dried in vacuum to obtain the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(L-arginine) 15 (168 mg, yield: 95.5 percent) as a dark solid.

HPLC: 97.5% of

MC m/z (IER): 457,9 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.59 (m, 4H), 7.06 (m, 2H), 6.98 (d, J=3.6 Hz, 1H), 6.92 (t, J=8.0 Hz, 1H), 3.57 (t, J=6.4 Hz, 2H), 3.19 (m, 4H), 2.78 (m, 4H), 2.36 (s, 3H), 1.83 (m, 8H), 1.73 (m, 4H)

Example 16

(Z)-5-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid bis-(ethanolamine)

Stage 1

(Z)-5-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid 5-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 4g (300 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 ml, 1 M) then adding dropwise 1.2 ml of a solution of sodium nitrite (73 mg, 1.05 mmol) under cooling in a bath of ice-water. After the mixture was subjected to interact for 10 minutes, was sequentially added 2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 1i (193 mg, 0.9 mmol), sodium bicarbonate (1.26 g, 15 mmol) and 4,4 ml of e is anola. The mixture was subjected to interaction at room temperature for 24 hours. The mixture was filtered and the filter cake was washed with 20 ml water, and then was dissolved in 20 ml of water. When cooled in a bath of ice-water mixture is brought to pH<5 with concentrated hydrochloric acid, filtered and dried to obtain the connection specified in the header, (Z)-5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid 16A (287 mg, yield 71,8%) as a yellow solid.

MC m/z (IER): 443 [M-1]

1H NMR (400 MHz, DMSO-d6): δ 13.73 (br.s, 1H), 9.97 (br.s, 1H), 7.78 (s, 1H), 7.70 (m, 2H), 7.57 (m, 1H), 7.36 (d, J=3.6 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.15 (m, 1H), 2.89 (m, 4H), 2.32 (s, 3H), 2.03 (m, 2H)

Stage 2

(Z)-5-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid bis-(ethanolamine)

(Z)-5-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid 16A (1,825 g, 4,11 mmol) was dissolved in 20 ml of tetrahydrofuran. To the reaction mixture was added ethanolamine (501 mg, by 8.22 mmol) and was stirred for 2 hours at room temperature. The solid was besieged from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 MLH) and dried under vacuum to obtain the connection specified in the header, (N)-5-{2-hydroxy-3-['-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-HYDR, Asino]-phenyl}-furan-2-carboxylic acid bis-(ethanolamine) 16 (near 1.615 g, output: 69,4%) as a dark red solid.

MC m/z (IER): 443 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.67 (s, 1H), 7.53 (m, 3H), 7.21 (d, J=8.0 Hz, 1H), 7.02 (m, 1 H), 6.97 (d, J=3.2 Hz, 1 H), 6.70 (m, 1 H), 3.70 (m, 4H), 2.92 (m, 4H), 2.88 (m, 4H), 2.35 (s, 3H), 2.08 (m, 2H)

Example 17

(Z)-5-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino-phenyl}-furan-2-carboxylic acid bis-(diethylamine)

(Z)-5-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid 16A (150 mg, 0.38 mmol) suspended in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added dropwise diethylamine (49 mg, 0.67 mmol) to form a purple solution was stirred for 2 hours at room temperature. The solid was besieged from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 MLH) and dried under vacuum to obtain the connection specified in the header, (Z)-5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid bis-(diethylamine) 17 (163 mg, yield: 81.9 percent) in the form of a dark red solid.

HPLC:99,18%

MS m/z (IER): 442,7 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.71 (s, 1H), 7.60 (m, 3H), 7.24 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.82 (m, 1H), 3.73 (m, 2H), 2.95 (m, 8H), 2.37 (s, 3H), 2.13 (m, 2 is), 1.87 (m, 2H), 1.28 (m, N)

Example 18

(Z)-5-{2-Hydroxy-3[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid bis-(piperazine)

(Z)-5-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid 16A (150 mg, 0.38 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added piperazine (58 mg, of 0.68 mmol) forming a purple solution and was stirred for 3 hours at room temperature. The solid was besieged from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 MLH) and dried under vacuum to obtain the connection specified in the header, (Z)-5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid bis-(piperazine) 18 (185 mg, yield: 88,9%) in the form of a dark red solid.

HPLC: 96,52%

MS m/z (IER): 443,2 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.73 (s, 1H), 7.61-7.64 (m, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.78-6.90 (m, 2H), 3.03 (s, 16H), 2.89-2.95 (t, 4H), 2.35 (s, 3H), 2.12 (t, J=7.2 Hz, 4H)

Example 19

(Z)-4-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino-phenyl}-thiophene-2-carboxylic acid bis-(ethanolamine)

Stage 1 4-(3-Nitro-2-methoxyphenyl)-thiophene-2-carboxylic acid

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan 4d (0,81 g, 2.9 mmol), 4-bromothiophene-2-carboxylic acid (0.3 g, 1,45 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0,073 mmol) and sodium carbonate (0.31 g, 2.9 mmol) was dissolved in a solvent mixture of 20 ml of 1,4-dioxane and 10 ml of water. The reaction mixture is boiled under reflux for 0.5 hours. The mixture was brought to pH 3 1 N. hydrochloric acid and was extracted with ethyl acetate (20 ml×3). The combined organic extracts were concentrated under reduced pressure and the residue was purified column chromatography on silica gel with getting the connection specified in the header, 4-(3-nitro-2-methoxyphenyl)-thiophene-2-carboxylic acid 19a (0.54 g) as a brown oil, which was directly used in the next stage.

MS m/z (IER): 277,6 [M-1]

Stage 2 4-(3-Amino-2-methoxyphenyl)-thiophene-2-carboxylic acid

4-(3-Nitro-2-methoxyphenyl)-thiophene-2-carboxylic acid 19 (400 mg, 1,45 mmol) was dissolved in 30 ml of ethyl acetate, followed by addition of 100 mg of palladium on carbon (10%) and ammonium formate (360 mg, 5.8 mmol). The mixture was boiled under reflux for 3 hours. The mixture was filtered and concentrated under reduced pressure to get the connection specified in the header, 4-(3-amino-2-methoxyphenyl)-thiophene-2-carbon is th acid 19b (410 mg) as a brown oil, which is directly used in the next stage.

MS m/z (IER): 247,8 [M-1]

Stage 3

4-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide

4-(3-Amino-2-methoxyphenyl)-thiophene-2-carboxylic acid hydrobromide 19b (360 mg, 1,45 mmol) was dissolved in 5 ml of dichloromethane followed by the addition dropwise of tribromide boron (2.8 ml, 5.6 mmol). The reaction mixture was subjected to interaction at room temperature for 4.5 hours. To the reaction mixture were added 5 ml of methanol and concentrated under reduced pressure. The residue was diluted with 10 ml ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake was dried to obtain the connection specified in the header, 4-(3-amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 19s (80 mg, yield of 17.5%) as a gray solid.

MS m/z (IER): 236,1 [M+1]

Stage 4

(Z)-4-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid

4-(3-Amino-2-hydroxyphenyl)-thiophene-2-carboxylic acid hydrobromide 19 (120 mg, 0.38 mmol) was dissolved in 2.7 ml of 1 M hydrochloric acid while cooling in a bath of ice-water followed by the addition dropwise of 0.45 ml of a solution of sodium nitrite (29 mg, 0.42 mmol). After the mixture was subjected to interaction within 20 minutes, was added 2-indan-5-yl-5-methyl-2,4-dihydro shall irsol-3-one 1i (73 mg, 0.34 mmol). The mixture was brought to pH 8 with saturated sodium bicarbonate solution followed by the addition of 2 ml of ethanol. The reaction mixture was subjected to interaction overnight at room temperature. The mixture was filtered and the filter cake was added to 20 ml of water. The mixture was brought to pH 3-4 with concentrated hydrochloric acid and filtered. Then to the filtration cake was added 5 ml of ethyl acetate and the mixture was stirred for 1 hour. The mixture was filtered and the filter cake was dried to obtain the connection specified in the header, (Z)-4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid 19d (45 mg, yield 28,7%) as a yellow solid.

