Thiophene compounds and thrombopoietin receptor activators

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

 

Background of the invention

The scope of the invention

The present invention relates to a means for prevention, treatment or improvement of diseases in which activation of the receptor thrombopoetin is effective, which have affinity to the receptor thrombopoetin and agonistic action on this receptor. In particular, it relates to pharmaceutical compositions comprising compounds that increase the number of platelets after stimulation of differentiation and proliferation of hematopoietic stem cells, megakaryocytes of progenitor cells and megakaryocytes, or compounds for therapeutic angiogenesis or possessing activity against arteriosclerosis, which stimulate differentiation and proliferation of endothelial cells of blood vessels and endothelial precursor cells.

Prior art

Thrombopoetin is a cytokine that consists of 332 amino acids, which increases the production of platelets by stimulating the differentiation and proliferation of hematopoietic stem cells, megakaryocytes of progenitor cells and megakaryocytes, mediated by its receptor, and is therefore promising as a drug from hematological disorders. Appeared in the last time reports he stimulates the differentiation and proliferation of endothelial cells of blood vessels and endothelial precursor cells, was the basis for expectations of therapeutic angiogenesis, action against atherosclerosis and prevention of cardiovascular disorders (for example, non-patent document 1, non-patent document 2 and non-patent document 3).

Biologically active substances, which have been known up to the present time, regulate the production of platelets in the receptor thrombopoetin include, in addition to thrombopoetin, low molecular weight peptides having affinity to the receptor thrombopoetin (for example, patent document 1, patent document 2, patent document 3 and patent document 4).

As a result of a search for ones low molecular weight compounds that increase the production of platelet-mediated receptor thrombopoetin it was reported that low molecular weight compounds with affinity for the receptor thrombopoetin (for example, patent document 5, patent document 26).

1) Applications Hokuriku Seiyaku Co., Ltd., related to 1,4-benzodiazepine derivatives (patent documents 5 and 6)

2) International laid patent application Shionogi & Co., Ltd. (patent documents 7-10)

3) International laid patent application filed by SmithKline Beecham Corp (patent is haunted documents 11-19)

4) Japanese laid patent application Torii Pharmaceutical Co., Ltd. (patent document 20)

5) international laid patent application filed by Roche Diagnostics GMBH (patent document 21)

6) International laid patent application Yamanouchi Pharmaceutical Co., Ltd. (patent document 22 and 23)

7) Japanese laid patent application Japan Tabacco Inc. (patent document 24)

8) international laid patent application filed by Nissan Chemical Industries, Ltd. (patent documents 25 and 26)

Patent document 1 JP-A-10-72492

Patent document 2 WO96/40750

Patent document 3 WO96/40189

Patent document 4 WO98/25965

Patent document 5 JP-A-11-1477

Patent document 6 JP-A-11-152276

Patent document 7 WO01/07423

Patent document 8 WO01/53267

Patent document 9 WO02/059099

Patent document 10 WO02/059100

Patent document 11 WO00/35446

Patent document 12 WO00/66112

Patent document 13 WO01/34585

Patent document 14 WO01/17349

Patent document 15 WO01/39773

Patent document 16 WO01/21180

Patent document 17 WO01/89457

Patent document 18 WO02/49413

Patent document 19 WO02/085343

Patent document 20 JP-A-2001-97948

Patent document 21 WO99/11262

Patent document 22 WO02/062775

Patent document 23 WO03/062233

Patent document 24 JP-A-2003-238565

Patent document 25 WO04/033433

Patent document 26 WO0/108683

Non-patent document 1 Microvasc. Res., 1999: 58, p,108-113

Non-patent document 2 Circ. Res., 1999: 84, p.785-796

Non-patent document 3 Blood 2001:98, p.71a-72a

Disclosure of invention

Thrombopoetin and low molecular weight peptides having affinity to the receptor thrombopoetin, apparently, are easily decomposed in the gastrointestinal tract, and they are usually difficult to be administered orally. As for thrombopoetin, reported on the appearance of antibodies against thrombopoetin.

In addition, although, possibly orally to enter ones low molecular weight compounds, no practical interest of medicines was not put on the market.

Therefore there was a need for oral input low molecular weight compounds having an excellent affinity to the receptor thrombopoetin and agonistic action in respect of this receptor, as tools for the prevention, treatment or improvement of diseases in which activation of the receptor thrombopoetin is effective. Specifically, there was a need for low molecular weight compounds, which can serve as a means to increase the number of platelets or means of increasing the number of other blood cells by stimulating the differentiation and proliferation of hematopoietic stem cells, megakaryocytes cells-preaches the members and megakaryocytes, or low molecular weight compounds that can be used for therapeutic angiogenesis or as a means to prevent and treat atherosclerosis by stimulating endothelial cells and endothelial progenitor cells.

The authors of the present invention conducted in-depth research to identify low molecular weight compounds having affinity and agonistic action on the receptor thrombopoetin, and as a result, it was found that the compounds of the present invention have high affinity and agonist activity, which allows them to take strong action to increase the number of platelets by stimulating the differentiation and proliferation megakaryocytes of progenitor cells and megakaryocytes. The present invention was created on the basis of this discovery.

Namely, the present invention relates to:

1. The compound represented by formula (I):

where R1represents a phenyl group (this phenyl group may be substituted by one or more C1-6alkyl groups, one or more C1-3alkyl groups (specified C1-3alkyl groups substituted by one or more halogen atoms), one or more C1-3alkoxygroup (indicated what data C 1-3alkoxygroup can be substituted by one or more halogen atoms) or one or more halogen atoms),

R2represents a hydrogen atom or a C1-3alkyl group (the specified C1-3the alkyl group may be substituted by one or more halogen atoms),

R3represents a phenyl group, pyridyloxy group or thienyl group (this phenyl group specified Peregrina group and the specified thienyl group substituted by one or more substituents selected from the group comprising hydrogen atoms, nitro group, halogen atom and C1-3alkyl group (specified C1-3alkyl groups can be substituted by one or more halogen atoms) and a group (C=O)R5(where R5represents NR6R7(where R6represents a hydrogen atom or a C1-3alkyl group (the specified C1-3the alkyl group may be substituted by one or more halogen atoms), and R7represents a C1-6alkyl group (the specified C1-6the alkyl group may be substituted by one or more halogen atoms, one or more hydroxyl groups, one or more C1-3alkoxygroup or one or more C2-14aryl groups (specified C2-14realnye group may be substituted by one or more C 1-3alkyl groups, one or more C1-3alkoxygroup, one or more carboxyl groups, one or more carbamaepine groups, one or more cyano groups or one or more halogen atoms, and in the case of aryl groups containing one or more nitrogen atoms may be in the form of their N-oxides)), phenyl group, thienyl group, pyridyloxy group or the pyridyl-N-oxide group (this phenyl group specified thienyl group specified Peregrina group and the specified pyridyl-N-oxide group may be substituted by one or more halogen atoms), or NR6R7represents, in General, the nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group may be substituted by one or more hydrogen atoms, one or more C1-6alkyl groups (specified C1-6alkyl groups can be substituted by one or more halogen atoms), one or more halogen atoms, one or more hydroxyl groups or one or more C1-3alkoxygroup (specified C1-3alkoxygroup can be substituted by one or more halogen atoms))or C1-6alkyl group (the specified C1-6the alkyl group may be behind esena one or more halogen atoms, one or more peredelnyj groups, one or more pyridyl-N-oxide groups, one or more FullName groups, one or more thienyl groups or one or more phenyl groups is substituted by one or more cyano groups))),

R4represents a hydrogen atom or a C1-3alkyl group (the specified C1-3the alkyl group may be substituted by one or more halogen atoms), a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

2. The compound according to claim 1, where R2represents a methyl group, and R4represents a hydrogen atom, a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

3. The compound according to claim 2, where R1represents a 3,4-dimethylphenyl group, 4-tert-butylphenyl group, 4-triftormetilfullerenov group, 3-chloraniline group, 4-chloraniline group, 4-florfenicol group, 3,4-dichloraniline group, 4-bromperidol group or 4-triphtalocyaninine group, a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

4. The compound according to claim 3, where R3represented by formula (II):

(where R6is the battle methyl group or ethyl group, and R7C1-6alkyl group (the specified C1-6the alkyl group may be substituted by one or more methoxypropane)), a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

5. The compound according to claim 3, where R3represented by formula (II):

(where R6represents a methyl group or ethyl group, and R7represents a C1-3alkyl group (the specified C1-3alkyl group substituted by one or more phenyl groups or one or more peredelnyj groups)), a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

6. The compound according to claim 3, where R3represented by formula (II):

(where R6represents a hydrogen atom, and R7represents a C1-6alkyl group (the specified C1-6alkyl group substituted by one or more methoxypropane) or pyridyloxy group), a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

7. The compound according to claim 3, where R3represented by formula (II):

where NR6R7in General, represented by the formula (III):

(where R 9represents a C1-3alkyl group)), a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

8. The compound according to claim 3, where R3represented by formula (IV):

(where R6represents a hydrogen atom, R7represents a C1-3alkyl group (the specified C1-3the alkyl group may be substituted by one or more hydroxyl groups), and R8represents a methyl group or a chlorine atom), a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

9. The compound according to claim 3, where R3represented by formula (V):

(where R10represents a hydrogen atom or a C1-3alkyl group), a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

10. The compound according to claim 3, where R3represented by formula (II):

(where R6represents a hydrogen atom, and R7represents an ISO-propyl group, methyl group, ethyl group or through normal group (specified methyl group specified ethyl group and the specified normal sawn group is unsubstituted or substituted one or several and peredelnyj groups, one or more pyridyl-N-oxide groups, one or more FullName groups, one or more personalname groups, one or more imidazolinium groups, one or more pyrazolidine groups or one or more isoxazolidine groups (specified peredelnye group, the pyridyl-N-oxide group, these foreline groups specified personilnya groups specified imidazolidine groups specified pyrazolidine group and these isoxazolidine group may be substituted by one or more methyl groups, one or more methoxypropane, one or more carboxyl groups or one or more halogen atoms))), tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

11. The compound according to any one of PP 4-10, where R1represents a 3,4-dimethylphenyl group, a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

12. The compound according to any one of PP 4-10, where R1represents a 3,4-dichloraniline group, a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

13. The compound according to any one of PP 4-10, where R1is a 4-chloraniline group, tautomer, is alacarte or pharmaceutically acceptable salts of such compounds or their MES.

14. The compound according to any one of PP 4-10, where R1is a 4-triftormetilfullerenov group, a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

15. The compound according to any one of PP 4-10, where R1is a 4-bromperidol group, a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

16. The compound according to any one of PP 4-10, where R1is a 4-triphtalocyaninine group, a tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES.

17. The activator receptor thrombopoetin containing compound according to any one of PP 1-16, tautomer, prodrug or pharmaceutically acceptable salts of such compounds or their MES, as an active ingredient.

18. The means for prevention, treatment or improvement of diseases in which activation of the receptor thrombopoetin is effective, which contains the activator of the receptor thrombopoetin at 17 as an active ingredient.

19. Means for increasing the number of platelets containing activator receptor thrombopoetin at 17 as an active ingredient.

20. Medicinal product containing the compound according to any one of PP 1-16, tautomer, prodrug or pharmaceutically when mleay salt of such compounds or their MES as an active ingredient.

The effects provided by the present invention

Thiophene compounds of the present invention have affinity to the receptor thrombopoetin and agonistic action in respect of this receptor and demonstrate a strong effect on increasing the number of platelets after stimulation of differentiation and proliferation megakaryocytes of progenitor cells and megakaryocytes.

Thiophene compounds of the present invention is easily absorbed from the gastrointestinal tract and have a strong stimulating effect on the formation of colonies of megakaryocytes. Oral absorbable thiophene compounds are retained in the blood in large quantities and therefore are particularly useful as oral medicines.

Although patent document 26 discloses compounds having the action of increasing the number of platelets, it does not disclose thiophene compounds of the present invention sufficiently to predict especially high oral absorbiruyaci and high activity by stimulation of colonies of megakaryocytes thiophene compounds of the present invention.

Therefore, thiophene compounds of the present invention are useful as medicines and are used as tools for the prevention, treatment or the improvement of the status of the diseases, in which activation of the receptor thrombopoetin is effective, especially as a means to increase the number of platelets.

The best way of carrying out the invention

Following is a detailed description of the present invention.

In the present invention, “n” means normal, “Deuteronomy” means secondary, “t” means tertiary, “c” means cyclo, “o” means ortho, “m” means meta, “p” means the couple, “Ph” means phenyl, “Py” means pyridyl, “Me” means methyl, “Et” means ethyl, “Pr” means propyl and “Bu” means butyl.

First is the explanation of terms in the respective substituents R1- R10.

As the halogen atom, you can specify a fluorine atom, chlorine atom, bromine atom or iodine atom.

C1-3the alkyl group may be a linear or branched C3cycloalkyl group, and you can specify methyl, ethyl, n-sawn, ISO-propyl and cyclopropyl group, etc.

C1-6the alkyl group may be a linear, branched or a C3-6cycloalkyl group, and in addition to the above groups, you can specify n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, n-pentyl, 1-methyl-n-butyl, 2-methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-what-propyl, 1,2-dimethyl-n-propyl, 2,2-dimethyl-n-propyl, 1-ethyl-n-propyl, cyclopentyl, 1-methylcyclohexyl, 2-methylcyclohexyl, 3-methylcyclobutene, 1,2-dimethylcyclopropane, 2,3-dimethylcyclopropane, 1-ethylcyclopropane, 2-ethylcyclopropane, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 3-methyl-n-pentyl, 4-methyl-n-pentyl, 1,1-dimethyl-n-butyl, 1,2-dimethyl-n-butyl, 1,3-dimethyl-n-butyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, 3,3-dimethyl-n-butyl, 1-ethyl-n-butyl, 2-ethyl-n-butyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 1-ethyl-1-methyl-n-propyl, 1-ethyl-2-methyl-n-propyl, cyclohexyl, 1-methylcyclopentene, 2-methylcyclopentene, 3-methylcyclopentene, 1-ethylcyclohexyl, 2-ethylcyclohexyl, 3-ethylcyclohexyl, 1,2-dimethylcyclobutyl, 1,3-dimethylcyclobutyl, 2,2-dimethylcyclobutyl, 2,3-dimethylcyclobutyl, 2,4-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, 1-n-propylcyclohexyl, 2-n-propylcyclohexyl, 1-isopropylcyclohexane, 2-isopropylcyclohexane, 1,2,2-trimethylpropyl, 1,2,3-trimethylpropyl, 2,2,3-trimethylpropyl, 1-ethyl-2-methylcyclopropyl, 2-ethyl-1-methylcyclopropyl, 2-ethyl-2-methylcyclopropyl, 2-ethyl-3-methylcyclopropyl etc.

C1-3alkoxygroup may include linear or branched C3cycloalkanes, you can specify and methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropane etc.

C2-14aryl group may be a C6-14aryl group, does not contain asuu no heteroatoms as part of the ring atoms, or C2-9aromatic heterocyclic group, and this C2-9aromatic heterocyclic group may be a 5-7-membered C2-6heterogenities group or an 8-10-membered C5-9condensed heterobicyclic group containing from 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms, individually or in combination.