MS m/z (IER): 458,8 [M-1]

1H NMR (400 MHz, DMSO-d6): δ 13.79 (br.s, 1H), 9.68 (br.s, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.78 (s, 1H), 7.67 (m, 2H), 7.32 (m, 2H), 7.13 (t, J=8.0 Hz, 1H), 2.87 (m, 4H), 2.32 (s, 3H), 2.05 (m, 2H)

Stage 5

(Z)-4-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid bis-(ethanolamine)

(Z)-4-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid 19d (1.3 g, and 2.83 mmol) was dissolved in 40 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added ethanolamine (344 mg, the 5.65 mmol) with the formation of purple races the thief and was stirred for 2 hours at room temperature. From the solution deposited a large amount of solid substance was filtered, then the filter cake was washed with tetrahydrofuran (1 ml×3) and dried under vacuum to obtain the connection specified in the header, (Z)-4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid bis-(ethanolamine) 19 (1,513 g, output: 92,0%) as a dark red solid.

HPLC: 98,65%

MS m/z (IER): 458,7 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.94 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 7.55-7.59 (m, 2H), 7.28-7.30 (m, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.83 (t, J=8.0 Hz, 3H), 3.65-3.68 (m, 4H), 2.88-2.92 (m, 8H), 2.38 (s, 3H), 2.06-2.14 (m, 2H)

Example 20

(Z)-4-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid bis-(diethylamine)

(Z)-4-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid 19d (150 mg, 0.33 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added dropwise diethylamine (49 mg, 0.66 mmol) to form a purple solution was stirred for 2 hours at room temperature. The solid was besieged from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 MLH) and dried under vacuum to obtain compounds of the decree is tion in the header, (Z)-4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid bis-(diethylamine) 20 (157 mg, in the form of a dark red solid). Yield: 79.3 percent.

HPLC: 98,98%

MS m/z(IER): 458,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.81 (s, 1H), 7.73 (s, 1H), 7.68-7.70 (m, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.22-7.26 (m, 2H), 7.06 (t, J=8.0 Hz, 1H), 3.03 (q, J=7.2 Hz, 8H), 2.90-2.97 (t, 4H), 2.37 (s, 3H), 2.07-2.15 (m, 2H), 1.29 (t, J=7.2 Hz, N)

Example 21

(Z)-4-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1.5-dihydropyrazol-4-ilidene)-hydrazino-phenyl}-thiophene-2-carboxylic acid bis-(piperazine)

(Z)-4-{2-Hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid 19d (150 mg, 0.33 mmol) was dissolved in 5 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added piperazine (56 mg, of 0.65 mmol) to form a purple solution was stirred for 2 hours at room temperature. The solid was besieged from solution, filtered, then the filter cake was washed with tetrahydrofuran (1 MLH) and dried under vacuum to obtain the connection specified in the header, (Z)-4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid bis-(piperazine) 21 (195 mg, yield: 94.7 percent) in the form of a dark red solid.

VE is X:98,17%

MS m/z(IER): 458,8 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.85 (s, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.62 (m, 2H), 7.26 (m, 2H), 6.95 (t, 1H), 2.96 (m, N), 2.91 (m, 4H), 2.37 (s, 3H), 2.11 (m, 2H)

Example 22

(Z)-4-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthyl-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(ethanolamine)

Stage 1

4-Bromofuran-2-carboxylic acid

A mixture of 4,5-dibromofuran-2-carboxylic acid 22A (5.5 g, 20.3 mmol) and 18 ml of ammonium hydroxide was added 63 ml of water followed by the addition of powdered zinc (1,46 g, 22,33 mmol). After complete addition, the reaction mixture was stirred at room temperature for 6 hours. The mixture was brought to pH 3 1 M hydrochloric acid with the formation of a large amount of precipitation. The mixture was filtered and the filter cake was washed with n-hexane (15 MLH), and dried to obtain the connection specified in the header, 4-bromofuran-2-carboxylic acid 22b (3.2 g, yield 83,1%) as a white solid.

MS m/z (IER): amounts to 188.7 [M-1]

Stage 2

4-(3-Nitro-2-methoxyphenyl)-furan-2-carboxylic acid

2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan 4d (4 g, 14,34 mmol), 4-bromofuran-2-carboxylic acid 22b (2,18 g, 11,47 mmol), tetrakis(triphenylphosphine)palladium (829 mg, 0,717 mmol) and potassium carbonate (3,96 g, 28,68 mmol) was dissolved in a mixture of plants is of aricela 80 ml of 1,4-dioxane and 30 ml of water. The reaction mixture is boiled under reflux for 2.5 hours. The mixture was brought to pH 3 1 M hydrochloric acid, and then extracted with ethyl acetate (80 ml×3). The combined organic extracts were concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 4-(3-nitro-2-methoxyphenyl)-furan-2-carboxylic acid 22s (3.42 g, yield 90.7 percent) as a brown oil.

MS m/z (IER): 261,8 [M-1]

Step 3 4-(3-Amino-2-methoxyphenyl)-furan-2-carboxylic acid

4-(3-Nitro-2-methoxyphenyl)-furan-2-carboxylic acid at 22 ° C (500 mg, 1.9 mmol) was dissolved in 15 ml of ethyl acetate, followed by addition of 100 mg of palladium on carbon and ammonium formate (429 mg, 7.6 mmol). The reaction mixture is boiled under reflux for 3 hours. The mixture was filtered to remove the palladium on carbon and then concentrated under reduced pressure to get the connection specified in the header, 4-(3-amino-2-methoxyphenyl)-furan-2-carboxylic acid 22d (325 mg, yield 73,4%) as a yellow oil.

MS m/z (IER): 231,8 [M-1]

Stage 4

4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide

4-(3-Amino-2-methoxyphenyl)-furan-2-carboxylic acid 22d (325 mg, 1.4 mmol) was dissolved in 5 ml of dichloromethane followed by the addition dropwise of tribromide boron (2.8 ml, 5.6 mmol). A mixture of experience and interaction at room temperature for 4.5 hours. Added 5 ml of methanol, and then the mixture was concentrated under reduced pressure. The residue was diluted with 10 ml ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake was dried to obtain the connection specified in the header, 4-(3-amino-2-hydroxyphenyl)-furan-2-carboxylic acid hydrobromide 22E (174 mg, yield 57,1%) as a gray solid.

MS m/z (IER): 217,7 [M-1]

Stage 5

(Z)-4-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthyl-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid

4-(3-Amino-2-hydroxyphenyl)-furan-2-carboxylic acid 22E (170 mg, or 0.57 mmol) was dissolved in hydrochloric acid (1.9 ml, 1 M) under cooling in a bath of ice-water, followed by adding dropwise 0.7 ml of a solution of sodium nitrite (43 mg, to 0.63 mmol). After the mixture was subjected to interaction within 20 minutes, was added 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2,4-dihydropyrazol-3-one 7C (116 mg, 0.51 mmol). The mixture was brought to pH 8-9 with saturated sodium bicarbonate solution followed by the addition of 2 ml of ethanol. The mixture was subjected to interaction at room temperature for 24 hours. The mixture was filtered, and then to the filtration cake was added 15 ml of water. When cooled in a bath of ice-water mixture is brought to pH 2~3 with concentrated hydrochloric acid and filtered. The filter cake washed with ethyl acetate, the m and dried to obtain compound, specified in the header, (Z)-4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthyl-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 22f(13 mg, yield of 5.5%) as a red solid.

MC m/z (IER): 456,7 [M-1]

1H NMR (400 MHz, DMSO-d6): δ 13.75 (br. s, 1H), 13.20 (br. s, 1H), 9.68 (br. s, 1H), 8.37 (s, 1H), 7.62-7.68 (m, 4H), 7.41-7.43 (m, 1H), 7.11-7.15 (m, 2H), 2.67-2.76 (m, 2H), 2.31 (s,3H), 1.75 (m,4H)

Stage 6

(Z)-4-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthyl-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(ethanolamine)

(Z)-4-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthyl-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 22f (1.2 g, 2.6 mmol) was dissolved in 20 ml of tetrahydrofuran with the formation of a dark red suspension. To the reaction mixture was added ethanolamine (399 mg, 6.5 mmol) with the formation of the purple solution was stirred for 6 hours at room temperature. From the solution deposited a large amount of solid substance was filtered, then the filter cake was washed with tetrahydrofuran (1 ml×3) and dried under vacuum to obtain the connection specified in the header, (Z)-4-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthyl-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid bis-(ethanolamine) 22 (1.51 g, in the form of a red solid), output is 72.8 percent.

HPLC:97,16%

MS m/z (IER): 456,7 [M-1]

1H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.51-7.56 (m, 3H), 7.31-7.35 (m, 2H), 7.07 (d, J=9.2 Hz, 1H), 6.89 (t, J=8.0 Hz, 1H), 3.68-3.71 (m, 4H), 2.90-2.95 (m, 4H), 2.76-2.81 (m, 4H), 2.39 (s, 3H), 1.80-1.85 (m, 4H)

Example 23

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid choline

(Z)-5-(2-Hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid (1.1 g, 2.4 mmol) was dissolved in 19 ml of a mixture solvent of ethyl acetate and ethanol (V/V=12:7), then the reaction mixture was heated to 40°C and was stirred for 15 minutes with formation of a suspension chestnut color. To the reaction mixture was slowly added a 1 M solution of choline in methanol (2.4 ml, 2.4 mmol) with the formation of the black solution up until the solid disappeared. To the reaction solution was added 1 ml of water, then cooled to 35°C and were subjected to interaction within 3 hours, then stirred for 72 hours at room temperature. The orange solid was besieged, was filtered, then the filter cake was washed with ethyl acetate (5 ml×3) and dried with getting the connection specified in the header, (Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-g is draino}-phenyl)-furan-2-carboxylic acid choline (620 mg, output: 46,0%) as an orange solid.

MS m/z (IER): 456,7 [M-1]

1H NMR (400 MHz, CD3OD): δ 7.66-7.57 (m, 4H), 7.09-7.04 (m, 3H), 6.92 (d, J=3.6 Hz, 1H), 4.03-3.99 (m, 2H), 3.51-3.48 (m, 2H), 3.22 (s, 9H), 2.81-2.75 (m, 4H), 2.33 (s, 3H), 1.83-1.81 (m, 4H)

Example 24

Composition in tablet form

Lactose, microcrystalline cellulose, sodium salt starch glycolate, magnesium stearate and the compound of Example 7 is mixed in the ratios shown in the following table 1. The mixture is then pressed into tablets.

Table 1
INGREDIENTmg
The compound of Example 78,45
microcrystalline cellulose112
Lactose70
Sodium salt of starch glycolate8
magnesium stearate2

Example 25

Injectable parenteral composition

The injectable form of the introduction of the compounds of Example 7 is obtained by mixing 5.0 mg compound in 1.0 ml of normal saline.

Test example

Analysis of solubility

<> In accordance with the generally accepted method of determining the solubility tested the solubility of the compounds of the Examples and their salts in three different systems: water, 0.1% of hydrochloric acid and methanol.

Solubility characterized as described below:

The term "very soluble" means that 1 g (ml) of solute can dissolve less than 1 ml of solvent;

The term "freely soluble" means that 1 g (ml) of solute can be dissolved in the solvent is from 1 ml to 10 ml, not including 10 ml of solvent;

The term "soluble" means that 1 g (ml) of solute can be dissolved in the solvent is from 10 ml to 30 ml, not including 30 ml solvent;

The term "sparingly soluble" means that 1 g (ml) of solute can be dissolved in the solvent of 30 ml to 100 ml, not including 100 ml of solvent;

The term "partially soluble" means that 1 g (ml) of solute can be dissolved in the solvent from 100 ml to 1000 ml, not including 1000 ml of solvent;

The term "very low" means that 1 g (ml) of solute can be dissolved in the solvent from 1000 ml to 10,000 ml, not including 10000 ml solvent;

The term "practically insoluble or insoluble" means that 1 g (ml) of a dissolved substance now is should dissolve completely in 10,000 ml of solvent.

The results of solubility is presented below:

Example No.Solubility (mg/ml)
0.1% of hydrochloric acidwatermethanol
1J<0,001<0,001<0,001
1<0,0010,0031,469
3<0,0012,2901,534
4h<0,001<0,001<0,001
40,0242,90519,001
6<0,001<0,0013,009
7d<0,001<0,001<0,001
70,0293,960 22,377
8<0,0015,0494,595
9<0,0019,97419,331
10<0,0013,7153,417
11<0,0013,0033,617
12<0,0015,94518,823
13<0,001<0,00115,432
14<0,0011,8763,722
15<0,001to 0.6453,023
16a<0,001<0,001<0,001
17<0,0012,0005,849
18<0,0012,7416,096
19d<0,001<0,001<0,001
20<0,0010,0682,221
21<0,0010,8142,416
23<0,0010,28622,597

This result showed that, compared with the compound of Example 1j, Example 4h, 7d, Example 16 and Example 19d solubility of their salts significantly increased, especially in water and in methanol. Specifically, a salt of Example 4 and Example 7 had a relatively better solubility in 0.1% hydrochloric acid, and two salts were very low, while others were practically insoluble or insoluble.

The structure of the compounds of Example 1j, Example 4h, 7d, Example 16 and Example 19d shown below:

Example No.StructureName
1j(Z)-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydropyrazol-4-ilidene)-hydrazino]-diphenyl-3-carboxylic acid 1j
4h(Z)-5-(3-{N'-[1-(3,3-dimethyl-indan-5-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene]-hydrazino}-2-hydroxyphenyl)-furan-2-carboxylic acid
7d(Z)-5-(2-hydroxy-3-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydropyrazol-4-ilidene]-hydrazino}-phenyl)-furan-2-carboxylic acid
16a(Z)-5-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-furan-2-carboxylic acid
19d(Z)-4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ilidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid

Analysis of hygroscopicity

Test hygroscopic compounds of the present invention after standing for 48 hours Protocol:

1. Dry glass vessel for vzveshival the I tube (outer diameter 50 mm, height 15 mm) appropriately placed at 25°C±1°C in temperature-controlled dryer (saturated solution of ammonium sulfate was poured into the lower part, the humidity was 79%) the day before analysis, the exact mass was measured as (m1);

2. The above vessel for weighing covered by the compounds according to the invention (approximately 1 g), and the thickness of the compounds usually was 1 mm, the exact mass was measured as (m2);

3. The neck of the vessel for weighing kept open and placed the tube in the above described conditions at a constant temperature and humidity for 48 hours;

4. Put the stopper back on the vessel, the exact mass was measured as (m3)

The percentage increase in mass =m3-m2m2-m1

The degree of hygroscopicity was determined as described below:

Dissolution: the conversion into a liquid by absorbing sufficient moisture.

High hygroscopicity: the percentage increase of mass due to the hygroscopicity is not less than 15%.

Hygroscopicity: the percentage increase of mass due to the hygroscopicity of less than 15%, but not less than 2%.

Moderate hygroscopicity: the percentage of expansion of the mass due to the hygroscopicity of less than 2%, but not less than 0.2%.

No hygroscopicity or almost no hygroscopic: the percentage increase of mass due to the hygroscopicity is less than 0.2%.