As C6-14aryl group containing no heteroatoms, you can specify a phenyl group, 1-indenolol group, 2-indenolol group, 3-indenolol group, 4-indenolol group, 5-indenolol group, 6-indenolol group, 7-indenolol group, and α-naftalina group, a β-naftalina group, 1-tetrahydronaphthyl group, 2-tetrahydronaphthalene group, 5-tetrahydronaphthyl group, 6-tetrahydronaphthyl group, and o-biphenylyl group, m-biphenylyl group, p-biphenylyl group, 1-untilnow group, 2-untilnow group, 9-untilnow group, 1-phenanthroline group, 2-phenanthroline group, 3-phenanthroline group, 4-phenanthroline group, 9-phenanthroline group or the like

5-7-Membered C2-6heterophilically group can be a 2-thienyl group, 3-thienyl group, 2-follow group, 3-follow group, 2-pyranyloxy group, 3-pyranyloxy group, 4-pyranyloxy group, 1-pyrrolidinyl group, 2-pyrrolidinyl groups who, 3-pyrrolidinyl group, 1-imidazolidinyl group, 2-imidazolidinyl group, 4-imidazolidinyl group, 1-pyrazolidine group, 3-pyrazolidine group, 4-pyrazolidine group, 2-thiazolidine group, 4-thiazolidine group, 5-thiazolidine group, 3-isothiazolinone group, 4-isothiazoline group, 5-isothiazolinone group, 2-oxazolidinyl group, 4-oxazolidinyl group, 5-oxazolidinyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-pyridyloxy group, 3-pyridyloxy group, 4-pyridyloxy group, 2-personilnya group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-1,3,4-oxadiazolyl group, 2-1,3,4-thiadiazolyl group, 3-1,2,4-oxadiazolyl group, 5-1,2,4-oxadiazolyl group, 3-1,2,4-thiadiazolyl group, 5-1,2,4-thiadiazolyl group, a 3-1,2,5-oxadiazolyl group, a 3-1,2,5-thiadiazolyl group, 3-4H-1,2,4-triazolyl group, 3-1H-1,2,4-triazolyl group, 5-1H-1,2,4-triazolyl group, 4-2H-1,2,3-triazolyl group, 5-2H-1,2,3-triazolyl group, 4-1H-1,2,3-triazolyl group, 5-1H-1,2,3-triazolyl group or the like

8-10-membered C5-9the condensed heterocyclic group may be a 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl g is the SCP, 6-benzofuranyl group, 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothiazoline group, 3-benzothiazoline group, 4-benzothiazoline group, 5-benzothiazoline group, 6-benzothiazoline group, 7-benzothiazoline group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-romanello group, 3-romanello group, 4-romanello group, 5-romanello group, 6-romanello group, 7-romanello group, 8-romanello group, 1-indolizinyl group, 2-indolizinyl group, 3-indolizinyl group, 5-indolizinyl group, 6-indolizinyl group, 7-indolizinyl group, 8-indolizinyl group, 1-isoindolyl group, 2-isoindolyl group, 4-isoindolyl group, 5-isoindolyl group, 1-indolering group, 2-indolering group, 3-indolering group, 4-indolering group, 5-indolering group, 6-indolering group, 7-indolering group, 1-indazolinone group, 2-indazolinone group, 3-indazolinone group, 4-indazolinone group, 5-indazolinone group, 6-indazolinone group, 7-indazolinone group, 1-parinello group, 2-parinello group, 3-parinello group, 6-parinello group, 7-parinello group, 8-parinello group, 2-pinolillo group, 3-pinolillo group, 4-hinai is inuu group, 5-pinolillo group, 6-pinolillo group, 7-pinolillo group, 8-pinolillo group, 1-izohinolinove group, 3-izohinolinove group, 4-izohinolinove group, 5-izohinolinove group, 6-izohinolinove group, 7-izohinolinove group, 8-izohinolinove group, 1-phthalazinone group, 5-talinolol group, 6-talinolol group, 1-2,7-naphthyridinone group, 3-2,7-naphthyridinone group, 4-2,7-naphthyridinone group, 1-2,6-naphthyridinone group, 3-2,6-naphthyridinone group, 4-2,6-naphthyridinone group, 2-1,8-naphthyridines group, 3-1,8-naphthyridines group, 4-1,8-naphthyridines group, 2-1,7-naphthyridinone group, 3-1,7-naphthyridinone group, 4-1,7-naphthyridinone group, 5-1,7-naphthyridinone group, 6-1,7-naphthyridinone group, 8-1,7-naphthyridinone group, 2-1,6-naphthyridinone group, 3-1,6-naphthyridinone group, 4-1,6-naphthyridinone group, 5-1,6-naphthyridinone group, 7-1,6-naphthyridinone group, 8-1,6-naphthyridinone group, 2-1,5-naphthyridines group, 3-1,5-naphthyridines group, 4-1,5-naphthyridines group, 6-1,5-naphthyridines group, 7-1,5-naphthyridines group, 8-1,5-naphthyridines group, 2-khinoksalinona group, 5-khinoksalinona group, 6-khinoksalinona group, 2-chinazolinei group, 4-chinazolinei group, 5-chinazolinei group, 6-chinazolinei group, 7-chinazolinei the th group, 8-chinazolinei group, 3-indolinyl group, 4-indolinyl group, 5-indolinyl group, 6-indolinyl group, 7-indolinyl group, 8-indolinyl group, 2-parrinello group, 4-parrinello group, 6-parrinello group, 7-parrinello group or the like

The nitrogen-containing heterocyclyl group represents a C2-9heterogenities or condensed heterobicyclic group that contains one or more nitrogen atoms and may optionally contain one or more atoms, optionally, selected from oxygen atoms and sulfur atoms, and can be specified:

Specific preferred examples of the substituent R1are phenyl groups substituted by one or more of the following substituents.

Deputies: C1-6alkyl group, a C1-3alkyl group (the specified C1-3alkyl group substituted by one or more halogen atoms), C1-3alkoxygroup (specified C1-3alkoxygroup substituted by one or more halogen atoms) and a halogen atom.

Particularly preferred examples of the substituent R1are 3,4-dimethylaniline group, 4-tert-butylphenyl group, 4-triftormetilfullerenov group, 3-chloraniline group, 4-chloraniline group, 4-forfe the ilen group, 3,4-dichloraniline group, 4-bratinella group and 4-triphtalocyaninine group.

Specific preferred examples of the substituent R2are a hydrogen atom, methyl group, ethyl group, isopropyl group, n-sawn group and triptorelin group.

Especially preferred example of the substituent R2is a methyl group.

Specific preferred examples of the substituent R3are phenyl group, peredelnye group (2-Peregrina group, 3-Peregrina group and 4-Peregrina group and thienyl group (2-thienyl group and 3-thienyl group), substituted by one or more substituents selected from the following group of substituents A, and one or more substituents selected from the following group of substituents B.

The group of substituents A: the hydrogen atom, the nitro-group, a halogen atom, a C1-3alkyl group, and C1-3alkyl group substituted by one or more fluorine atoms.

The group of substituents B: (C=O)R5(where R5represents NR6R7(where R6represents a hydrogen atom or a C1-3alkyl group (the specified C1-3the alkyl group may be substituted by one or more halogen atoms), and R7represents a C1-6the alkyl group is u (specified C 1-6the alkyl group may be substituted by one or more halogen atoms, one or more hydroxyl groups, one or more C1-3alkoxygroup or one or more C2-14aryl groups (specified C2-14aryl groups can be substituted by one or more C1-3alkyl groups, one or more C1-3alkoxygroup, one or more carboxyl groups, one or more carbamaepine groups, one or more cyano groups or one or more halogen atoms, and in the case of aryl groups containing one or more nitrogen atoms that may be present in their N-oxides)), phenyl group, thienyl group, pyridyloxy group or the pyridyl-N-oxide group (the phenyl group, thienyl group, Peregrina group and pyridyl-N-oxide group may be substituted by one or more halogen atoms), or NR6R7in General, represents a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group may be substituted by one or more hydrogen atoms, one or more C1-6alkyl groups (specified C1-6alkyl groups can be substituted by one or more halogen atoms), one or more halo atoms is s, one or more hydroxyl groups or one or more C1-3alkoxygroup (specified C1-3alkoxygroup can be substituted by one or more halogen atoms)), or C1-6alkyl group (the specified C1-6the alkyl group may be substituted by one or more halogen atoms, one or more peredelnyj groups, one or more pyridyl-N-oxide groups, one or more FullName groups, one or more thienyl groups or one or more phenyl groups is substituted by one or more cyano groups)).

Particularly preferred examples of the substituent R3represented by formula (II):

(where R6represents a methyl group or ethyl group, and R7represents a C1-6alkyl group (the specified C1-6the alkyl group may be substituted by one or more methoxypropane)).

Another particularly preferred example of the substituent R3represented by formula (II):

(where R6represents a methyl group or ethyl group, and R7represents a C1-3alkyl group (the specified C1-3alkyl group substituted by one or more phenyl GRU is the groups or one or more peredelnyj groups)).

Another particularly preferred example of the substituent R3represented by formula (II):

(where R6represents a hydrogen atom, and R7represents a C1-6alkyl group (the specified C1-6alkyl group substituted by one or more methoxypropane) or pyridyloxy group).

The following particularly preferred example of the substituent R3represented by formula (IV):

(where R6represents a hydrogen atom, R7represents a C1-3alkyl group (the specified C1-3the alkyl group may be substituted by one or more hydroxyl groups), and R8represents a methyl group or a chlorine atom).

Another particularly preferred example of the substituent R3is a group represented by the formula (II) or formula (IV), where the group NR6R7in General, represented by the formula (III):

(where R9represents a C1-3alkyl group).

Another particularly preferred example of the substituent R3represented by formula (V):

(where R10represents a hydrogen atom or a C1-3alkyl group).

Another particularly preferred example, the Deputy is R 3represented by formula (II):

(where R6represents a hydrogen atom, and R7represents an ISO-propyl group, methyl group, ethyl group or through normal group (mentioned methyl group, the ethyl groups and specified normal sawn group are unsubstituted or substituted by one or more peredelnyj groups, one or more pyridyl-N-oxide groups, one or more FullName groups, one or more personalname groups, one or more imidazolinium groups, one or more pyrazolidine groups or one or more isoxazolidine groups (specified peredelnye group, pyridyl-N-oxide group, foreline group, personilnya group, imidazolidinyl group, pyrazolidine group and isoxazolidine group may be substituted by one or more methyl groups, one or more methoxypropane, one or more carboxyl groups or one or more halogen atoms))).

Specific preferred examples of the substituent R4are a hydrogen atom, methyl group, ethyl group, isopropyl group, n-sawn group and triptorelin group.

Especially preferred example Zam is stichele R 4are a hydrogen atom.

Preferred compounds for use as activator receptor thrombopoetin, means for prevention, treatment or improvement of diseases in which activation of the receptor thrombopoetin is effective, and means for increasing the number of platelets according to the present invention are as follows.

1) Compounds represented by formula (I), where R2represents a methyl group, and R4represents a hydrogen atom, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

2) the Compound according to claim 1, where R1represents a 3,4-dimethylphenyl group, 4-tert-butylphenyl group, 4-triftormetilfullerenov group, 3-chloraniline group, 4-chloraniline group, 4-florfenicol group, 3,4-dichloraniline group, 4-bromperidol group or 4-triphtalocyaninine group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their

3) the Compound according to claim 2, where R3represented by formula (II):

(where R6represents a methyl group or ethyl group, and R7represents a C1-6alkyl group (the specified C1-6the alkyl group may be substituted by one or more of methoxy what uppada)), the tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

4) the Compound according to claim 2, where R3represented by formula (II):

(where R6represents a methyl group or ethyl group, and R7represents a C1-3alkyl group (the specified C1-3alkyl group substituted by one or more phenyl groups or one or more peredelnyj groups)), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

5) the Compound according to claim 2, where R3represented by formula (II):

(where R6represents a hydrogen atom, and R7represents a C1-6alkyl group (the specified C1-6alkyl group substituted by one or more methoxypropane) or pyridyloxy group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

6) the Compound according to claim 2, where the group NR6R7in the formula (II), generally represented by the formula (III):

(where R9represents a C1-3alkyl group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

7) the Compound according to claim 2, where R3presents what armoloy (IV):

(where R6represents a hydrogen atom, R7represents a C1-3alkyl group (the specified C1-3the alkyl group may be substituted by one or more hydroxyl groups), and R8represents a methyl group or a chlorine atom), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

8) the Compound according to claim 2, where R3represented by formula (V):

(where R10represents a hydrogen atom or a C1-3alkyl group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

9) Compounds according to claim 2, where R3represented by formula (II):

(where R6represents a hydrogen atom, and R7represents an ISO-propyl group, methyl group, ethyl group or through normal group (specified methyl group specified ethyl group and the specified normal sawn group are unsubstituted or substituted by one or more peredelnyj groups, one or more pyridyl-N-oxide groups, one or more FullName groups, one or more personalname groups, one or more imidazolidinyl group is AMI, one or more pyrazolidine groups or one or more isoxazolidine groups (specified peredelnye group, pyridyl-N-oxide group, foreline group, personilnya group, imidazolidinyl group, pyrazolidine group and isoxazolidine group may be substituted by one or more methyl groups, one or more methoxypropane, one or more carboxyl groups or one or more halogen atoms))), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

10) Compounds according to any one of 3 percentage points) - 9), where R1represents a 3,4-dimethylphenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

11) Compounds according to any one of 3 percentage points) - 9), where R1represents a 3,4-dichloraniline group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

12) Compounds according to any one of 3 percentage points) - 9), where R1is a 4-chloraniline group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

13) Compounds according to any one of 3 percentage points) - 9), where R1is a 4-triftormetilfullerenov group, tautomers, prodrugs or pharmaceutically acceptable salts so the x compounds or their solvate.

14) Compounds according to any one of 3 percentage points) - 9), where R1is a 4-bromperidol group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

15) Compounds according to any one of 3 percentage points) - 9), where R1is a 4-triphtalocyaninine group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

16) Compounds, where R4represents a hydrogen atom, and R1, R2and R3are any of the following combinations shown in table 1, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

Presented in table 1, the symbols denote the following substituents.

Table 1

Table 1 (continued)

17) Compounds, where R4represents a hydrogen atom, and R1, R2and R3are any of the following combinations shown in table 1, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvate (provided that in the case of 17) Q1a, Q1b, Q1c, Q1d, Q1e, Q1f, Q1g, Q1h, Q3a, Q3b, Q3c, Q3d, Q3e, Q3f, Q3g, Q3h, Q3i, Q3j, Q3k and Q3l presented in the table represent the following substituents).

18) Compounds, where R4represents a hydrogen atom, and R1, R2and R3are any of the following combinations shown in table 1, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvate (provided that in the case of 18) Q1a, Q1b, Q1c, Q1d, Q1e, Q1f, Q1g, Q1h, Q3a, Q3b, Q3c, Q3d, Q3e, Q3f, Q3g, Q3h, Q3i, Q3j, Q3k and Q3l presented in the table represent the following substituents).

19) Compounds, where R4represents a hydrogen atom, and R1, R2and R3are any of the following combinations shown in table 2, the tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

Presented in table 2, the symbols denote the following substituents.

Table 2

20) Compounds, where R4represents a hydrogen atom, and R1, R2and R3are any of the following combinations shown in table 3, the tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

Presented in table 3, the symbols denote the following substituents.

Table 3

21) Compounds, where R4represents a hydrogen atom, and R1, R2and R3are any of the following combinations shown in table 4, the tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

Presented in table 4, the symbols denote the following substituents.

Table 4

22) Compounds, where R4represents a hydrogen atom, and R1, R2and R3are any of the following combinations shown in table 5, the tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

Presented in table 5, the symbols denote the following substituents.

Table 5

23) Compounds, where R4represents a hydrogen atom, and R1, R2and R3are any of the following combinations shown in table 6, the tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

Presented in table 6, the symbols denote the following substituents.

Table 6

24) of the Connection points 16) - 23), where R2converted to a hydrogen atom, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

25) Connection p.p. 16) - 23), where R2converted to triptorelin group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

26) of the Connection points 16) - 23), where R2converted into ethyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

27) Connection p.p. 16) - 23), where R2converted to n-sawn group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

28) Connection p.p. 16) - 23), where R2converted into isopropyl, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

29) Connection p.p. 16) - 28), where R4converted into a methyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

30) Connection p.p. 16) - 28), where R4converted to triptorelin group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds, or their solvate.

31) of the Connection points 16) - 28), where R4converted to the ethyl group, the tautomers, Proletarskaya pharmaceutically acceptable salts of such compounds, or their solvate.

32) Activators of receptor thrombopoetin containing compounds in percentage points 1) to 31), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvate as an active ingredient.

33) is a Tool for prevention, treatment or improvement of diseases in which activation of the receptor thrombopoetin is effective that contain activators of receptor thrombopoetin on p) as the active ingredient.

34) Means to increase the number of platelets containing activators of receptor thrombopoetin on p) as the active ingredient.

35) Medicines containing any of the compounds in percentage points 1) to 31) or compounds represented by formula (I), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvate as an active ingredient.

In the present invention the compounds of the present invention, represented by formula (I)can be present in the form of the tautomers or geometrical isomers, which are industriously or ekzoticheskoy isomerization, mixtures of the tautomers or geometrical isomers or their mixtures. When the compounds of the present invention contain an asymmetric center, regardless of whether this is a result of isomerization of the compounds according to the present image is the shadow can be in the form of separated optical isomers or in the form of mixtures, containing them in certain proportions.

Compounds of the present invention, represented by formula (I)or their pharmaceutically acceptable salts can be in the form of arbitrary crystals or arbitrary hydrates, depending on the conditions of reception. The present invention covers such crystals, hydrates and mixtures. They can be in the form of a solvate with an organic solvent, such as acetone, ethanol, and tetrahydrofuran, and the present invention covers any of these forms.

Compounds of the present invention, represented by formula (I)may be converted into pharmaceutically acceptable salts, or may be selected from the obtained salts, if necessary. Pharmaceutically acceptable salts of the present invention may, for example, be a salt with alkali metals (such as lithium, sodium and potassium), alkaline earth metals (such as magnesium and calcium), ammonium, organic bases and amino acids. They may be a salt with inorganic acids (such as hydrochloric acid, Hydrobromic acid, phosphoric acid and sulfuric acid) and organic acids (such as acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzolsulfonat acid and p-toluensulfonyl the traveler acid).

Compounds which serve as prodrugs, are derivatives of the present invention, containing a chemically or metabolically degradable group, which give the pharmacologically active compounds of the present invention as a result of solvolysis or under physiological conditions in vivo. The methods of selecting or obtaining the appropriate prodrugs are disclosed, for example, in Design of Prodrugs (Elsevier, Amsterdam 1985). In the present invention, when the compound contains a hydroxyl group as prodrugs you can specify, for example, acyloxy-derivatives, obtained by the interaction of the compounds with suitable acylhomoserine or suitable anhydrides of the acids. Allocryptopine, particularly preferred as prodrugs include-OCOC2H5, -OCO(t-Bu), -OCOC15H31, -OCO(m-CO2Na-Ph), -OCOCH2CH2CO2Na, -OCOCH(NH2)CH3, -OCOCH2N(CH3)2etc. When the compound of the present invention contains an amino group, as prodrugs you can specify, for example, amide derivatives, obtained by the interaction of the compounds containing the amino group, with suitable halides of acids or suitable mixed anhydrides of the acids. Amides, particularly preferred as prodrugs include-NHCO(CH2)20OCH3, -NHCOCH(NH2)CH 3etc. When the compound of the present invention contains a carboxyl group as prodrugs you can specify, for example, esters of carboxylic acids with aliphatic alcohols or esters of carboxylic acids, obtained by the interaction with Nesporova hydroxyl group, 1,2 - or 1,3-diglycerides. Particularly preferred prodrugs are methyl ester and complex ethyl esters.

Funds for prevention, treatment or improvement of diseases in which activation of the receptor thrombopoetin is effective, or means to increase the number of platelets, which contain activators of receptor thrombopoetin of the present invention as the active ingredient, as a rule, you can enter in the form of oral medicines, such as tablets, capsules, powder, granules, pills and syrup, in the form of rectal medications, percutaneous medicines or injections. The means according to the present invention can be entered as single therapeutic agents or as mixtures with other therapeutic agents. Although you can enter them as such, they are usually administered in the form of medical compositions. Such pharmaceutical preparations can be obtained by adding pharmacologically and pharmaceutically acceptable additives traditionally the diversified ways. Namely, for oral medicines, you can use the usual excipients, lubricants, binders, disintegrating agents, humectants, plasticizers and coating agents. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be supplied in the form of dry syrups for mixing with water or other suitable solvents before use. Such liquid preparations may contain conventional additives such as suspendresume substances, fragrances, solvents and emulsifiers. In the case of rectal administration, you can enter them in the form of suppositories. As the basis of suppositories you can use a suitable substance, such as cocoa butter, lauric oil, Macrogol, glycoregulation, Witepsol, sodium stearate, and mixtures thereof, and, if necessary, they may contain an emulsifier, suspendisse substance, preservative, etc. For injection can be used pharmaceutical ingredients such as distilled water for injection, saline solution, 5% glucose, propylene glycol or other solvents or solubilizing agents, pH Adjuster, an isotonicity agent and stabilizer to obtain water dosage forms or dosage forms which must be dissolved before use.

Dose really means to the invention for administration to man is usually from about 0.1 to 1000 mg/person/day in the case of oral drugs or rectal injection for adults, and from about 0.05 mg to 500 mg/person/day in the case of injection for adults, although it depends on the age and condition of the patient. The ranges specified above are given only as examples, and the dose should be determined depending on the condition of the patient.

The present invention is applied, when it is expected that the use of compounds which have affinity to the receptor thrombopoetin and act as agonists of the receptor thrombopoetin, improve pathological condition. For example, you can specify hematological disorders, accompanied by an abnormal number of platelets. Specifically, it is effective for the treatment or prevention of diseases of humans and mammals caused by an abnormal megakaryopoiesis, especially those that are accompanied by thrombocytopenia. Examples of such diseases include thrombocytopenia associated with chemotherapy or radiotherapy for cancer, thrombocytopenia arising during antiviral therapy in the treatment of diseases such as hepatitis C, thrombocytopenia caused by bone marrow transplantation, surgery, and severe infections, or gastrointestinal bleeding, but such diseases are not limited to the above. Typical thrombocytopenia, such as aplastic anemia, idiopathic thrombocytopenic purpura, myelodysplastic with ngram, liver disease, HIV infection and the lack of thrombopoetin, are also targets for medium according to the present invention. The present invention can be used as matters of peripheral stem cells, inductor differentiation megakaryoblastic or megakaryocytic leukemia cells and means for increasing the number of platelets for platelet donors. In addition, potential applications include therapeutic angiogenesis, based on differentiation and proliferation of endothelial cells of blood vessels and endothelial precursor cells, the prevention and treatment of arteriosclerosis, myocardial infarction, unstable angina, occlusal peripheral artery disease, but there are no restrictions.

Compounds represented by formula (I)receive, for example, by a method represented by the formula (1) below.

The interaction of the compound (IV) with aminoguanidinium (VII) in a solvent and, if necessary, in the presence of a catalyst, by heating and stirring gives the desired compound or its predecessor. The precursor can, if necessary, be subjected to hydrolysis to remove the protection, restoration or oxidation to the desired connection. Compounds of the present invention can usually be cleared column chromium is ografia, thin-layer chromatography, high performance liquid chromatography (HPLC) or high performance liquid chromatography-mass spectrometry (LC-MS) and, if necessary, they can be obtained with high purity by recrystallization or washing with solvents.

For the synthesis of intermediate compounds (VI) can, for example, specify the following method disclosed in JP-A-48-026755:

For the synthesis of amino compounds (VII)can be, for example, to specify the methods disclosed in Synthetic Commun., 28(7), 1223-1231 (1998), J. Chem. Soc., 1225 (1948) and J. Chem. Soc., 2831 (1952).

Compounds represented by formula (I)can also be obtained by the method represented by the formula (3) below.

The interaction of the compound (VIII) with compound (IX) in a solvent and, if necessary, in the presence of a catalyst, dehydrating agent, condensing, by heating and stirring gives the desired compound or its predecessor. The precursor can, if necessary, be subjected to hydrolysis to remove the protection, restoration or oxidation to the desired connection. Compounds of the present invention can usually be cleaned by column chromatography, thin-layer chromatography, high performance liquid chromatography (HPLC) or high-performance zhidkosti the th chromatography-mass spectrometry (LC-MS) and if necessary, they can be obtained with high purity by recrystallization or washing with solvents.

The compound (VIII) can be obtained by mixing the compound (VI) with hydrazine or its derivatives in a solvent and, if necessary, in the presence of a catalyst, when heated.

EXAMPLES

Hereinafter the present invention will be described in more detail with reference to referential examples, synthesis examples synthesis examples, test examples and formulation. However, it should be clear that the present invention should not be limited to these specific examples.

Analysis1H-NMR was carried out at 300 MHz, and definitions LC/MS was carried out under the following conditions.

LC/MS, the condition 1

Column: Waters SunFire C18 (3.5 µm, a 4.6×30 mm)

Eluent: acetonitrile/0.1% aqueous formic acid (10/90 to 30/70)

LC/MS, the condition 2

Column: Waters SunFire C18 (3.5 µm, a 4.6×30 mm)

Eluent: acetonitrile/0.1% aqueous formic acid (10/90 to 60/40)

LC/MS conditions 3

Column: Waters SunFire C18 (3.5 µm, a 4.6×30 mm)

Eluent: acetonitrile/0.1% aqueous formic acid (10/90 to 85/15)

LC/MS conditions 4

Column: Waters Xterra MSC18 (5 μm, a 4.6×50 mm)

Eluent: acetonitrile/0.1% aqueous formic acid (10/90 to 30/70)

LC/MS conditions 5

Column: Waters Xterra MSC18 (5 μm, a 4.6×50 mm)

Eluent: acetonitrile/0.1% in the command formic acid (10/90 to 60/40)

LC/MS conditions 6

Column: Waters Xterra MSC18 (5 μm, a 4.6×50 mm)

Eluent: acetonitrile/0.1% aqueous formic acid (10/90 to 85/15)

LC/MS conditions 7

Column: Waters Xterra MSC18 (5 μm, a 4.6×50 mm)

Eluent: acetonitrile/0.1% aqueous formic acid (20/80 to 100/0)

LC/MS conditions 8

Column: Waters Xterra MSC18 (3.5 µm and 2.1×20 mm)

Eluent: acetonitrile/0.2% aqueous solution of formic acid (20/80 to 90/10)

REFERENCE SYNTHESIS EXAMPLE 1

Synthesis of 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carbohydrazide

A solution of 59 mg (0.02 mmol) of methyl 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carboxylate, dissolved in 2 ml of ethanol was heated with 100 μl of hydrazine monohydrate at 80°C for 5 hours while boiling under reflux. After cooling, the reaction solution was poured into a liquid mixture of 5 ml water and 5 ml of a saturated aqueous solution of sodium chloride and was extracted with 20 ml ethyl acetate and 20 ml of chloroform.

The extract was dried over magnesium sulfate and the solvent evaporated at 40°C with 30 mg of the desired product, 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carbohydrazide (51%yield).

Morphology: colourless solid

LC/MS: condition 4, the retention time of 0.32 (min)

LC/MS (ESI+) m/z 297 [M+1]+

LC/MS (ESI-) m/z 295 [M-1]-

REFERENCE SYNTHESIS EXAMPLE 2

Synthesis of 5-(morpholine-4-carbonyl)thiophene-carbohydrazide

Followed the procedure of reference synthesis example 1, using methyl 5-(morpholine-4-carbonyl)thiophene-2-carboxylate, to give the desired product, 5-(morpholine-4-carbonyl)thiophene-2-carbohydrazide (51%yield).

Morphology: colourless solid

LC/MS: condition 5, the retention time of 0.34 (min)

LC/MS (ESI+) m/z 256 [M+1]+

LC/MS (ESI-) m/z 254 [M-1]-

REFERENCE SYNTHESIS EXAMPLE 3

Synthesis of diethylamide 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference synthesis example 1, using methyl 5-(diethylcarbamoyl)thiophene-2-carboxylate, to give the desired product, diethylamide 5-hydrazinecarboxamide-2-carboxylic acid (yield 89%).

Morphology: white solid

LC/MS: condition 8, the retention time of 0,63 (min)

LC/MS (ESI+) m/z 242 [M+1]+

REFERENCE EXAMPLE synthesis of 4

Synthesis of 5-(pyrrolidin-1-carbonyl)thiophene-2-carbohydrazide

Followed the procedure of reference synthesis example 1, using methyl 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylate, to give the desired product, 5-(pyrrolidin-1-carbonyl)thiophene-2-carbohydrazide.

Morphology: white solid

LC/MS: condition 8, the retention time of 0.50 (min)

LC/MS (ESI+) m/z 240 [M+1]+

REFERENCE EXAMPLE synthesis of 5

Synthesis of dimethylamide 5-hydrazinecarboxamide the-2-carboxylic acid

Followed the procedure of reference synthesis example 1, using methyl 5-(dimethylcarbamoyl)thiophene-2-carboxylate, to give the desired product, dimethylamide 5-hydrazinecarboxamide-2-carboxylic acid (yield 23%).

Morphology: colourless solid

LC/MS: condition 6, the retention time of 0.37 (min)

LC/MS (ESI+) m/z 214 [M+1]+

LC/MS (ESI-) m/z 212 [M-1]-

REFERENCE EXAMPLE synthesis of 6

Synthesis of 2-methoxyethylamine 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference synthesis example 1, using methyl 5-(2-methoxyethanol)thiophene-2-carboxylate, to give the desired product, 2-methoxyethylamine 5-hydrazinecarboxamide-2-carboxylic acid (yield 84%).