The results of hygroscopicity of the compounds of the present invention are presented below:

Example No.The percentage increase in massHygroscopicity
71,2%Moderate hygroscopicity
813,9%Hygroscopicity
1015,7%High hygroscopicity
122,71%Hygroscopicity
238,48%Hygroscopicity

These results showed that, compared with other salts salt of Example 7, i.e. salt of bis-(ethanolamine) compounds 7d, less hygroscopic and has better stability in a wet environment, which can help to avoid potential problems changing the mass of the active ingredients during the preparation of capsules, or that the notches, resistant to gas and suitable for receiving conventional medication, and can be stored for a long period of time.

BIOLOGICAL ANALYSIS

Test Example 1: Effect of proliferation of a series of compounds TPO cells BAF3-TPOR

1. Material and reagents

a) RPM11640 Medium, powder, 10*1 l containing HEPES (Gibco, catalog No. 23400021).

b) Fetal bovine serum (Gibco, catalog No. 10099-141).

c) a SOLUTION of PENICILLIN AND STREPTOMYCIN (Gibco, catalog No. 15140-122).

d) Geneticin (G418) (Gibco, catalog No. 11811-098).

(e) Recombinant IL-3 mouse (Chemicon, catalog No. IL015).

f) R Mab to thrombopoetin (TPO) person (R&D, No. MAV).

g) DMSO, (AppliChem, catalog No. A).

h) Set for multiple site-directed mutagenesis QuikChange®, 10 reactions (Stratagene ST200515).

i) a Set of 8 for counting cells (Dojindo, catalog No. SC-13)

j) BaF3 Cells (joint center for cell cultures, catalog No. 0095)

k) EX-EGFP-M02 (FulenGen, catalog No. EX - EGFP-M02 Control)

l) EX-B0010-M02 (FulenGen, catalog No. EX V-m)

2. The process:

(1) Plasmid construction: based on the information sequence of the TPO receptor (TPOR) from Entrez Gene ID: 4325, Refseq: NM_005373) double point mutation was carried out in a plasmid EX-B0010-M02 through the use of the kit for multiple site-directed mutagenesis QuikChange® (Stratagene). Were developed sequences of primers provided the multiple point mutations:

g491a: 5'-gggaacttcagatcagctgggaggagccg-3'

g491a_antisense: 5'-cggctcctcccagctgatctgaagttccc-3';

c965t: 5'-caggaccatgctagctcccaaggcttcttct-3',

c965t_antisense: 5'-agaagaagccttgggagctagcatggtcctg-3'.

Competent cells of E. coli DH5α transformed the mutated plasmid and positive colonies were collected through selection on ampicillin. The mutation was confirmed by sequence analysis.

(2) Stable transfusiona cell line BAF3-TPOR:

following the method used for construction of BaF3 cells, which stably has hyperexpression TPOR person. Successfully mutated plasmid EX-B0010-M02 (25 mcg), which is expressed TPOR human gene and the neomycin for screening, transfusional in BaF3 cells wild type (1×107) by electroporation at 250 V for 18 MS, using electropulsing (Electro Square Porator ECM, WITH Division of Genetronic, Inc. US). Stable transfetsirovannyh cells BAF3-TPOR were selected by G418 (Gibco, US), then incubated in RPMI1640 medium with addition of 10% FBS (Gibco, US), 800 ng/ml of G418, 5 ng/ml rmlL-3 (Chemicon, US).

3. Screening compounds

(1) Wash the cells by centrifugation: an appropriate amount of cell suspension was centrifuged at 1000 rpm for 5 minutes and supernatant was discarded. Added 10 ml of medium for cell culture without IL-3. Then the resulting cell suspension was centrifuged at 1000 rpm for 5 minutes and the supernatant Ambra ivali.

(2) was Added 1 ml of medium for cell culture without IL-3 to split the cells to homogeneity, and after dilution counted the number of cells in an appropriate amount of cell suspension.

(3) In accordance with the result of counting of cells was prepared cell suspension at a concentration of 100,000 cells/ml

(4) 100 μl of cell suspension was transferred into each well of 96-well culture tablet and put 3 parallel wells, that is, a blank control group (C), negative control group (N), positive control group TPO (R) and the test compound (S).

(5) the Test compound was dissolved in DMSO to obtain a 10 mm initial solution, and then this solution was diluted with RPMI medium 1640 with obtaining a series of test samples at different concentrations: 30 μm, 10 μm, 3 μm, 1 μm, 0.3 μm, 0.1 ám, 0.03 µm, 0.01 µm, of 0.003 μm to 0.001 μm.

(6) 10 μl of a solution of test compound was transferred into each well, respectively; 1 μl gptre (10 μg/ml) was added to positive control wells.

(7) the plates were incubated in an incubator with 5% CO2and 37°C for 24 hours.

(8) After incubation each well was added 10 μl of a solution of CCK-8 and the plates were incubated in the incubator for another 24 hours.

(9) was Determined by the OD value at 450 nm using a reader for tablets VICTOR3 (Perkin Elmer 1420-120).

4. Analysis the definition of calculation

(1) the Rate of proliferation was calculated as follows:

Speed = [(S-B)/ (R-In)] * 100%

S: the Value of OD of the wells that contain test the connection.

In: the OD Value of blank control wells

R: the OD Value of the positive control wells

(2) the Value of the EU50was calculated using the software Origin 7.0. 5. The results:

EU50activity TPO compounds of the present invention

ExampleEU50(nm)
Eltrombopag299
1j200
1150
4h32
425
519
636
7d21
719
84,4
914
1016
1121
1214
1320
1419
1516
16a100
1618
1755
1829
19d43
1937
2051
21116
22f42
2239
2343

The results of this study showed that, compared with the free acid salts of the present invention have a stronger proproliferative effects on cells BAF3-TPOR. The procedure was as follows: salts of the present invention > free acid > Eltrombopag, and the activity of the salts according to the present izobreteny what was more, than the activity Eltrombopag.

PHARMACOKINETIC ANALYSIS

Test Example 1: Pharmacokinetic analysis of the compounds of the present invention in rats

1.Purpose

Compounds of the present invention was administered intragastrically to rats to determine the concentration of drug in plasma at different time points by HPLC-UV. Pharmacokinetic properties of the compounds of the present invention researched and evaluated in rats.

2. Protocol

2.1. Samples

The compound of Example 1j, Example 1-3, Example 4h, Example 4, Example 5, Example 6, Example 7d, Example 7-15, Example 16, Example 16-18, Example 19d, Example 19, Example 20, Example 21, Example 22f, Example 22 and Example 23.

2.2. Experimental animals

Healthy adult SD rats, half male and half female, were purchased from S1NO-BRITSH SIPPR/BK LAB.ANIMAL LTD., CO, license number: SCXK (Shanghai) 2003-0002.

2.3. The device

High-performance liquid chromatograph Waters 2695-2996, Waters Corp., USA.

2.4. Getting tested compounds

The test compound was diluted with 1% sodium salt of carboxymethyl cellulose to 5 mg/ml (in terms of free acid) suspension before use.

2.5. Introduction

Healthy adult SD rats, half male and half female, were divided into 23 groups. After fasting during the night the rats were injected connection intragastrically at a dose of 50.0 mg/kg (pereras is the free acid) in a volume of 10 ml/kg

2.6. Sampling

Blood samples (0.2 ml) was taken from the sockets before the introduction and after 0,5,1,0, 2,0, 3,0, 4,0, 5,0, 6,0, 8,0, 11,0, 14,0, 24,0, 36,0 and 48.0 hours after administration, and kept them in heparinised tubes and centrifuged for 10 minutes at 3500 rpm plasma Samples were stored at -20°C until analysis. Rats fed 2 hours after injection.

2.7. Analytical methods

50 μl of plasma of rats, obtained at different time points after injection, 50 μl of internal standard solution and 20 ml of solvent mixture of methanol and water (80:20, V/V) was well mixed, and then added 100 μl of methanol, which has resulted in the precipitation of protein. Then the mixture was stirred for 3 minutes using a vortex, and centrifuged for 10 minutes at 13500 rpm 40 μl of the supernatant was analyzed using HPLC-UV.