Morphology: white solid

LC/MS: conditions 1 retention time 0,34 (min)

LC/MS (ESI+) m/z 244 [M+1]+

LC/MS (ESI-) m/z 242 [M-1]-

REFERENCE EXAMPLE synthesis of 7

Synthesis of 3-pyridylamino 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference synthesis example 1, using methyl 5-(3-pyridylcarbonyl)thiophene-2-carboxylate, to give the desired product, 3-pyridylamino 5-hydrazinecarboxamide-2-carboxylic acid (yield 78%).

Morphology: colourless solid

LC/MS: conditions 1, retention time 0,34 (min)

LC/M is (ESI +) m/z 263 [M+1]+

LC/MS (ESI-) m/z 261 [M-1]-

REFERENCE EXAMPLE 8 SYNTHESIS

Synthesis of 2-chloro-4-hydrazinophenyl-N-(2-hydroxyethyl)benzamide

Followed the procedure of reference synthesis example 1, using methyl ester methyl 3-chloro-N-(2-hydroxyethyl)terephthalic acid, to give the desired product, 2-chloro-4-hydrazinophenyl-N-(2-hydroxyethyl)benzamide (yield 66%).

Morphology: colourless solid

LC/MS: conditions 2, retention time 0,32 (min)

LC/MS (ESI+) m/z 258, 260 [M+1]+

LC/MS (ESI-) m/z 256, 258 [M-1]-

REFERENCE EXAMPLE 9 SYNTHESIS

Synthesis of 5-(2-cyanobutane)thiophene-2-carbohydrazide methyl 5-(2-cyanobutane)thiophene-2-carboxylate

To butyronitrile (957 μl, 11 mmol) in tetrahydrofuran was added hexamethyldisilazide lithium (12.5 ml 1M solution in tetrahydrofuran, 12.5 mmol) at -78°C and the resulting solution was stirred for 1 hour and added dropwise to 5-methoxycarbonylmethyl-2-carbonylchloride (1,02 g, 5 mmol) in tetrahydrofuran at -78°C for 30 minutes and the resulting reaction mixture was stirred at room temperature for 1 hour. The solvent is evaporated, the reaction solution was mixed with ethyl acetate and washed with saturated aqueous solution of ammonium chloride and a saturated solution of sodium chloride and purified column chromatography on silica compound the gel (eluent hexane/ethyl acetate = 3/1) to give the desired product, methyl 5-(2-cyanobutane)thiophene-2-carboxylate (yield 41%).

Morphology: yellow solid

LC/MS: condition 3, the retention time of 2.45 (min)

LC/MS (ESI+) m/z 238 [M+1]+

LC/MS (ESI-) m/z 236 [M-1]-

5-(2-Cyanobutane)thiophene-2-carbohydrazide

Methyl 5-(2-cyanobutane)thiophene-2-carboxylate (213 mg, 0.90 mmol) in methanol was mixed with 0,1M potassium hydroxide in methanol (9.0 ml, 0.90 mmol) at room temperature for 10 minutes and then hydrazine monohydrate (225 mg, 4,50 mg) at 80°C for 6 hours. After adding a saturated aqueous solution of sodium chloride, the reaction solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to obtain the crude desired product.

Morphology: yellow solid

REFERENCE EXAMPLE 10 SYNTHESIS

Synthesis of methyl-2-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference synthesis example 1, using methyl 5-(methyl-2-picolylamine)thiophene-2-carboxylate, to give the desired product, methyl-2-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid (yield 77%).

Morphology: white solid

LC/MS: condition 8, the retention time of 0.45 (min)

LC/MS (ESI+) m/z 291 [M+1]+

LC/MS (ESI-) m/z 289 [M-1]-

REFERENCE EXAMPLE 11 SYNTHESIS

Methyl 5-(3-picolylamine)thiophene-2-carboxylate (860 mg, 3.11 mmol) in ethanol (34 ml) was stirred with hydrazine monohydrate (1.57 in ml, of 31.1 mmol) at 85°C for 12 hours. The reaction solution was concentrated and stirred with diethyl ether at 0°C for 1 hour. The precipitated solid was isolated by filtration and washed with a liquid mixture of diethyl ether and ethanol and dried to give the desired product, 3-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid (yield 92%).

Morphology: white solid

LC/MS: conditions 1, retention time 0,23 (min)

LC/MS (ESI+) m/z 277 [M+1]+

LC/MS (ESI+-) m/z 275 [M-1]-

REFERENCE EXAMPLE 12 SYNTHESIS

Synthesis of 4-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 11 synthesis using methyl 5-(4-picolylamine)thiophene-2-carboxylate, to give the desired product, 4-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid (yield 81%).

Morphology: white solid

LC/MS: conditions 1, retention time 0,23 (min)

LC/MS (ESI+) m/z 277 [M+1]+

LC/MS (ESI-) m/z 275 [M-1]-

REFERENCE EXAMPLE 13 SYNTHESIS

Synthesis of (furan-2-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 11 synthesis, use what I methyl 5-(furan-2-letiltasaval)thiophene-2-carboxylate, to give the desired product (furan-2-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid (yield 86%).

Morphology: white solid

LC/MS: condition 3, the retention time of 1.50 (min)

LC/MS (ESI+) m/z 266 [M+1]+

LC/MS (ESI-) m/z 264 [M-1]-

REFERENCE EXAMPLE 14 SYNTHESIS

Synthesis methylamide 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 11 synthesis using methyl 5-(methylcarbamoyl)thiophene-2-carboxylate, to give the desired product, methylamide 5-hydrazinecarboxamide-2-carboxylic acid (yield 83%).

Morphology: pale yellow solid

LC/MS: condition 3, the retention time of 0.37 (min)

LC/MS (ESI+) m/z 200 [M+1]+

LC/MS (ESI-) m/z 198 [M-1]-

REFERENCE EXAMPLE 15 SYNTHESIS

Synthesis of Isopropylamine 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 11 synthesis using methyl 5-(isopropylcarbamate)thiophene-2-carboxylate, to give the desired product, Isopropylamine 5-hydrazinecarboxamide-2-carboxylic acid (yield 45%).

Morphology: white solid

LC/MS: conditions 2, retention time of 1.07 (min)

LC/MS (ESI+) m/z 228 [M+1]+

LC/MS (ESI-) m/z 226 [M-1]-

REFERENCE EXAMPLE 16 SYNTHESIS

Synthesis of 2-picolylamine-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 11 synthesis using methyl 5-(2-picolylamine)thiophene-2-carboxylate, to give the desired product, 2-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid (yield 81%).

Morphology: white solid

LC/MS: conditions 1, retention time of 0.28 (min)

LC/MS (ESI+) m/z 277 [M+1]+

LC/MS (ESI-) m/z 275 [M-1]-

REFERENCE EXAMPLE 17 SYNTHESIS

Synthesis of (2-pyridin-4-yl)ethylamide 5-hydrazinecarboxamide-2-carboxylic acid

Methyl 5-[2-(pyridin-4-yl)ethylcarbamate]thiophene-2-carboxylate (0.40 g, 1.4 mmol) suspended in a liquid mixture of methanol (4.0 ml) and tetrahydrofuran (2.0 ml) and left at 55°C to confirm the transformation in homogeneous amber solution. After adding 80% solution of hydrazine monohydrate (0.17 ml, 2.8 mmol) and the mixture was left to stand at 55°C for 24 hours. After adding 80% solution of hydrazine monohydrate (0.17 ml, 2.8 mmol) and the mixture was left to stand at 55°C for 4.5 hours and then at room temperature for 14 hours. The precipitated solid was isolated by filtration and dried to give the desired product (2-pyridin-4-yl)ethylamide 5-hydrazinecarboxamide-2-carboxylic acid (yield 82%).

Morphology: white solid

1H-NMR (DMSO-d6) δ: 2,86 (t, J=7,0 Hz, 2H), 3,50 (dt, J=5.5 and 7.0 Hz, 2H), to 4.52 (users, 2H), 7,26 (d, J=6.0 Hz, 2H), 8,46 (d, J=6.0 Hz, 2H), 8,72 (t, J=5.5 Hz, 1H), 9,90 (users, 1H).

REFERENCE EXAMPLE 18 SYNTHESIS

Synthesis of 5-(hydrazinophenyl)-N-[(1-methyl-1H-pyrazole-5-yl)methyl]thiophene-2-carboxamide

Methyl 5-(1-methyl-1H-pyrazole-5-letiltasaval)thiophene-2-carboxylate (0.25 g, 0.90 mmol) in methanol (2.5 ml) was stirred with hydrazine monohydrate (0.17 ml, 3.6 mmol) at 70°C for 3.5 hours. The precipitated solid was isolated by filtration, washed with chloroform and dried to give the desired product, 5-(hydrazinophenyl)-N-[(1-methyl-1H-pyrazole-5-yl)methyl]thiophene-2-carboxamide (yield 49%).

Morphology: white solid

LC/MS: conditions 2, retention time of 0.40 (min)

LC/MS (ESI+) m/z 280 [M+1]+

LC/MS (ESI-) m/z 278 [M-1]-

REFERENCE EXAMPLE 19 SYNTHESIS

Synthesis of (5-methylisoxazol-3-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 18 synthesis using methyl 5-(5-methylisoxazol-3-letiltasaval)thiophene-2-carboxylate, to give the desired product (5-methylisoxazol-3-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid (yield 47%).

Morphology: white solid

LC/MS: conditions 2, retention time 1.00 (min)

LC/MS (SI+) m/z 281 [M+1]+

LC/MS (ESI-) m/z 279 [M-1]-

REFERENCE EXAMPLE 20 SYNTHESIS

Synthetic is (5-methylpyrazine-2-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid

Methyl 5-(5-methylpyrazine-2-letiltasaval)thiophene-2-carboxylate (304 mg, 1.04 mmol) in methanol (3 ml) was stirred with hydrazine monohydrate at 60°C for 12 hours. After addition of chloroform, the mixture was stirred at room temperature for 5 hours. The precipitated solid was isolated by filtration to give the desired product (5-methylpyrazine-2-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid (yield 72%).

Morphology: white solid

LC/MS: condition 3, the retention time is 0.69 (min)

LC/MS (ESI+) m/z 292 [M+1]+

LC/MS (ESI-) m/z 290 [M-1]-

REFERENCE EXAMPLE 21 SYNTHESIS

Synthesis of (isoxazol-5-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 18 synthesis using methyl 5-(isoxazol-5-letiltasaval)thiophene-2-carboxylate, to give the desired product (isoxazol-5-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid (yield 46%).

Morphology: white solid

LC/MS: conditions 2, retention time of 0.62 (min)

LC/MS (ESI+) m/z 267 [M+1]+

LC/MS (ESI-) m/z 265 [M-1]-

REFERENCE EXAMPLE 22 SYNTHESIS

Synthesis of (3-methoxyethoxy-5-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 18 synthesis using methyl -(3-methoxyethoxy-5-letiltasaval)thiophene-2-carboxylate, to give the desired product (3-methoxyethoxy-5-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid (yield 50%).

Morphology: colourless solid

LC/MS: condition 2, the retention time of 1,25 (min)

LC/MS (ESI+) m/z 297 [M+1]+

LC/MS (ESI-) m/z 295 [M-1]-

REFERENCE EXAMPLE 23 SYNTHESIS

Synthesis of (1,5-dimethyl-1H-pyrazole-3-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 18 synthesis using methyl 5-(1,5-dimethyl-1H-pyrazole-3-letiltasaval)thiophene-2-carboxylate, to give the desired product (1,5-dimethyl-1H-pyrazole-3-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid (yield 59%).

Morphology: white solid

LC/MS: conditions 2, retention time 1.00 (min)

LC/MS (ESI+) m/z 294 [M+1]+

LC/MS (ESI-) m/z 292 [M-1]-

REFERENCE EXAMPLE 24 SYNTHESIS

Synthesis of (pyrazin-2-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid

Followed the procedure of reference example 18 synthesis using methyl 5-(pyrazin-2-letiltasaval)thiophene-2-carboxylate, to give the desired product (pyrazin-2-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid ((yield 82%).

Morphology: white solid

LC/MS: conditions 2, retention time of 0.37 (min)

LC/MS (ESI+) m/z 278 [M+] +

LC/MS (ESI-) m/z 276 [M-1]-

REFERENCE EXAMPLE 25 SYNTHESIS

a)Synthesis of 4-[{5-(methoxycarbonyl)thiophene-2-carboxamido}methyl]pyridine 1-oxide

4-Picolylamine 5-hydrazinecarboxamide-2-carboxylic acid (0.20 g, to 0.72 mmol)obtained in Reference example 12 synthesis in chloroform (4.0 ml) was mixed with 65% wt. m-chloroperbenzoic acid (0.21 g, 0.80 mmol) at room temperature for 9 hours, then the mixture was left to stand for 18 hours and then concentrated to dryness under reduced pressure. To the residue was added chloroform (30 ml), saturated aqueous sodium hydrogen carbonate solution (3 ml) and water (7 ml) and the organic layer was separated. The aqueous layer was extracted with chloroform (10 ml ×2) and hot chloroform (10 ml ×1). The obtained organic layer was concentrated to give the desired crude product, 4-[{5-(methoxycarbonyl)thiophene-2-carboxamido}methyl]pyridine 1-oxide (purity 80% of the mass, yield 62%).

Morphology: white solid

LC/MS: conditions 2, retention time 1,77 (min)

LC/MS (ESI+) m/z 293 [M+1]+

LC/MS (ESI-) m/z 291 [M-1]-

b)Synthesis of 4-[{5-hydrazinophenyl)thiophene-2-carboxamido}methyl]pyridine 1-oxide

4-[{5-(Methoxycarbonyl)thiophene-2-carboxamido}methyl]pyridine 1-oxide (0.12 g, 0.34 mmol)obtained above, suspended in methanol (2.0 ml)was left at 6°C. After adding 80% solution of hydrazine monohydrate (0,082 ml, 1.4 mmol) and the mixture was left to stand at 60°C for 3.5 hours, then at room temperature for 5.5 hours and at 0°C for 11.5 hours. The precipitated solid was isolated by filtration and dried to give the desired product, 4-[{5-hydrazinophenyl)thiophene-2-carboxamido}methyl]pyridine 1-oxide (yield 51%).

Morphology: pale yellow solid

LC/MS: conditions 2, retention time of 0.37 (min)

LC/MS (ESI+) m/z 293 [M+1]+

LC/MS (ESI-) m/z 291 [M-1]-

1H-NMR (DMSO-d6) δ: 4,42 (users, 2H), 4,51 (users, 0,7H), 7,32 (d, J=7,0 Hz, 2H), 7,68 (d, J=4.0 Hz, 1H), of 7.75 (d, J=7,0 Hz, 1H), 8,17 (d, J=7,0 Hz, 2H), 9,25 (t, J=6.0 Hz, 0,3H), 9,92 (users, 0,3H).

REFERENCE EXAMPLE 26 SYNTHESIS

Synthesis of 3-(pyridin-4-yl)propylamide 5-hydrazinecarboxamide-2-carboxylic acid

80% Solution of hydrazine monohydrate (0.17 ml, 2.8 mmol) was added to methyl 5-[3-(pyridin-4-yl)propellerblades]thiophene-2-carboxylate (0.28 g, to 0.92 mmol) in methanol (10 ml) and the reaction solution was left at 50°C for 95 hours. After adding 80% solution of hydrazine monohydrate (0.17 ml, 2.8 mmol) and the mixture was left to stand at 55°C for 14 hours and then concentrated to dryness by evaporation of the solvent under reduced pressure. To the residue was added methanol (2 ml) and the resulting solution was placed in the device is for processing ultrasound. The precipitated solid was isolated by filtration and dried to give the desired product, 3-(pyridine-4-yl)propylamide 5-hydrazinecarboxamide-2-carboxylic acid (yield 61%).

Morphology: white solid

1H-NMR (DMSO-d6) δ: 1,84 (TT, J=7.5 and 6.5 Hz, 2H), 2,64 (t, J=7.5 Hz, 2H), 3,25 (dt, J=5.5 And a 6.5 Hz, 2H), 4,54 (users, 1,6N), 7,26 (d, J=6.0 Hz, 2H), 7,65 (d, J=4.0 Hz, 1H), to 7.67 (d, J=4.0 Hz, 1H), 8,45 (d, J=6.0 Hz, 2H), 8,65 (ushort, J=5.5 Hz, 0,N), 9,90 (users, 0,N).

REFERENCE EXAMPLE 27 SYNTHESIS

Synthesis of 5-(hydrazinophenyl)-N-[(1-methyl-1H-imidazol-5-yl)methyl]thiophene-2-carboxamide

Followed the procedure of reference example 18 synthesis using methyl 5-(1-methyl-1H-imidazol-5-letiltasaval)thiophene-2-carboxylate, to give the desired product, 5-(hydrazinophenyl)-N-[(1-methyl-1H-imidazol-5-yl)methyl]thiophene-2-carboxamide (yield 70%).

Morphology: pale yellow solid

LC/MS: condition 3, the retention time of 0.30 (min)

LC/MS (ESI+) m/z 280 [M+1]+

LC/MS (ESI-) m/z 278 [M-1]-

REFERENCE EXAMPLE 28 SYNTHESIS

Synthesis of 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carbohydrazide

Followed the procedure of reference example 18 synthesis using methyl 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carboxylate, to give the desired product, 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carbohydrazide (yield 53%).

Morphology: white tortoiseshell

EXAMPLE of SYNTHESIS 1

Synthesis of {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carboxylic acid

{1-[5-(3,4-Dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carboxylic acid hydrochloride

28 mg of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate (synthesised in accordance with WO 2004/108683) and 29.7 mg of 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carbohydrazide obtained in Reference synthesis example 1 in 2 ml of isopropyl alcohol was heated with 3 mg of the monohydrate of p-toluensulfonate acid and 25 μl (1 EQ) of a solution of 4M hydrogen chloride/dioxane at 105°C for 8 hours. The reaction solution was again heated with 2 ml of dimethylformamide at 105°C for 5 hours and cooled to room temperature. The precipitated solid was isolated by filtration and washed with 1 ml of isopropyl alcohol and 1 ml of chloroform, and the obtained crystals were dried to give the desired product (yield 54%).

Morphology: colourless solid

LC/MS: condition 5, the retention time of 3.80 (min)

LC/MS (ESI+) m/z 565, 567 [M+1]+

LC/MS (ESI-) m/z 563, 565 [M-1]-

{1-[5-(3,4-Dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carboxylic acid

{1-[5-(3,4-Dichlorophenyl)-4-Ki is recitifer-3-yl]ethylidene}hydrazide 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carboxylic acid. hydrochloride (14 mg, of 0.025 mmol) suspended in methanol (2.7 ml) and the solution was added 0,1M potassium hydroxide in methanol (0,24 ml) and methanol (5.4 ml). The suspension was heated at 50°C and then concentrated to dryness under reduced pressure to give the desired product (yield 100%).

Morphology: light brown solid

EXAMPLE of SYNTHESIS 2

Synthesis of potassium salt of {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(morpholine-4-carbonyl)thiophene-2-carboxylic acid

{1-[5-(3,4-Dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(morpholine-4-carbonyl)thiophene-2-carboxylic acid

28 mg of 2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonate and 26 mg of 5-(morpholine-4-carbonyl)thiophene-2-carbohydrazide obtained in Reference synthesis example 2, was heated in isopropyl alcohol with 3 mg of the monohydrate of p-toluensulfonate acid at 105°C for 18 hours and cooled to room temperature. The precipitated solid was isolated by filtration and washed with 1 ml of isopropyl alcohol and the obtained crystals were dried to give the desired product (yield 86%).

Morphology: pale yellow solid

LC/MS: conditions 5, retention time 4,89 (min)

LC/MS (ESI+) m/z 524, 526 [M+1]+

LC/MS (ESI-) m/z 522, 524 [M-1]-

Potassium salt of {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(morpholine-carbonyl)thiophene-2-carboxylic acid

{1-[5-(3,4-Dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(morpholine-4-carbonyl)thiophene-2-carboxylic acid (20 mg, of 0.038 mmol) suspended in methanol (2.4 ml) was added a solution of 0.1 m potassium hydroxide in methanol (0,38 ml)and then methanol (5.6 ml). The suspension was heated at 50°C and then concentrated to dryness under reduced pressure to give the desired product (yield 100%).

EXAMPLE of SYNTHESIS 3

Synthesis of potassium salt of diethylamide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

Diethylamid 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and diethylamid 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference synthesis example 3 (yield 76%).

Morphology: pale yellow solid

LC/MS: condition 5, the retention time of 5.82 (min)

LC/MS (ESI+) m/z 510, 512 [M+1]+

LC/MS (ESI-) m/z 508, 510 [M-1]-

Potassium salt of diethylamide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using diethylamid 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-and the]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid (yield 100%).

Morphology: orange solid

EXAMPLE of SYNTHESIS 4

Synthesis of potassium salt of {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid

{1-[5-(3,4-Dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbamyl)thiophene and 5-(pyrrolidin-1-carbonyl)thiophene-2-carbohydrazide obtained in reference example synthesis of 4 (yield 94%).

Morphology: pale yellow solid

LC/MS: condition 5, the retention time of 5.34 (min)

LC/MS (ESI+) m/z 508, 510 [M+1]+

LC/MS (ESI-) m/z 506, 508 [M-1]-

Potassium salt of {1-[5-{3, 4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid (yield 100%).

Morphology: orange solid

EXAMPLE of SYNTHESIS of 5

Synthesis of potassium salt of dimethylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

Dimethylamide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl] this is Eden}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and dimethylamide 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference synthesis example 5 (yield 65%).

Morphology: colourless solid

LC/MS: condition 5, the retention time is 4.93 (min)

LC/MS (ESI+) m/z 482, 484 [M+1]+

LC/MS (ESI-) m/z; 480, 482 [M-1]-

Potassium salt of dimethylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using dimethylamide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid (yield 100%).

Morphology: orange solid

EXAMPLE of SYNTHESIS 6

Synthesis of potassium salt of 2-methoxyethylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

2-Methoxyethylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene)hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and 2-methoxyethylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference example synthesis of 6 (Ihad 80%).

Morphology: pale yellow solid

LC/MS: 7, the retention time of 3.15 in (min)

LC/MS (ESI+) m/z 512, 514 [M+1]+

LC/MS (ESI-) m/z 510, 512 [M-1]-

Potassium salt of 2-methoxyethylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 2-methoxyethylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid (yield 100%).

Morphology: orange solid

EXAMPLE of synthesis of 7

Synthesis of potassium salt of 3-pyridylamino 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid

3-Pyridylamino-[(2-{1-[5- (3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

28 mg of 2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonate and 26 mg of 3-pyridylamino 5-hydrazinecarboxamide-2-carboxylic acid was dissolved in 2 ml of dimethylsulfoxide and heated at 100°C for 18 hours and the solvent evaporated. Recrystallization from chloroformmethanol ether gave the desired product (yield 94%).

Morphology: pale yellow solid

LC/MS: conditions 2, retention time was 4.02 (min)

LC/MS (ESI+) m/z 531, 533 [M+1]+

LC/MS (ESI-)m/z; 529, 531 [M-1]-

Potassium salt of 3-pyridylamino 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 3-pyridylamino 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid (yield 76%).

Morphology: orange solid

EXAMPLE of SYNTHESIS 8

Synthesis of diethylamide 5-[(2-{1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 2-(4-triptoreline)-3-hydroxy-4-methylcarbonate (synthesised in accordance with WO 2004/108683) and diethylamid 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference synthesis example 3 (yield 67%).

Morphology: pale yellow solid

LC/MS: condition 6, the retention time of 3,82 (min)

LC/MS (ESI-) m/z 508 [M-1]-

EXAMPLE 9 SYNTHESIS

Synthesis of potassium salt of {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carboxylic acid

{1-[5-(4-Triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carboxylic acid

The synthesis was carried out in the same is the procedure, as in synthesis example 7 using 2-(4-triptoreline)-3-hydroxy-4-methylcarbonate and 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carbohydrazide obtained in reference synthesis example 1 (yield 55%).

Morphology: yellow solid

LC/MS: condition 3, retention time 2,49 (min)

LC/MS (ESI+) m/z 565 [M+1]+

LC/MS (ESI-) m/z 563 [M-1]-

Potassium salt of {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(4-Isopropylpiperazine-1-carbonyl)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carboxylic acid (yield 100%).

Morphology: red solid

EXAMPLE 10 SYNTHESIS

Synthesis of potassium salt of {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid

{1-[5-(4-Triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 2-(4-triptoreline)-3-hydroxy-4-methylcarbonate and 5-(pyrrolidin-1-carbonyl)thiophene-2-carbohydrazide obtained in reference example synthesis of 4 (yield 82%).

Morphology: bled the yellow solid

LC/MS: condition 8, the retention time of 5,10 (min)

LC/MS (ESI+) m/z 508 [M+1]+

LC/MS (ESI-) m/z 506 [M-1]-

Potassium salt of {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid (yield 100%).

Morphology: red solid

EXAMPLE 11 SYNTHESIS

Synthesis of potassium salt of 2-chloro-4-(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazinophenyl)-N-(2-hydroxyethyl)benzamide

2-chloro-4-(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazinophenyl)-N-(2-hydroxyethyl) benzamide

To 2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonate (40 mg, 0.14 mmol) and 2-chloro-4-hydrazinophenyl-N-(2-hydroxyethyl)benzamide (43 mg, 0,17 mmol)obtained in Reference example 8 synthesis in dimethylformamide (0.7 ml) was added concentrated hydrochloric acid (12 μl, 0.14 mmol) at room temperature and the resulting mixture was stirred at room temperature for 1 day and was stirred with 2-chloro-4-hydrazinophenyl-N-(2-hydroxyethyl) benzamide (18 mg, 0.07 mmol) in 1 day. After adding water, the resulting crystals were isolated filters the tion and dried. Added chloroform, and the obtained crystals were isolated by filtration to give the desired product (yield 83%).

Morphology: pale green solid

LC/MS: condition 3, the retention time of 3.42 (min)

LC/MS (ESI+) m/z 526, 528 [M+1]+

LC/MS (SI-) m/z 524, 526 [M-1]-

Potassium salt of 2-chloro-4-(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazinophenyl)-N-(2-hydroxyethyl)benzamide

The synthesis was carried out in the same manner as in synthesis example 2,using 2-chloro-4-(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazinophenyl)-N-(2-hydroxyethyl)benzamide (yield 77%).

Morphology: red solid

EXAMPLE 12 SYNTHESIS

Synthesis of potassium salt of methyl 2-picolylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid

Methyl-2-picolylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 7 using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and methyl-2-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference example 10 synthesis (yield 66%).

Morphology: pale yellow solid

LC/MS: condition 3, retention time 3/57 (min)

LC/MS (ESI+) m/z 559, 561 [M+1]

LC/MS (ESI-) m/z 557, 559 [M-1]-

Potassium salt of methyl-2-picolylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using methyl-2-picolylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid (yield 100%).

Morphology: red solid

EXAMPLE of SYNTHESIS 13

Synthesis of potassium salt of methyl 2-picolylamine 5-[(2-{1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

Methyl-2-picolylamine 5-[(2-{1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 7 using 2-(4-triptoreline)-3-hydroxy-4-methylcarbonate and methyl-2-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference example 10 synthesis.

Morphology: pale green solid

Potassium salt of methyl-2-picolylamine 5-[(2-{1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using methyl-2-picolylamine 5-[(2-{1-[5-(4-triptoreline)-4-hydroxamate the-3-yl]ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid (yield 100%).

Morphology: orange solid

EXAMPLE 14 SYNTHESIS

Synthesis of potassium salt of {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid

{1-[5-(3,4-Dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 7 using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and 5-(2-cyanobutane)thiophene-2-carbohydrazide obtained in reference example 9 synthesis (yield 36%).

Morphology: yellow solid

LC/MS: condition 3, the retention time of 3.45 (min)

LC/MS (ESI+) m/z 506, 508 [M+1]+

LC/MS (ESI-) m/z 504, 506 [M-1]-

Potassium salt of {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid (yield 75%).

Morphology: red solid

EXAMPLE 15 SYNTHESIS

Synthesis of potassium salt of {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid

{1-[5-(4-Triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carbon is th acid

The synthesis was carried out in the same manner as in synthesis example 7 using 2-(4-triptoreline)-3-hydroxy-4-methylcarbonate and 5-(2-cyanobutane)thiophene-2-carbohydrazide obtained in Reference example 9 synthesis (yield 53%).

Morphology: yellow solid

LC/MS: condition 3, retention time 3,82 (min)

LC/MS (ESI+) m/z 506 [M+1]+

LC/MS (ESI-) m/z 504 [M-1]-

Potassium salt of {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid (yield 91%).

Morphology: red solid

EXAMPLE 16 SYNTHESIS

Synthesis of potassium salt of {1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid

{1-[5-(4-Bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 7 using 2-(4-bromophenyl)-3-hydroxy-4-methylcarbonate (synthesized according to WO2004/108684) and 5-(2-cyanobutane)thiophene-2-carbohydrazide obtained in Reference example 9 synthesis (yield 51%).

Morphology: yellow solid in the society

LC/MS: condition 3, the retention time of 3.85 (min)

LC/MS (ESI+) m/z 516, 518 [M+1]+

LC/MS (ESI-) m/z 514, 516 [M-1]-

Potassium salt of {1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl] ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using {1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(2-cyanobutane)thiophene-2-carboxylic acid (yield 91%).

Morphology: red solid

EXAMPLE 17 SYNTHESIS

Synthesis of 3-picolylamine-[(2-{1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

2-(4-Bromophenyl)-3-hydroxy-4-methylcarbonate (50.5 mg, 0,17 mmol) (synthesized according to WO 2004/108683) and 3-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference synthesis example 11, was dissolved in dimethyl sulfoxide (4.0 ml) and heated at 110°C for 24 hours. The solvent is evaporated and the residue was washed with methanol and water to give the desired product (yield 81%).