2.8. Calculation of pharmacokinetic parameters

Chamber pharmacokinetic model was aligned with the tested compounds and to calculate the basic pharmacokinetic parameters, where Cmaxand tmaxwere actually measured values.

3. Results pharmacokinetic parameters

Pharmacokinetic parameters of the compounds of the present invention are presented below:

10,5±1,18
Room Pharmacokinetic analysis (50 mg/kg)
Plasma concentrationTime to peakThe area under the curveThe half-lifeAverage duration of stayClearanceThe apparent volume of distribution
Cmax(ág/ml)Tmax(h)AUC (μg/ml*h)t1/2(h)MRT (h)CL/F (l/h/kg)Vz/F (l/kg)
Eltrombopag61,8±18,75,5±1,0680±255of 7.82±1,3411,2±2,60,089±0,0520,95±0,42
1J29,05±11,444,00±1,41131±474,21±1,863,89±1,780,049±0,0350,29±0,18
190,1±35,33,25±1,5501±178 5,39±0,944,96±1,160,098±0,0720,45±0,32
283,9±11,25,0±1,16833±64of 9.55±1,4411,08±0,760,06±0,0050,83±0,16
379±9,35,5±1,0842±1858,87±0,7813,0±0,90,062±0,0130,78±0,15
4h1,29±0,382,5±1,09,5±8,319,8±16,431,7±24,63,26±1,93of 83.4±54,8
42,32±1,802,25±2,4719,0±12,627,0±31,538,3±36,52,42±1,6058,1±47,7
519,8±3,83,25±1,5255±9515,0 who 6,2 20,8±9,10,22±0,07to 4.23±0,42
613,0±6,52,5±1,0175±4145,0±70,360,4±90,20,30±0,08416,0±22,8
7d16,2±3,92,5±1,0132±1247,42±7,1911,0±8,138,14±8,4436,1±17,9
774,1±34,51,75±0,5469±27413,9±6,0713,3±5,120,175±0,1692,48±0,92
836,2±46,21,38±1,11352±58610,6±9,0212,1±8,230,926±1,0138,55±remaining 9.08
921,2±10,42,88±2,59146±69,79,65±2,480,391±0,1455,15±1,46
1065,6±44,51,63±0,75381±30612,9±6,3211,5±5,720,494±0,7544,54±4,17
1140,2±24,31,5±0,58270±17812,1±7,1910,0±3,900,877±1,4655,80±5,30
1217,8±10,31,38±1,1158,5±23,85,1±2,41by 5.87±1,681,00±0,5046,35±1,38
138,10±3,351,38±1,1142,8±33,25,70±2,508,05±2,011,63±0,8314,9±12,1
1417,8±22,6the 5.25±1,5132±1894,72±2,82 7,20±2,132,40±2,419,54±8,03
1523,3±13,62,0±1,16168±1186,56±3,80of 8.92±2,040,758±0,995the 3.65±1,79
16Afor 6.81±6,232,75±0,9615,0±17,21,82±0,684,03±2,552,98±2,7511,5±7,5
1619,6±16,32,00±0,8252,4±48,02,08±1,743,84±1,031,94±0,646,33±4,57
1721,5±10,53,38±3.04 from138±3312,7±14,714,0±12,00,38±0,0938,16±11,09
1823,3±11,61,63±1,63119±1023,99±1,60 5,31±2,640,63±0,353,02±1,01
19dto $ 7.91±6,842,50±0,5836,1±36,41,84±1,053,01±1,991,44±0,8310,4±8,4
1920,8±17,31,81±2,79of 89.2±7,25,71±3,68the 7.85±2,920,88±0,615,47±2,72
2046,1±15,74,5±1,0275±1167,24±2,45to 7.59±1,330,21±0,0882,05±0,68
2161,1±1,385,5±1,0380±1096,86±0,488,61±0,310,14±0,041,37±0,32
22f8,73±2,584,25±1,26151±97of 9.21±1,57 11,8±4,50,69±0,558,49±2,16
2239,8±18,25,0±2,0603±2409,95±0,6014,8±1,00,24±0,113,41±1,75
2317,2±12,33,25±3,18123±89,5to 7.61±1,3411,7±1,150,527±0,245,52v2,18

The results showed that after the introduction of rats compared with the free acid pharmacokinetics and bioavailability of salts of the present invention is markedly improved. Pharmacokinetic data salt of Example 7, i.e. salts of bis-(monoethanolamine) of Example 7d, are the best and she has good pharmacokinetic properties.

Test Example 2: Pharmacokinetic analysis of the compounds of the present invention dogs breed Beagle

1. Purpose

Compounds of Example 7, Example 8, Example 10 and Example 12 was administered intragastrically to breed Beagle to determine the concentration of drug in plasma at different time points by HPLC-UV. Pharmacokinetic properties connect the developments of the present invention researched and evaluated on the breed Beagle.

2. Protocol

2.1. Samples

Compounds of Example 7, Example 8, Example 10 and Example 12.

2.2. Experimental animals

12 healthy adult dogs of the breed Beagle, male, bought from Suzhou Xishan Drug Research and Development CO., LTD. License number: SCXK(Suzhou)2007-0005.

2.3. The device

High-performance liquid chromatograph Agilent 1100, Agilent Corp., USA.

2.4. Getting tested compounds

The test compound was dissolved in 0.5% sodium salt of carboxymethyl cellulose to 2.5 mg/ml (in terms of free acid) suspension before use.

2.5. Introduction

12 healthy adult dogs of the breed Beagle, males were divided into 4 groups. After fasting during the night the dogs were injected compounds intragastrically at a dose of 5.0 mg/kg (in terms of free acid) in a volume of 2 ml/kg

2.6. Sampling

Blood samples (1.2 ml) was taken from the veins of the fore limbs before the introduction and after 0,25, 0,5, 1,0, 1,5, 2,0, 3,0, 5,0, 6,0, 8,0, 12,0, 14,0, 24,0 and 48.0 hours after administration, and kept them in heparinised tubes and centrifuged for 10 minutes at 3500 rpm plasma Samples were stored at -20°C until analysis. The Beagle dogs were fed 2 hours after injection.

2.7. Analytical methods

50 μl of plasma of Beagle dogs, obtained at different time points after injection, 20 μl of internal standard solution and 150 μl of methanol was added to result in about the Adenau proteins. Then the mixture was stirred for 1 minute using a vortex, and centrifuged for 5 minutes at 11000 rpm 50 μl of the supernatant was analyzed using HPLC-UV.

2.8. Calculation of pharmacokinetic parameters

Chamber pharmacokinetic model was aligned with the tested compounds and to calculate the basic pharmacokinetic parameters, where Cmaxand tmaxwere actually measured values.

Data of four salts in the present study showed that the compound of Example 7 was significantly better in relation to pharmacokinetics.

In conclusion, obtaining the compounds of the present invention was simple and gave good yield. Specifically, ethanolamine salt, a salt of choline, salts diethylamine and salts of piperazine had the advantage of the method of synthesis, because they can crystallize directly. Compared with the free acid solubility of the salts of the present invention is markedly improved in the conventional solvents. Salt ethanolamine were less hygroscopic and were suitable for receiving conventional medication, and easily stored. The biological activity of the salts of the present invention is markedly improved. Pharmacokinetics also significantly improved in rats and Beagle dogs, and these salts had the best headlight is cokinetics properties especially ethanolamine salt.

1. Pharmaceutically acceptable salts of the compounds of formula (I):

where:
Het is selected from the group consisting of phenyl, purile and tanila;
R1, R2, R3and R4each independently selected from the group consisting of hydrogen and alkyl;
n is 0, 1 or 2;
where salt is selected from the group consisting of salts of sodium, lithium salts, potassium salts, calcium salts, magnesium salts, arginine salt, lysine salt, salt methanamine, dimethylamine salt, salts of trimethylamine, salt, ethylamine salt diethylamine, salts of triethylamine, ethanolamine salt, piperazine salt, salt dibenziletilendiaminom, salt meglumine, tromethamine salts, Quaternary salts of Tetramethylammonium, Quaternary salts of tetraethylammonium and salts of choline.