Morphology: pale yellow solid

LC/MS: condition 6, the retention time 4,15 (min)

LC/MS (ESI+) m/z 555, 557 [M+1]+

LC/MS (ESI-) m/z 553, 555 [M-1]-

EXAMPLE 18 SYNTHESIS

Synthesis of 4-picolylamine-[(2-{1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-karbonovoi acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(4-bromophenyl)-3-hydroxyl-4-methylcarbonate and 4-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference example 12 synthesis (yield 72%).

Morphology: pale yellow solid

LC/MS: condition 6, the retention time is 4.03 (min)

LC/MS (ESI+) m/z 555, 557 [M+1]+

LC/MS (ESI-) m/z 553, 555 [M-1]-

EXAMPLE 19 SYNTHESIS

Synthesis of furan-2-ylmethylamino 5-[(2-{1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

2-(4-Bromophenyl)-3-hydroxy-4-methylcarbonate (50,1 mg, 0,17 mmol) and (furan-2-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid (45.0 mg, 0,17 mmol)obtained in Reference example 13 synthesis in 2-propanol (4.0 ml) was heated with monohydrate p-toluensulfonate acid (6 mg) at 100°C for 7.5 hours and cooled to room temperature. The precipitated solid was isolated by filtration, washed with 2-propanol (1 ml) and dried to give the desired product (yield 72%).

Morphology: pale yellow solid

LC/MS: condition 6, the retention time to 4.98 (min)

LC/MS (ESI+) m/z 544, 546 [M+1]+

LC/MS (ESI-) m/z 542, 544 [M-1]-

EXAMPLE 20 SYNTHESIS

Synthesis methylamide 5-[(2-{1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)is arbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 19, using 2-(4-bromophenyl)-3-hydroxy-4-methylcarbonate and methylamide 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 14 synthesis (yield 65%).

Morphology: pale yellow solid

LC/MS: condition 6, the retention time of 4.67 (min)

LC/MS (ESI+) m/z 478, 480 [M+1]+

LC/MS (SI)-m/z 476, 478 [M-1]-

EXAMPLE 21 SYNTHESIS

Synthesis isopropylamino-[(2-{1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 19, using 2-(4-bromophenyl)-3-hydroxy-4-methylcarbonate and isopropylated 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 15 synthesis (yield 70%).

Morphology: white solid

LC/MS: conditions 2, retention time 4,50 (min)

LC/MS (SI+) m/z 506, 508 [M+1]+

LC/MS (ESI-) m/z 504, 506 [M-1]-

EXAMPLE 22 SYNTHESIS

Synthesis of 2-picolylamine 5-[(2-{1-[4-hydroxy-5-(4-trifloromethyl)thiophene-3-yl]ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17, using 3-hydroxy-2-(4-trifloromethyl)-4-methylcarbonate (synthesised in accordance with WO 2004/108683) and 2-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid, obtained in reference example 16 synthesis (yield 76%).

Morphology: pale yellow solid

LC/MS: conditions 2, retention time to 3.92 (min)

LC/MS (ESI+) m/z 561 [M+1]+

LC/MS (SI-) m/z 559 [M-1]-

EXAMPLE 23 SYNTHESIS

Synthesis of Isopropylamine 5-[(2-{1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 19, using 2-(4-triptoreline)-3-hydroxy-4-methylcarbonate (synthesised in accordance with WO 2004/108683) and Isopropylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 15 synthesis (yield 83%).

Morphology: light grey solid

LC/MS: condition 3, the retention time of 3.65 (min)

LC/MS (SI+) m/z 496 [M+1]+

LC/MS (ESI-) m/z 494 [M-1]-

EXAMPLE 24 SYNTHESIS

Synthesis of 4-picolylamine 5-[(2-{1-[5-(4-chlorophenyl)-4-hydroxythiophene-3-yl] ethylidene)hydraena) carbonyl] thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(4-chlorophenyl)-3-hydroxy-4-methylcarbonate (synthesised in accordance with WO 2004/108683) and 4-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 12 synthesis (yield 69%).

Morphology: light brown solid vases is in

LC/MS: condition 3, the retention time of 2.55 (min)

LC/MS (ESI+) m/z 511, 513 [M+1]+

LC/MS (SI-) m/z 509, 511 [M-1]-

EXAMPLE 25 SYNTHESIS

Synthesis of 2-picolylamine 5-[(2-{1-[5-(4-chlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(4-chlorophenyl)-3-hydroxy-4-methylcarbonate and 2-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference example 16 synthesis (yield 68%).

Morphology: yellow solid

LC/MS: condition 3, retention time 3,10 (min)

LC/MS (ESI+) m/z 511, 513 [M+1]+

LC/MS (ESI-) m/z 509, 511 [M-1]-

EXAMPLE 26 SYNTHESIS

Synthesis of 3-picolylamine 5-[(2-{1-[5-(4-chlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(4-chlorophenyl)-3-hydroxy-4-methylcarbonate and 3-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 11 synthesis (yield 50%).

Morphology: yellow solid

LC/MS: condition 3, the retention time of 2.72 (min)

LC/MS (SI+) m/z 511, 513 [M+1]+

LC/MS (ESI-) m/z 509, 511 [M-1]-

EXAMPLE 27 SYNTHESIS

Synthesis methylamide 5-[(2-{1-[5-(4-chlorophenyl)-4-hydroxythiophene-3-yl]atili the Yong}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 19, using 2-(4-chlorophenyl)-3-hydroxy-4-methylcarbonate and methylamide 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference example 14 synthesis (yield 82%).

Morphology: pale yellow solid

LC/MS: condition 6, the retention time 4,62 (min)

LC/MS (ESI+) m/z 434, 436 [M+1]+

LC/MS (SI-) m/z 432, 434 [M-1]-

EXAMPLE 28 SYNTHESIS

Synthesis of Isopropylamine 5-[(2-{1-[5-(3,4-dimetilfenil)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 19, using 2-(3,4-dimetilfenil)-3-hydroxy-4-methylcarbonate (synthesised in accordance with WO 2004/108683) and Isopropylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 15 synthesis (yield 71%).

Morphology: pale yellow solid

LC/MS: conditions 2, retention time and 4.40 (min)

LC/MS (ESI+) m/z 456 [M+1]+

LC/MS (ESI-) m/z 454 [M-1]-

EXAMPLE 29 SYNTHESIS

Synthesis of 2-picolylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(3,4-dichlorophenyl-3-hydroxy-4-methylcarbonate (synthesized in soo is Ted WO 2004/108683) and 2-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid, obtained in reference example 16 synthesis (yield 65%).

Morphology: yellow solid

LC/MS: condition 3, retention time 3,30 (min)

LC/MS (ESI+) m/z 545, 547 [M+1]+

LC/MS (SI-) m/z 543, 545 [M-1]-

EXAMPLE 30 SYNTHESIS

Synthesis of 4-picolylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and 4-picolylamine 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 12 synthesis (yield 51%).

Morphology: pale yellow solid

LC/MS: conditions 2, retention time of 3.25 (min)

LC/MS (ESI+) m/z 545, 547 [M+1]+

LC/MS (ESI-) m/z 543, 545 [M-1]-

EXAMPLE 31 SYNTHESIS

Synthesis of 2-(pyridin-4-yl)ethylamide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonate (0.11 g, 0.38 mmol) and (2-pyridin-4-yl)ethylamide 5-hydrazinecarboxamide-2-carboxylic acid (0.10 g, 0.34 mmol)obtained in reference example 17 synthesis, suspended in N,N-dimethylformamide (2.0 ml) and the mixture was left to stand at 100°C for 5 hours and then at room temperature for 20 hours. Was added water (0,20 ml) is ri stirring and the precipitated solid was isolated by filtration, washed with chloroform and dried to give the desired product, 2-(pyridin-4-yl)ethylamide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid (yield 66%).

Morphology: white solid

LC/MS: condition 3, retention time to 2.67 (min)

LC/MS (ESI+) m/z 559, 561 [M+1]+

EXAMPLE 32 SYNTHESIS

Synthesis of (1-methyl-1H-pyrazole-5-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid

2-(3,4-Dichlorophenyl) -3-hydroxy-4-methylcarbonate (50 mg, 0,17 mmol) and 5-(hydrazinophenyl)-N-[(1-methyl-1H-pyrazol-5-yl)methyl]thiophene-2-carboxamide (49 mg, 0,17 mmol)obtained in reference synthesis example 18, was dissolved in N,N-dimethylformamide (0,50 ml) and heated at 70°C for 24 hours and cooled to room temperature. After addition of water precipitated crystals were isolated by filtration, washed with water and chloroform and dried to give the desired product (yield 76%).

Morphology: pale yellow solid

LC/MS: condition 3, the retention time of 3.60 (min)

LC/MS (ESI+) m/z 548, 550 [M+1]+

LC/MS (ESI-) m/z 546, 548 [M-1]-

EXAMPLE 33 SYNTHESIS

Synthesis of (5-methylisoxazol-3-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid

Synthesis OS is Westley in the same way, as in synthesis example 32 using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and (5-methylisoxazol-3-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 19 synthesis (yield 67%).

Morphology: yellow solid

LC/MS: condition 3, the retention time of 3.77 (min)

LC/MS (ESI+) m/z 549, 551 [M+1]+

LC/MS (ESI-) m/z 547, 549 [M-1]-

EXAMPLE 34 SYNTHESIS

Synthesis of (5-methylpyrazine-2-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and (5-methylpyrazine-2-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference example 20 synthesis (yield 74%).

Morphology: pale yellow solid

LC/MS: condition 3, retention time 3,62 (min)

LC/MS (ESI+) m/z 560, 562 [M+1]+

LC/MS (ESI-) m/z 558, 560 [M-1]-

EXAMPLE 35 SYNTHESIS

Synthesis of (isoxazol-5-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 19, using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and (isoxazol-5-ylmethyl) amide 5-hydrazinobenzene the thiophene-2-carboxylic acid, obtained in Reference example 19 synthesis (yield 74%).

Morphology: pale yellow solid

LC/MS: condition 3, the retention time of 3.69 (min)

LC/MS (ESI+) m/z 535, 537 [M+1]+

LC/MS (SI-) m/z 533, 535 [M-1]-

EXAMPLE 36 SYNTHESIS

Synthesis of (3-methoxyethoxy-5-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example synthesis of 19, using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and (3-methoxyethoxy-5-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference example 22 synthesis (yield 52%).

Morphology: pale yellow solid

LC/MS: condition 3, the retention time of 3.75 (min)

LC/MS (ESI+) m/z 565, 567 [M+1]+

LC/MS (ESI-) m/z 563, 565 [M-1]-

EXAMPLE 37 SYNTHESIS

Synthesis of (1,5-dimethyl-1H-pyrazole-3-ylmethyl)amide 5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidenenorbornene}thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and (1,5-dimethyl-1H-pyrazole-3-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 23 synthesis (yield 86%).

Morphology: yellow solid

LC/MS (ESI+) m/z 562, 564 [M+1]+

LC/MS (ESI-) m/z 560, 562 [M-1]-

EXAMPLE 38 SYNTHESIS

Synthesis of (pyrazin-2-ylmethyl)amide 5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidenenorbornene}thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate and (pyrazin-2-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid obtained in Reference example 24 synthesis (yield 88%).

Morphology: pale yellow solid

LC/MS: condition 3, the retention time of 3.57 (min)

LC/MS (ESI+) m/z 546, 548 [M+1]+

LC/MS (ESI-) m/z 544, 546 [M-1]-

EXAMPLE 39 SYNTHESIS

Synthesis of 4-[{5-(2-[1-{5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl}ethylidene]hydrazinophenyl)thiophene-2-carboxamido}methyl]pyridine 1-oxide

2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonate (32 mg, 0.11 mmol) and 4-[{5-hydrazinophenyl)thiophene-2-carboxamido}methyl]pyridine 1-oxide (30 mg, 0.10 mmol)obtained in Reference example 25 synthesis, suspended in N,N-dimethylformamide (0,60 ml) and stirred at 80°C for 90 hours. After adding 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonate (26 mg, 0,091 mmol) the suspension was stirred at 80°C for 24 hours, left at room temperature for 5 hours and conc the Wali dry, obtaining crude yellow paste (91 mg). The paste is suspended in chloroform (2.0 ml) and the insoluble substance was isolated by filtration and dried to give the desired product, 4-[{5-(2-[1-{5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl}ethylidene]hydrazinophenyl)thiophene-2-carboxamido}methyl]pyridine 1-oxide (yield 52%).

Morphology: pale yellow solid

LC/MS: condition 3, retention time 3,29 (min)

LC/MS (ESI+) m/z 561, 563 [M+1]+

LC/MS (ESI-) m/z 559, 561 [M-1]-

EXAMPLE 40 SYNTHESIS

Synthesis of 3-(pyridin-4-yl)propylamide 5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidenenorbornene}thiophene-2-carboxylic acid

2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonate (42 mg, 0.14 mmol) and 3-(pyridin-4-yl)propylamide 5-hydrazinecarboxamide-2-carboxylic acid (40 mg, 0.13 mmol)obtained in Reference example 26 synthesis, was dissolved in N,N-dimethylformamide (1.0 ml) and the mixture was left to stand at 70°C for 16 hours and then at room temperature for 24 hours. Was added water (0,36 ml) under stirring and the precipitated solid was isolated by filtration to give the desired product, 3-(pyridine-4-yl)propylamide 5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidenenorbornene}thiophene-2-carboxylic acid (yield 95%).

Morphology: pale yellow solid

LC/MS: conditions 2,retention time of 3.31 (min)

LC/MS (ESI+) m/z 573, 575 [M+1]+

LC/MS (ESI-) m/z 571, 573 [M-1]-

EXAMPLE 41 SYNTHESIS

Synthesis of (1-methyl-1H-imidazol-5-ylmethyl)amide 5-{1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidenenorbornene}thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2-(4-triptoreline)-3-hydroxy-4-methylcarbonate and (1-methyl-1H-imidazol-5-ylmethyl)amide 5-hydrazinecarboxamide-2-carboxylic acid obtained in reference example 27 synthesis (yield 39%).

Morphology: pale yellow solid

LC/MS: conditions 2, retention time to 3.02 (min)

LC/MS (ESI+) m/z : 548 [M+1]+

LC/MS (ESI-) m/z 546 [M-1]-

EXAMPLE 42 SYNTHESIS

Synthesis of {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazide 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbamyl)thiophene and 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carbohydrazide obtained in Reference example 28 synthesis (yield 97%).

Morphology: yellow solid

LC/MS: condition 6, the retention time 3,47 (min)

LC/MS (ESI+) m/z 524, 526 [M+1]+

LC/MS (ESI-) m/z 522, 524 [M-1]-

EXAMPLE 43 SYNTHESIS

Synthesis of {1-[5-(4-triptoreline)-4-hydroxamate the-3-yl]ethylidene}hydrazide 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 2-(4-triptoreline)-3-hydroxy-4-methylcarbamyl)thiophene and 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carbohydrazide obtained in Reference example 28 synthesis (yield 84%).