2. Pharmaceutically acceptable salts under item 1, where the salt is selected from the group consisting of salts of diethylamine, ethanolamine salt, salt, choline chloride, salt, piperazine salt of meglumine and tromethamine salts.

3. Pharmaceutically acceptable salts under item 1, where the salt is selected from the group consisting of ethanolamine salt, a salt of choline, salts meglumine and tromethamine salts.

4. Pharmaceutically acceptable salts under item 1, where the salt is a salt of ethanolamine.

5. Pharmaceutically acceptable salts under item 1, where the salt is selected from the group consisting of:







.

6. The way to obtain pharmaceutically acceptable salts according to any one of paragraphs.1-5, comprising the following stages:
(a) the dissolution or suspension of the compounds of formula (I) in an organic solvent, where the organic solvent is selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and tetrahydrofuran;
(b) adding to the mixture of the base with stirring;
(c) obtaining the pharmaceutically acceptable salts of the compounds of formula (I),
where the base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lysine, arginine, methanamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenziletilendiaminom, meglumine, tromethamine, Quaternary of Tetramethylammonium, the Quaternary of tetraethylammonium and choline hydroxide.

7. The method according to p. 6, where the specified organic solvent represents tetrahydrofuran.

8. The method according to p. 6, where the base is selected from the group consisting of diethylamine, ethanolamine, piperazine, meglumine, tromethamine and choline hydroxide.

9. The method according to p. 6, where the base is selected from the group consisting of ethanolamine, meglumine, tromethamine and choline hydroxide.

10. The method according to p. 6, where the base is an ethanolamine.

11. The method according to p. 6, where the ratio of equivalents of the compounds of formula (I) and the base is 1:5~5:1.

12. The method according to p. 6, where the ratio of equivalents of the compounds of formula (I) and the base is 1:1~1:3.

13. The method according to p. 6, where the ratio of equivalents of the compounds of formula (I) and the base is 1:1~1:2.

14. Pharmaceutical composition for treating thrombocytopenia, containing a therapeutically effective amount of pharmaceutically acceptable salts under item 1 and pharmaceutically acceptable carriers or diluents.

15. The method of obtaining the composition according to p. 14, including the state of the Union connection on p. 1 with pharmaceutically acceptable carriers or diluents.

16. The use of pharmaceutically acceptable salts of the compounds of formula (I) under item 1 for agonist thrombopoetin receptor.

17. The use of pharmaceutically acceptable salts of the compounds of formula (I) under item 1 to obtain drugs for the treatment of thrombocytopenia.

18. Application under item 17, where the drug is in the form of oral dosage forms.

19. Application under item 17, where the drug is in the form of parenteral dosage forms.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinoxaline derivatives of general formula

,

a based pharmaceutical composition, using them as therapeutic agents, as well as to a based therapeutic agent for treating tumour diseases. In general formula I X represents: oxygen or sulphur; R1 represents hydrogen, R2/R3 represents hydrogen, R4 represents: (i) C1-C12-alkyl, (ii) saturated C3-C8-cycloalkyl, optionally substituted by C6-aryl, (iii) unsaturated C3-C8-cycloalkyl, (iv) heterocyclyl substituted by C(O)CF3, (v) C1-C6-alkyl substituted by C6-aryl, the above C6-aryl can be substituted by F, Cl, Br, I, -O-C1-C6-alkyl, C1-C6-alkyl, C6-aryl or hydroxy, (vi) C1-C6-alkyl substituted by C5-heteroaryl, (vii) C1-C8-alkylene, (viii) 1-adamantyl, (ix) C1-C6-alkyl substituted by C6-heterocyclyl containing a nitrogen atom and an oxygen atom, (x) C1-C6-alkyl substituted by C3-C6-cycloalkyl, or (xi) C1-C6-alkyl substituted by C6-heteroaryl; R5 represents hydrogen, R6 represents (i) aryl optionally substituted by C1-C6-alkyl, -O-C1-C6-alkyl, hydroxy, F, Cl, Br, I or amino, or (ii) C5-heteroaryl containing 2 nitrogen atoms optionally substituted by C1-C6-alkyl, R7 and R8 represent hydrogen.

EFFECT: producing the therapeutic agent for treating the tumour diseases.

7 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to a compound of Formula

,

where Y represents a group of formula -(CR9R10)-; X is selected from the group, consisting of -C(=O)-, -OC(=O)-, -NHC(=O)-, -(CR11R12)- and -S(-O)2-; Z represents a group of formula -(CR13R14)q-; R1 is selected from the group, consisting of C1-C12alkyl, optionally substituted with one substituent, selected from naphthyl, indole and biphenyl; C2-C12alkenyl, substituted with a substituent, selected from thienyl, naphthyl and phenyl, with the said phenyl being optionally substituted with 1-2 substituents; selected from halogen, trifluoroalkyl, C1-C6alkyl, methoxy and hydroxy; C3-C6cycloalkyl; C6-C10aryl, optionally substituted with 1-2 substituents, selected from halogen, phenyl, amino, phenoxy, C1-C6alkyl, methoxy, hydroxyl and carboxy; and C4-C9heteroaryl, selected from indole, quinoline, quinoxaline, benzofuranyl, benzothiophene, benzimidazole, benzotriazole, benzodioxin, benzothiasole, pyrazole, furyl and isoxazole, optionally substituted with a substituent, selected from C1-C6alkyl and phenyl; R2 and R3 each is independently selected from the group, consisting of H and C1-C12alkyl; R4a is selected from the group, consisting of H, C1-C12alkyl, optionally substituted with phenyl; C2-C12alkenyl, C3-C6cycloalkyl, C6aryl, C(=O)R15, C(=O)NR15R16, C(=O)OR15, SO2R15 and -C(=NR15)-NR16R17; R4d represents hydrogen or R4a and R4b, taken together with a nitrogen atom, which they are bound to, form an optionally substituted heterocyclic fragment, selected from piperidine, morpholine, pyrrolidine and azetidine, where the substituent is selected from C1-C12alkyl, hydroxy, halogen, carboxy and oxo; each R5a and R5b represents H, or R6, R7 and R8 each is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6-C10aryl, optionally substituted with halogen, or taken together with a carbon atom, which they are bound to, two or more of R6, R7 and R8 form a fragment, selected from the group, consisting of C2-C12alkenyl; C3-C6cycloalkyl, optionally substituted with C1-C6alkyl; C6aryl, optionally substituted with 2 substituents, selected from halogen; each R9 and R10 represents H or C1-C12alkyl, substituted with naphthyl; each R11 and R12 represents H; R13 and R14 represent H, or each R15, R16 and R17 is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6aryl, substituted with one substituent, selected from C1-C6alkyl; and C5-heteroaryl, additionally containing one nitrogen atom, with the said heteroaryl representing pyridyl; q represents an integer number, selected from the group, consisting of 2, 3 and 4; r represents 1; or its pharmaceutically acceptable salt. The invention also relates to particular compounds of 1,4-diazepan-2-one derivatives.

EFFECT: obtaining 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists.

21 cl, 7 tbl, 110 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel derivative of N-acylanthranilic acid, represented by the following general formula 1, or to its pharmaceutically acceptable salt, in which R1, R2, R3, X1, X2, X3, X4 and A are determined in the invention formula.

EFFECT: invention relates to an inhibitor of collagen production, a medication for treating diseases, associated with the excessive production of collagen, containing N-acylanthranilic acid derivative Formula 1.

FIELD: chemistry.