Morphology: pale yellow solid

LC/MS: condition 6, the retention time 3,34 (min)

LC/MS (ESI+) m/z 524, 525 [M+1]+

LC/MS (ESI-) m/z 522, 523 [M-1]-

Structures of the compounds obtained in reference examples and synthesis examples synthesis presented below.

The TEST EXAMPLE 1

Stimulation of proliferation of thrombopoietin-dependent cell line

The ability of the compounds of examples of synthesis of the present invention to interact with the receptor thrombopoetin (TPO) was evaluated using cell lines of human leukemia UT7/EPO-mpl.

(1) Cells and cell culture

UT7/EPO-mpl is a stably transformed cell line, obtained by introducing into the cell line of human leukemia UT7/EPO vector, which induces the expression of receptor thrombopoetin person (c-mp1) under control of the cytomegalovirus pretannage promoter way Takatoku et al. (J. Biol. Chem, 272:7259-7263 (1997)). The proliferation of this cell line stimulated by thrombopoietin, while its parent cell line UT7/EPO does not show any response to thrombopoietin. These two cell lines have subculturally in IMDM (GIBCO)containing 10% fetal bovine serum (Thermo Electron or BioWest), using CO2incubator (5% CO2, 37°C).

(2) Analysis of cell proliferation

Subculturally cells, described above, were washed two times with PBS and suspended in IMDM containing 10% fetal bovine serum at a density of cells 6×104cells/ml Cell suspension was transferred into a 96-well culture plates (CORNING) in a 100-µl aliquot. Then either thrombopoetin (Pepro Tech EC), or compounds of Examples synthesis, dissolved in dimethyl sulfoxide was diluted 83-fold IMDM containing 10% fetal bovine serum, and added to the above cell suspension in 20-µl aliquot. Cell suspension was incubated in CO2incubator (5% CO2, 37°C) for 4 days. Cell proliferation was assessed using WST-8 reagent (Kishida Chemical Co., Ltd.) in accordance with the manufacturer's instructions. To each well of the culture of the tablet was added to a 10 μl aliquot of a solution of 5 mm reagent WST-8 and the plate is incubated at 37°C for 4 hours. Detection formed formisano pigment was carried out by measure the absorption at 450 nm using a reader for 96-well microplate (Nihon Molecular Devices, Spectramax 190). Connection Examples of synthesis of the present invention stimulated the proliferation of thrombopoetin-responsive cells, UT7/EPO-mpl dependent on the concentration of the way, while not observed any effect of the compounds of examples of synthesis on the proliferation of UT7/EPO, the parent cell line. These results show that the compounds of examples of synthesis of the present invention selectively act on the receptor thrombopoetin as its activators.

Connection examples synthesis 1-43 (in free form) were tested to determine the concentration of each compound, which provides the growth rate corresponding to 50% of the growth of cell lines of leukemia person UT7/EPO-mpl observed in the presence of 10 ng/ml TPO (EC50). All connections examples of synthesis 1-43 showed the value EC50about 10 ng/ml or below.

The TEST EXAMPLE 2

Each of the compounds of examples synthesis suspended in 99/1 liquid mixture of 0.5% solution of methylcellulose/polyoxyethylene sorbitan monooleate and oral was administered to 7-week old male rats Sprague-Dawley (Japan SLC, Inc.) at the dose of 10 mg/kg/10 ml through the gastric tube. In the interval from 0.5 to 2 hours after administration of the compounds periodically, the blood was collected from jugular vein using heparin as an anticoagulant. The blood was centrifuged at 3500 min-1within 10 minutes to obtain plasma. is the lazma added in system analysis to assess the proliferation of thrombopoietin-dependent cell line UT7/EPO-mpl in test Example 1 at a final concentration of from 0.1 to 3%, and assessed cell proliferation. The concentration of each compound in the plasma was calculated on the basis of cell proliferation in the presence of plasma, by comparison to a standard curve of cell proliferation against the concentration of the compound, which was obtained for each connection or determined by LC/MS (Agilent Technologies, Agilent 1100 series LC/MS (D). Each of the compounds of examples 1-16 synthesis, 31 and 38 (compound of example 31 synthesis and 38 were tested in the form of potassium salts) has reached the maximum blood concentration (Cmax) of about 300 ng/ml after 0.5-2 hours after oral administration to rats.

The TEST EXAMPLE 3

Activity to stimulate colony of megakaryocytes

The effect of the compounds of examples synthesis 1-43 of the present invention and reference examples of the synthesis of 29 and 30 on the proliferation, differentiation and maturation megakaryocytic cells was determined by the method of colony megakaryocytes using cells of human bone marrow (smfbl). Cells of human bone marrow CD34+(Cambrex Bio Science Walkersville) were incubated for 2-hole slide for 11 days in CO2incubator (5% CO2, 37°C) using MegaCultTM-C (StemCell Technologies)containing 0.1% (vol./about.) compounds of Examples synthesis, dissolved in dimethyl sulfoxide. After dehydration and fixation, cells were stained with antigliadin theine IIb/IIIa antibody in accordance with the manufacturer's instructions. Colonies consisting of at least 8 painted megakaryocytic cells in each well were counted under the microscope. The number of colonies of megakaryocytes in at least 2 holes were averaged.

The results show that the compounds of the present invention have excellent activity on stimulation colonies of megakaryocytes and increased numbers of platelets in such activity.

Table 7
Connection No.The number of colonies of megakaryocytes
The concentration of drug (ág/ml)
0,10,31
Example of synthesis 1154
Example of synthesis 2239
Example of synthesis 3348
Example of synthesis 484 148
Example of synthesis 5274
Example of synthesis 6115151
Example of synthesis 8147227
Example 10 synthesis105208
Example of synthesis 1361
Example 17 synthesis146
Example 18 synthesis125
Example 19 synthesis171
Example 20 synthesis185
Example 21 synthesis85
Example 22 synthesis96
Example 23 synthesis134
Example 24 synthesis164
Example 25 synthesis118
Example 26 synthesis182
Example 27 synthesis201
Example 28 synthesis105
Example 29 synthesis62
Example 30 synthesis145271
Example 31 synthesis 70136
Example 32 synthesis55
Example 33 synthesis53
Example 34 synthesis50
Example 35 synthesis135153
Example 36 synthesis102135
Example 37 synthesis81
Example 38 synthesis66
Example 39 synthesis86
Example 40 synthesis70
Primariness 41 41
Example 42 synthesis90
Example 43 synthesis109
Reference example synthesis 29231
Reference example synthesis 30123487

EXAMPLE of FORMULATION 1

Receive preparation in the form of pellets, containing the following ingredients

Ingredients
The compound of formula(I)10 mg
Lactose700 mg
Corn starch274 mg
HPC-L16 mg
1000 mg

The compound of formula (I) and lactose miss chere is C a sieve of 60 mesh. Corn starch is passed through a sieve of 120 mesh. They are mixed in the mixer, V-type. A powder mixture is mixed with a water solution of hydroxypropylcellulose (HPC-L) low viscosity, granularit (extrusion granulation, the size of the head of the extruder 0.5-1 mm) and dried. The obtained dried granules are passed through a vibrating sieve (12/60 mesh) to obtain a granulated product.

EXAMPLE of FORMULATION 2

Get the drug in powder form for insulinopenia containing the following ingredients

Ingredients
The compound of formula(I)10 mg
Lactose79 mg
Corn starch10 mg
Magnesium stearate1 mg
100 mg

The compound of formula (I) and lactose are passed through a sieve of 60 mesh. Corn starch is passed through a sieve of 120 mesh. They are mixed in the mixer, V-type. 10% of the powder is placed in a hard gelatin capsule No. 5, 100 mg each.

EXAMPLE of FORMULATION 3

Receive preparation in the form of granules for insular the tion, containing the following ingredients

Ingredients
The compound of formula(I)15 mg
Lactose90 mg
Corn starch42 mg
HPC-L3 mg
150 mg

The compound of formula (I) and lactose are passed through a sieve of 60 mesh. Corn starch is passed through a sieve of 120 mesh. The components are mixed in the mixer, V-type. A powder mixture is mixed with a water solution of hydroxypropylcellulose (HPC-L) low viscosity, granularit and dried. The obtained dried granules are passed through a vibrating sieve (12/60 mesh). The pellets are placed in a hard capsule No. 4, 150 mg each.

EXAMPLE of FORMULATION 4

Get the drug in the form of tablets containing the following ingredients

Ingredients
The compound of formula (I)10 mg
Lactose90 mg
Microcrystalline cellulose30 mg
Magnesium stearate5 mg
CMC-Na15 mg
150 mg

The compound of formula (I), lactose, microcrystalline cellulose and CMC-Na (sodium carboxymethyl cellulose) pass through a sieve of 60 mesh and mixed. A powder mixture is mixed with magnesium stearate to obtain a granular powder mixture. A powder mixture directly pressed in 150 mg tablets.

EXAMPLE of FORMULATION 5

An intravenous drug is produced as follows:

The compound of formula (I)100 mg
The glycerides of saturated fatty acids1000 ml

Solutions containing the above compositions are typically administered to a patient intravenously at a speed of 1 ml in 1 minute.

Industrial applicability

Compounds of the present invention, which have affinity to the receptor thrombopoetin and act as agonists of the receptor thrombopoetin are useful as tools for the of avoiding, cure or improvement of diseases in which activation of the receptor thrombopoetin is effective, especially as medicines for the treatment of hematological disorders, accompanied by abnormal platelet count, and as medicines for the treatment of diseases, treatment or prevention of which can be done by stimulating the differentiation and proliferation of endothelial cells of blood vessels and endothelial precursor cells, and are useful as pharmaceuticals.

1. The compound represented by formula (I):

where R1represents a phenyl group (this phenyl group substituted by one or more C1-6alkyl groups, one C1-3alkyl group (the specified C1-3alkyl group substituted by one or more halogen atoms), one C1-3alkoxygroup (specified C1-3alkoxygroup substituted by one or more halogen atoms) or one or more halogen atoms),
R2represents a C1-3alkyl group,
R3represents a phenyl group (this phenyl group substituted by one or more substituents selected from the group consisting of halogen atoms and the group (C=O)R 5'(where R5'represents NR6'R7'(where R6'represents a hydrogen atom, and R7'represents a C1-6alkyl group, a substituted hydroxyl group))),
thienyl group (provided thienyl group substituted by one or more substituents selected from the group comprising hydrogen atoms and a group (C=O)R5(where R5represents NR6R7(where R6represents a hydrogen atom or a C1-3alkyl group, and R7represents a C1-6alkyl group (specified With1-6the alkyl group may be substituted by one or more hydroxyl groups, one C1-3alkoxygroup or 5-6-membered aromatic heterocyclic group comprising 1-2 of heteroatom selected from oxygen or nitrogen, (where 5-6-membered aromatic heterocyclic group may be substituted by one or more C1-3alkyl groups, one or more1-3alkoxygroup, and in the case of a 5-6-membered aromatic heterocyclic group comprising one nitrogen atom may be in the form of N-oxide)), pyridyloxy group, or NR6R7represents, in General, nitrogen-containing heterocyclyl group, which is a 5-6-membered heterophilically a group that includes the one and the two nitrogen atom and may optionally contain one oxygen atom (specified nitrogen-containing heterocyclyl group may be substituted by one or more hydrogen atoms, one or more C1-6alkyl groups, one or more hydroxyl groups), or With1-6alkyl group (the specified C1-6the alkyl group may be substituted by one or more halogen atoms and is substituted by one cyano))),
R4represents a hydrogen atom or a pharmaceutically acceptable salt of the compounds.

2. The compound according to claim 1, where R2represents a methyl group, and R4represents a hydrogen atom,
or pharmaceutically acceptable salt of the compounds.

3. The compound according to claim 2, where R1represents a 3,4-dimethylphenyl group, 4-tert-butylphenyl group, 4-triftormetilfullerenov group, 3-chloraniline group, 4-chloraniline group, 4-florfenicol group, 3,4-dichloraniline group, 4-bromperidol group or 4-triphtalocyaninine group,
or pharmaceutically acceptable salt of the compounds.

4. The compound according to claim 3, where R3represented by formula (II):

(where R6represents a methyl group or ethyl group, and R7C1-6alkyl group (the specified C1-6the alkyl group may be substituted by one or more methoxypropane)), or a pharmaceutically acceptable salt of the compounds.

5. The connection is about to claim 3, where R3represented by formula (II):

(where R6represents a methyl group or ethyl group, and R7represents a C1-3alkyl group (specified With1-3alkyl group substituted by one or more phenyl groups or one or more peredelnyj groups)), or a pharmaceutically acceptable salt of the compounds.

6. The compound according to claim 3, where R3represented by formula (II):

(where R6represents a hydrogen atom, and R7represents a C1-6alkyl group (specified With1-6alkyl group substituted by one or more methoxypropane) or pyridyloxy group), or a pharmaceutically acceptable salt of the compounds.

7. The compound according to claim 3, where R3represented by formula (II):

where NR6R7in General, represented by the formula (III):

(where R9represents a C1-3alkyl group)), or a pharmaceutically acceptable salt of the compounds.

8. The compound according to claim 3, where R3represented by formula (IV):

(where R6represents a hydrogen atom, R7represents a C1-3alkyl group (specified With1-3Alki the other group may be substituted by one or more hydroxyl groups), and R8represents a chlorine atom),
or pharmaceutically acceptable salt of the compounds.

9. The compound according to claim 3, where R3represented by formula (V):

(where R10represents a hydrogen atom or a C1-3alkyl group), or a pharmaceutically acceptable salt of the compounds.

10. The compound according to claim 3, where R3represented by formula (II):

(where R6represents a hydrogen atom, and R7represents an ISO-propyl group, methyl group, ethyl group or through normal group (specified methyl group specified ethyl group and the specified normal sawn group are unsubstituted or substituted by one or more peredelnyj groups, one or more pyridyl-N-oxide groups, one or more FullName groups, one or more personalname groups, one or more imidazolinium groups, one or more pyrazolidine groups or one or more isoxazolidine groups (specified peredelnye group, the pyridyl-N-oxide group, these foreline groups specified personilnya groups specified imidazolidine group listed pyrazolidine group and these isoxazolidine group could the t to be substituted by one or more methyl groups, one or more methoxypropane))), or a pharmaceutically acceptable salt of the compounds.

11. The compound according to any one of claims 4 to 10, where R1represents a 3,4-dimethylphenyl group,
or pharmaceutically acceptable salt of the compounds.

12. The compound according to any one of claims 4 to 10, where R1represents 3, 4-dichloraniline group,
or pharmaceutically acceptable salt of the compounds.

13. The compound according to any one of claims 4 to 10, where R1is a 4-chloraniline group,
or pharmaceutically acceptable salt of the compounds.

14. The compound according to any one of claims 4 to 10, where R1is a 4-triftormetilfullerenov group,
or pharmaceutically acceptable salt of the compounds.

15. The compound according to any one of claims 4 to 10, where R1is a 4-bromperidol group,
or pharmaceutically acceptable salt of the compounds.

16. The compound according to any one of claims 4 to 10, where R1is a 4-triphtalocyaninine group,
or pharmaceutically acceptable salt of the compounds.