SUBSTANCE: invention relates to a photoinitiator, a method for production and use thereof and a coating composition. The photoinitiator is a compound of formula: (PI-Sp)n-BB (I), where PI is a thioxanthone group, optionally including additional substitutes in the Sp group; Sp is a spacer link selected from a group consisting of or , BB is a backbone chain link selected from a group consisting of

The method of producing the photoinitiator includes the following steps: (a) optionally substituted thioxanthone, containing at least one hydroxy group, reacts with epichlorohydrin or haloacetic acid ester; (b) the compound from step (a) reacts with the corresponding backbone chain link containing a functional group, or the compound from step (a) reacts with a compound containing a functional group, and the obtained intermediate then reacts with the corresponding backbone chain link; optionally (c) obtaining derivatives of the compounds from step (b). The photoinitiator is used to cure a coating composition, preferably printing ink containing a polymerisable component.

EFFECT: invention enables to obtain a photoinitiator with good curing activity, faint odour and good compatibility with other components of the composition.

10 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

,

wherein: each of R1, R2, R4, R5, R6, R7, R8 R9, R10, R11, R12, R13, R14, R15 R16 and R17 is independently specified in a group consisting of deuterium or hydrogen; and R3 is independently specified in a group consisting of CD3 and CH3; provided R3 represents CH3, at least one of the groups R1, R2, R4, R5, R6, R7, R8 R9, R10, R11, R12, R13, R14, R15 R16 and R17 represents deuterium; and R18 represents hydrogen. The invention also refers to a drug on the basis of the above compound for treating a condition causing pain.

EFFECT: there are prepared new compounds inhibiting MMPs (metalloproteinases) which show the high activity, metabolic stability and/or lower toxicity in relation to the currently known MMP inhibitors for treating pain and other diseases, such as cancer.

16 cl, 2 dwg, 14 tbl, 136 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 6-substituted isoquinoline and isoquinolinone derivatives of formula or to its stereoisomer and/or tautomer forms and/or a pharmaceutically acceptable salt, wherein R1 represents H, OH or NH2; R3 represents H; R4 represents H, a halogen atom, CN or (C1-C6)alkylene-(C6-C10)aryl; R5 represents H, a halogen atom, (C1-C6)alkyl; R7 represents H, a halogen atom, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 represents H; R9 and R6 are absent; R10 represents (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C6)hetrocycloalkyl, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C6)heterocycloalkyl; R11 represents H; R12 represents (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5)heteroaryl or (C6-C10)aryl; R13 and R14 independently represent H, (C1-C6)alkyl, (C1-C6)alkylene-R'; n is equal to 0; m is equal to 2 or 3; s is equal to 1 or 2; r is equal to 1; L represents O or NH; R' represents (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more OCH3; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms; wherein (C1-C8)heteroaryl group means (C1-C8)alkyl groups, wherein at least one carbon atom is substituted by O;. (C6)heterocycloalkyl group means a monocyclic carbon ring system containing 6 ring atoms wherein one carbon atom can be substituted by 1 oxygen atom or 1 sulphur atom which can be optionally oxidated; (C5)heteroaryl means a monoring system wherein one or more carbon atoms can be substituted by 1 nitrogen atom or 1 sulphur atom or a combination of various heteroatoms. Also, the invention refers to using the compound of formula (I) and to a therapeutic agent based on the compound of formula (I).

EFFECT: there are prepared new compounds effective for treating and/or preventing diseases associated with Rho-kinase and/or mediated by Rho-kinase by phosphorylation of myosin light chain phosphatase, and the compositions containing these compounds.

32 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula or to its therapeutically acceptable salt, where A1 represents N or C(A2); A2 represents H; B1 represents H, OR1 or NHR1; D1 represents H; E1 represents H; Y1 represents CN, NO2, F, Cl, Br, I, R17 or SO2R17; R1 represents R4 or R5; Z1 represents R26 or R27; Z2 represents R30; Z1A and Z2A both are absent; L1 represents R37; R26 represents phenylene; R27 represents indolyl; R30 represents piperasinyl; R37 represents R37A; R37A represents C2-C4 alkylene; Z3 represents R38, R39 or R40; R38 represents phenyl; R39 represents benzodioxilyl; R40 represents C4-C7cycloalkenyl, heterocycloalkyl, which represents monocyclic six- or seven-member ring, containing one heteroatom, selected from O, and zero of double bonds, or azaspiro[5.5]undec-8-ene; the remaining values of radicals are given in i.1 of invention formula. Invention also relates to pharmaceutical composition, based on claimed compound.

EFFECT: novel compounds, which can be applied in medicine for treatment of diseases, in the process of which anti-apoptotic Bcl-2 protein is expressed, are obtained.

8 cl, 2 tbl, 411 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula

,

where values A, R1-R6 are given in i.1 of the invention formula. Methods of obtaining the formula (I) compound are described.

EFFECT: compounds demonstrate an inhibiting activity of the cathepsin enzyme, which makes it possible to use them for the preparation of a pharmaceutical composition and for the preparation of a medication.

38 cl, 12 dwg, 495 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new macrocyclic compounds of formula

or their tautomer, pharmaceutically acceptable salt, solvate or ester, wherein: X represents O or NR; Y represents -O-(CH2)mCOOR or -O-(CH2)mCON(R)2, wherein groups related to a nitrogen atom, can be in a Z- or E-configuration; R1 and R2 independently represent hydrogen or halogen; R3, R4, R5, R6, R7, R8, R9 and R10 independently represent hydrogen, alkyl, OR, -O(CH2)mC(O)(CH2)pN(R)2, -O(CH2)mN(R)C(O)(CH2)pOR, -(CH2)mN3 or -O(CH2)mN3; and each R independently represents R11, hydrogen, alkyl, alkylamino, dialkylamino, alkoxycarbonyl, phenyl or a protective group; or two R on the same nitrogen are taken together with nitrogen for producing a 5-6-merous heterocyclic or heteroaryl ring; wherein the group contains more than one substitute R; wherein R is optionally substituted, and each R can be identical or different, and wherein the protective group is specified in ethoxymethyl, methoxymethyl, tert-butyldimethylsilyl (TBS), phenylmethylsilyl, trimethylsilyl (TMS), 2-trimethylsilyl ethoxymethyl (SEM), 2-trimethylsilylethyl, benzyl and substituted benzyl; R11 represents a group

,

wherein Z represents an inorganic or organic counter-ion specified in a halogen, -O-alkyl, toluene sulphonate, methylsulphonate, sulphonate, phosphate, formiate or carboxylate; n represents 0, 1 or 2; m and p independently represent 0, 1 or 2; and dashed lines mean either a single, or a double bond, wherein the necessary conditions of the valence are observed by additional hydrogen atoms; and wherein in formula I′, when n represents 1, and X represents O, and the double bond is present between the carbon atoms having R9 and R10, then at least one of R5, R6, R7, R8, R9 or R10 are other than hydrogen; and wherein in formula I′, when n represents 1, and X represents O, and the bond between the carbon atoms having R9 and R10, represents the single bond, then at least one of R5, R6, R7 or R8 is other than hydrogen. The invention also refers to pharmaceutical compositions containing these compounds, using them and methods of treating diseases mediated by kinases and a heat-shock protein 90 HSP90.

EFFECT: preparing the new macrocyclic compounds.

28 cl, 5 dwg, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention refers to new phenoxymethyl compounds of formula (I) or its pharmaceutically acceptable salts, wherein: HET represents a heterocyclic ring having formula A29 or A31, wherein the far left part is connected to the group X of formula (I); X represents substituted phenyl or optionally substituted pyridinyl, wherein the substitutes are specified in C1-C4alkoxy and cyano; Z represents imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl or imidazo[1,2-b]pyridazin-6-yl each of which can be substituted, wherein the substitutes are specified in C1-C4alkyl and a halogen atom; and each R2 are independently specified in C1-C4 alkyl inhibiting at least one phosphodiesterase 10, as well as to pharmaceutical compositions containing these compounds, and methods of treating various CNS disorders.

EFFECT: preparing the new compounds.

23 cl, 2 tbl, 732 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to a compound of Formula

,

where Y represents a group of formula -(CR9R10)-; X is selected from the group, consisting of -C(=O)-, -OC(=O)-, -NHC(=O)-, -(CR11R12)- and -S(-O)2-; Z represents a group of formula -(CR13R14)q-; R1 is selected from the group, consisting of C1-C12alkyl, optionally substituted with one substituent, selected from naphthyl, indole and biphenyl; C2-C12alkenyl, substituted with a substituent, selected from thienyl, naphthyl and phenyl, with the said phenyl being optionally substituted with 1-2 substituents; selected from halogen, trifluoroalkyl, C1-C6alkyl, methoxy and hydroxy; C3-C6cycloalkyl; C6-C10aryl, optionally substituted with 1-2 substituents, selected from halogen, phenyl, amino, phenoxy, C1-C6alkyl, methoxy, hydroxyl and carboxy; and C4-C9heteroaryl, selected from indole, quinoline, quinoxaline, benzofuranyl, benzothiophene, benzimidazole, benzotriazole, benzodioxin, benzothiasole, pyrazole, furyl and isoxazole, optionally substituted with a substituent, selected from C1-C6alkyl and phenyl; R2 and R3 each is independently selected from the group, consisting of H and C1-C12alkyl; R4a is selected from the group, consisting of H, C1-C12alkyl, optionally substituted with phenyl; C2-C12alkenyl, C3-C6cycloalkyl, C6aryl, C(=O)R15, C(=O)NR15R16, C(=O)OR15, SO2R15 and -C(=NR15)-NR16R17; R4d represents hydrogen or R4a and R4b, taken together with a nitrogen atom, which they are bound to, form an optionally substituted heterocyclic fragment, selected from piperidine, morpholine, pyrrolidine and azetidine, where the substituent is selected from C1-C12alkyl, hydroxy, halogen, carboxy and oxo; each R5a and R5b represents H, or R6, R7 and R8 each is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6-C10aryl, optionally substituted with halogen, or taken together with a carbon atom, which they are bound to, two or more of R6, R7 and R8 form a fragment, selected from the group, consisting of C2-C12alkenyl; C3-C6cycloalkyl, optionally substituted with C1-C6alkyl; C6aryl, optionally substituted with 2 substituents, selected from halogen; each R9 and R10 represents H or C1-C12alkyl, substituted with naphthyl; each R11 and R12 represents H; R13 and R14 represent H, or each R15, R16 and R17 is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6aryl, substituted with one substituent, selected from C1-C6alkyl; and C5-heteroaryl, additionally containing one nitrogen atom, with the said heteroaryl representing pyridyl; q represents an integer number, selected from the group, consisting of 2, 3 and 4; r represents 1; or its pharmaceutically acceptable salt. The invention also relates to particular compounds of 1,4-diazepan-2-one derivatives.

EFFECT: obtaining 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists.

21 cl, 7 tbl, 110 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formula A1 stands for CR10R11 or S; A2 stands for CR12R13, C(=O), O, S or S(=O)2; R1 stands for C1-10-alkyl, saturated or unsaturated, branched or non-branched, non-substituted, or monosubstituted, or polysubstituted; C3-10-cycloalkyl or 5- or 6-membered heterocyclyl with the O-atom, each time saturated or unsaturated, non-substituted, or monosubstituted, or polysubstituted; C6-10-aryl or C5-10-heteroaryl with 1-3 heteroatoms, selected from N, O or S, each time non-substituted, or monosubstituted, or polysubstituted; through C1-8-alkyl or C2-8-heteroalkyl bound by the bridge bond C3-10-cycloalkyl, each time saturated, non-substituted, and the alkyl or heteroalkyl chain each time can be branched or non-branched, saturated, non-substituted; or through C1-8-alkyl, bound by the bridge bond aryl or heteroaryl, each time non-substituted, or monosubstituted, or polysubstituted, and the alkyl chain each time can be branched or non-branched, saturated or unsaturated, non-substituted, or monosubstituted, or polysubstituted; R2, R3 and R4 each time independently on each other stand for H; F; Cl; Br; I; methyl; O-C1-6-alkyl or NRaRb, and Ra and Rb together with the nitrogen atom that binds them form heterocyclyl, saturated, non-branched, non-substituted; R5, R6, R7, R8, R10, R11, R12 and R13each time independently on each other stand for H; F; Cl; Br; I; OH or C1-10-alkul; or R5 and R6 or R7 and R11 together with carbon atom(s), that bind(s) them form C3-8-cycloalkyl, each time saturated or non-saturated, non-substituted, or monosubstituted, or polysubstituted; with respective remaining substituents R5, R6, R7, R8, R10, R11, R12 and R13 having the value given above; R9 stands for C3-10-cycloalkyl, saturated, non-substituted; C6-10-aryl or 5- or 6-membered heteroaryl with heteroatom, selected from N and S, each time non-substituted or monosubstituted.

EFFECT: invention relates to substituted nicotinamides of general formula (1), to a medication based on them and their application for treating KCNQ2/3-mediated diseases.

13 cl, 3 tbl, 224 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 6-substituted isoquinoline and isoquinolinone derivatives of formula or to its stereoisomer and/or tautomer forms and/or a pharmaceutically acceptable salt, wherein R1 represents H, OH or NH2; R3 represents H; R4 represents H, a halogen atom, CN or (C1-C6)alkylene-(C6-C10)aryl; R5 represents H, a halogen atom, (C1-C6)alkyl; R7 represents H, a halogen atom, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 represents H; R9 and R6 are absent; R10 represents (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C6)hetrocycloalkyl, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C6)heterocycloalkyl; R11 represents H; R12 represents (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5)heteroaryl or (C6-C10)aryl; R13 and R14 independently represent H, (C1-C6)alkyl, (C1-C6)alkylene-R'; n is equal to 0; m is equal to 2 or 3; s is equal to 1 or 2; r is equal to 1; L represents O or NH; R' represents (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more OCH3; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms; wherein (C1-C8)heteroaryl group means (C1-C8)alkyl groups, wherein at least one carbon atom is substituted by O;. (C6)heterocycloalkyl group means a monocyclic carbon ring system containing 6 ring atoms wherein one carbon atom can be substituted by 1 oxygen atom or 1 sulphur atom which can be optionally oxidated; (C5)heteroaryl means a monoring system wherein one or more carbon atoms can be substituted by 1 nitrogen atom or 1 sulphur atom or a combination of various heteroatoms. Also, the invention refers to using the compound of formula (I) and to a therapeutic agent based on the compound of formula (I).

EFFECT: there are prepared new compounds effective for treating and/or preventing diseases associated with Rho-kinase and/or mediated by Rho-kinase by phosphorylation of myosin light chain phosphatase, and the compositions containing these compounds.

32 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula or to its therapeutically acceptable salt, where A1 represents N or C(A2); A2 represents H; B1 represents H, OR1 or NHR1; D1 represents H; E1 represents H; Y1 represents CN, NO2, F, Cl, Br, I, R17 or SO2R17; R1 represents R4 or R5; Z1 represents R26 or R27; Z2 represents R30; Z1A and Z2A both are absent; L1 represents R37; R26 represents phenylene; R27 represents indolyl; R30 represents piperasinyl; R37 represents R37A; R37A represents C2-C4 alkylene; Z3 represents R38, R39 or R40; R38 represents phenyl; R39 represents benzodioxilyl; R40 represents C4-C7cycloalkenyl, heterocycloalkyl, which represents monocyclic six- or seven-member ring, containing one heteroatom, selected from O, and zero of double bonds, or azaspiro[5.5]undec-8-ene; the remaining values of radicals are given in i.1 of invention formula. Invention also relates to pharmaceutical composition, based on claimed compound.

EFFECT: novel compounds, which can be applied in medicine for treatment of diseases, in the process of which anti-apoptotic Bcl-2 protein is expressed, are obtained.

8 cl, 2 tbl, 411 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

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