17. Activator receptor thrombopoetin containing compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt of such compounds, as the active ingredient.

18. Means for preventing, treating or improving Zab the diseases, in which activation of the receptor thrombopoetin is effective, which contains the activator of the receptor thrombopoetin at 17 as an active ingredient.

19. Means for increasing the number of platelets containing activator receptor thrombopoetin at 17 as an active ingredient.

20. Drug for prevention or treatment of diseases in which activation of the receptor thrombopoetin is effective in containing the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt of such compounds as an active ingredient.

21. The compound or its pharmaceutically acceptable salt, which is:
(i) {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}-hydrazide 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carboxylic acid;
(ii) {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}-hydrazide 5-(morpholine-4-carbonyl)thiophene-2-carboxylic acid;
(iii) {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}-hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid;
(iv) 2-methoxyethylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-
hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(v) {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}-hydrazide 5-(pyrrolidin-1-carbonyl)thiophene-2-carboxylic acid;
(vi) 3-picolylamine 5-[(2-{1-[5-(4-bromophenyl)-4-g is proxytype-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(vii) methyl-2-picolylamine 5-[(2-{1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid;
(viii) 4-picoline 5-[(2-{1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(ix) furan-2-ylmethylene 5-[(2-{1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(XI) Isopropylamine 5-[(2-{1-[5-(4-bromophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(xii) 2-picolylamine 5-[(2-{1-[4-hydroxy-5-(4-trifloromethyl)thiophene-3-yl]ethylidene}hydrazino)-carbonyl]-thiophene-2-carboxylic acid;
(xiii) Isopropylamine 5-[(2-{1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(xiv) 4-picoline 5-[(2-{1-[5-(4-chlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(xv) 2-picolylamine 5-[(2-{1-[5-(4-chlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(xvi) 3-picolylamine 5-[(2-{1-[5-(4-chlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(xvii) Isopropylamine 5-[(2-{1-[5-(3,4-dimetilfenil)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid;
(xviii) 2-picolylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino carb the Nile]thiophene-2-carboxylic acid;
(xix) 4-picoline 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(xx) 2-(pyridine-4-yl)ethylamide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(xxi) (1-methyl-1H-pyrazole-5-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid;
(xxii) (5-methylisoxazol-3-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid;
(xxiii) (5-methylpyrazine-2-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid;
(xxiv) (isoxazol-5-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid;
(xxv) (3-methoxyethoxy-5-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid;
(xxvi) (1,5-dimethyl-1H-pyrazole-3-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid;
(xxvii) (pyrazin-2-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid;
(xxviii) 4-picolyl-1-oxide, amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)Carbo is Il]thiophene-2-carboxylic acid;
(xxix) of 3-(pyridin-4-yl)propylamide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]-thiophene-2-carboxylic acid;
(xxx) [(1-methyl-1H-imidazol-5-yl)methyl]amide 5-[(2-{1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid;
(XXI) {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}-hydrazide 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carboxylic acid;
(xxxii) {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl] ethylidene} hydrazide 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carboxylic acid.

22. Connection item 21, which represents a 2-methoxyethylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid or its pharmaceutically acceptable salt.

23. Connection item 21, which represents {1-[5-(4-triptoreline)-4-hydroxythiophene-3-yl]ethylidene}-hydrazide 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carboxylic acid or its pharmaceutically acceptable salt.

24. Connection item 21, which represents a 4-picolylamine 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl] ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid or its pharmaceutically acceptable salt.

25. Connection item 21, which represents a 2-(pyridine-4-yl)ethylamide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl] ethylidene}hydrazino) carbonyl] thiophene-2-carboxylic acid or its pharmaceutically acceptable salt.

26. Connection item 21, which represents a (isoxazol-5-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid or its pharmaceutically acceptable salt.

27. Connection item 21, which represents a (3-methoxyethoxy-5-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl] ethylidene}hydrazino)-carbonyl]thiophene-2-carboxylic acid or its pharmaceutically acceptable salt.

28. Connection item 21, which represents a (pyrazin-2-ylmethyl)amide 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl] ethylidene}hydrazino)carbonyl]thiophene-2-carboxylic acid or its pharmaceutically acceptable salt.

29. Connection item 21, which represents {1-[5-(3,4-dichlorophenyl)-4-hydroxythiophene-3-yl]ethylidene}-hydrazide 5-(3-hydroxypyrrolidine-1-carbonyl)thiophene-2-carboxylic acid or its pharmaceutically acceptable salt.

30. Activator receptor thrombopoetin containing compound according to any one of PP-29 or a pharmaceutically acceptable salt of such compounds, as the active ingredient.

31. The means for prevention, treatment or improvement of diseases in which activation of the receptor thrombopoetin is effective, which contains the activator of the receptor thrombopoetin on item 30 as the active ingredient.

32. The medium is to increase the number of platelets, containing activator receptor thrombopoetin on item 30 as the active ingredient.

33. Drug for prevention or treatment of diseases in which activation of the receptor thrombopoetin is effective in containing the compound according to any one of PP-29 or a pharmaceutically acceptable salt of such compounds as an active ingredient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxazole derivatives of general formula I. The disclosed compounds have affinity to the µ-opioid receptor. In general formula I

, n equals 0, 1 or 2, R1 denotes a phenyl residue bonded through a C1-C3alkyl chain, R2 denotes phenyl or thienyl, each of which is unsubstituted or mono-substituted with F or Cl, R3 and R4 independently denote a saturated, branched or straight C1-C6alkyl, phenyl or a phenyl residue bonded through a C1-C3akyl chain, or R3 and R4 together form an unsubstituted five-, six- or seven-member saturated ring which can optionally contain an extra heteroatom selected from a group comprising O or NR9, where R9 denotes phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which is unsubstituted or mono-substituted with a substitute selected from a group comprising F, Cl, Br, I and O-C1-C6alkyl, where the ring can be optionally condensed with a phenyl ring, R5 and R6 independently denote a saturated, branched or straight C1-C6alkyl, R7 and R8 independently denote a saturated, branched or straight unsubstituted C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, or R7 and R8 together form an unsubstituted or mono- or disubstituted five-, six- or seven-member saturated ring, where the substitutes are selected from a group comprising C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, where the ring can optionally contain an extra heteroatom selected from a group comprising S, O and NR10, where R10 denotes a phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which can be unsubstituted or mono-substituted with O-C1-C6alkyl. The invention also relates to methods of producing the disclosed compounds, a medicinal agent containing at least one substituted oxazole derivative of formula I, use of the compounds to prepare a medicinal agent.

EFFECT: improved properties.

13 cl, 1 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I ; or to its pharmaceutically acceptable salts where n represents 0, 1 or 2; Y1 represents a bond or a group C(O); Y2, represents a bond, the groups C(O) or S(O)2; R1 represents hydrogen, halogen, cyano, C1-2alkyl; R2 represents hydrogen, halogen, cyano, C1-4alkyl, C1-3alkoxy, halogen-substituted-C1-3alkyl, halogen-substituted-C1-3alkoxyl, C6aryl-C0alkyl, tetrazolyl, C3-6cycloalkyl-C0alkyl, C6-7heterocycloalkyl-C0-4alkyl where 1 or 2 carbon atoms in the ring are substituted by the groups selected from -O-, -NH-, -S(O) and -SO2-; and phenoxy groups; where said aryl and heterocycloalkyl groups R2 can be substituted by 1 or 2 radicals independently selected from C1-6alkyl; R3 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group and a group -NR6aR6b where R6a and R6b are independently selected from hydrogen and C1-4alkyl; R4 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group; R5 represents hydrogen or C1-3alkyl group; L represents a bivalent radical selected from ; ; ; ; ; ; ; ; ; ; ; ; and ; where asterisks the junctions of Y2 and R2; where any bivalent radical L can be substituted by 1 or 2 radicals independently selected from halogen, hydroxy, cyano, C1-4alkyl, C1-4alkyl carbonylamino, C1-4alkoxy, C1-4alkoxycarbonyl, halogen-substituted - C1-4alkyl, C1-3alkylsulfonyl, C1-3alkylsulfonyl-amino, cyano-substituted - C1-4alkyl and halogen-substituted -C1-4alkoxy radicals. Also, the invention refers to a method of Hedgehog path inhibition in a cell and to a method of undesired cell proliferation inhibition which involves the interaction of the compound of formula I and the cell.

EFFECT: new substituted imidazole derivatives which can be effective in treatment of some types of cancer are prepared.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel oxadiazole compounds of formula (1) and pharmaceutically acceptable salts thereof, where R1 and R2 assume values given in the description, Y is a single bond. The invention also relates to use of said compounds as DGAT1 inhibitors, for example for treating obesity and diabetes, and a method of inhibiting.

EFFECT: high treatment efficiency.

13 cl, 65 tbl, 712 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having structure

, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.

EFFECT: novel compounds which are active towards PPAR are obtained and described.

41 cl, 622 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one derivatives of general formula 1, , where 1a R=Br, R'=CH2OCH3, R"=CH3; 1b R=H, R'=CH2, R"=CH3; 1c R=H, R1=CH2OCH3, R"=Ph; 1d R=H, R'=CH3, R"=Ph; 1e R=Br, R=CH3, R" - fur-2-yl, which can be used as potential biologically active substances and intermediate products for synthesis of novel heterocyclic systems. The method of producing 3 -(2-substituted-1,3 -oxazol-4-yl)pyridin-2( 1 H)-ones of general formula I involves formation of a heterocyclic system of 3-(1,3-oxazol-4-yl)pyridin-2(1H)-one as a result of base-catalysed regrouping of 3-acylamino-2-furfurylfuro[2,3-b]pyridines while boiling said compounds in ethanol for 4-20 hours with addition of 6-7 mmol of potassium hydroxide per 1 mol of the initial 3-acylamino-2-furfurylfuro[2,3-b]pyridine.

EFFECT: high yield.

1 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oxazolidinone derivatives covered by general graphic formula (I) and to their pharmaceutically acceptable salts. In formula (I) R1, R2, R3 and R4 are independently chosen from a group including -H and halogen; A is chosen from a group including R5 and R6 are independently chosen from a group including -H, -F, -CI, -Br, -OH, alkyl(C1-C6), haloalkyl(C1-C6), alkoxygroup(C1-C6); R7 is chosen from a group including -H, alkyl(C1-C6); either R7 and R5 or R6 taken together form a cycle of 2 carbon atoms and include 1 group chosen from O which in turn can be substituted by one substitute chosen from alkyl(C1-C6); R12 is chosen from a group including -H, -COR14, -CSR14, -COOR14; R14 is chosen from a group including alkyl (C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), R16, R17 and R18 represent -H; R21 is chosen from a group including -H, alkyl(C1-C6); X is chosen from a group including O, S, and Y is chosen from a group including O, S, SO, SO2, and NR12; and optional substitutes of alkyl(C1-C6) groups can represent one or two groups chosen from the following: -OR21, -CN.

EFFECT: invention refers to methods for preparing the compounds of the invention, to application of oxazolidinone derivatives for preparing a drug for treating bacterial infections and to a pharmaceutical composition for treating bacterial infections, including a therapeutically effective amount of the compound of the invention.

36 cl, 10 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1, compounds of formula 5 and pharmaceutically acceptable salts thereof. In formulae 1 5 Y denotes -C(O)-, X denotes -N(R11)-, R1 denotes a residue of formula 1a or 1b - for formula 1 or residue of formulae 5a or 5b - for formula 5 1a 1b 5a 5b, R2 and R7 independently denote H, hydroxyl or (C1-C6)alkyl; R3 and R6 each independently denotes H, hydroxyl or (C1-C6)alkyl; R4 and R5 each independently denotes H or (C1-C6)alkyl; the rest of the radicals are described in the formula of invention. The invention also relates to separate compounds given in the formula of invention, a pharmaceutical composition having Bcl bound protein inhibiting properties, which contains a therapeutically effective amount of the disclosed compound, a method of treating a bc1 mediated disorder, involving introduction of a therapeutically effective amount of the disclosed compound and a method of treating a bc1 mediated disorder involving administration to a patient in need of treatment of an effective amount of camptothecin and therapeutically effective amount of the disclosed compound.

EFFECT: high efficiency of the composition.

84 cl, 12 tbl, 1 dwg, 217 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having structure

, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.

EFFECT: novel compounds which are active towards PPAR are obtained and described.

41 cl, 622 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

where there are R3/R3', R4/R4' and R5/R5' where at least one of either R4/R4' or R5/R5' always represents a fluorine atom, and the other radical values are disclosed in the description.

EFFECT: making the compounds which are γ-secretase inhibitors, and can be effective in treating Alzheimer's disease or advanced cancers, including but not limited to carcinoma of uterine cervix and breast carcinoma and malignant tumours of hematopoietic system.

15 cl, 3 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of formula I in which cycle A represents unsaturated carbocycle with double bonds, which is selected from phenyl or naphtyl; 1 can take value from 1 to 3; m can take value 0, 2 or 3; n can take value 0 or 2; R1 represents a hydrogen atom, (C1-3)alkyl group; R2 represents(C1-6)alkyl group, which is possibly substituted with substituent, selected from C6-cycloalkyl, monocyclic heteroaryl, selected from thiophene, aryl group, selected from phenyl, in form of base or salt of bonding with an acid. Invention also relates to pharmaceutical composition, based on formula I compound, to application of formula I compound for obtaining medication, to method of obtaining formula I compound and to application of formula compound for obtaining formula 1 compound.

EFFECT: obtained are novel isoquinoline and benzo[h]isoquinoline derivatives, possessing properties of antagonists of histamine type H3 receptor.

9 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, in which X is or ; Y is H; Z is -C(O)-; R1 and R3 each independently denotes H or (C1-C4) alkyl; R2 and R4 each independently denotes , , or ; R5 denotes H or (C1-C6) alkyl; R8 and R9 each independently denote (C1-C6) alkyl; and Q is H.

EFFECT: possibility of use in stimulating the growth hormone in a subject based on the said compounds.

49 cl, 2 tbl, 57 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds described by formula in which radical and symbol values are specified in the patent claim, and their pharmaceutically acceptable salts. These compounds inhibit tompomyosine-related kinases (Trk), and can find application in treating a malignant growth, such as breast cancer, rectal cancer and prostate cancer. Also, the invention relates to a method for producing these compounds, a based pharmaceutical composition and to methods of application thereof.

EFFECT: preparation of the pharmaceutical composition which can find application in treating a malignant growth.

18 cl, 134 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting P2X3 receptor antagonist activity. In formula (I), X represents -O-; Y represents -NRdRe where one of radicals Rd and Re means hydrogen, and the other means hydrogen; C1-C12alkyl; C5-C7cycloalkyl; C5-C7cycloalky-C1-C12alkyl; hydroxy-C1-C12alkyl; acetyl; aminocarbonyloxy- C1-C12alkyl or heterocyclyl representing a 6-members saturated ring containing heteroatom S substituted by two oxo groups; D represents optional oxygen; R1 represents isopropyl; R2 represents hydrogen; R5 represents hydrogen or C1-C12alkyl; R4 means hydrogen; C1-C12alkyl; halogen; halogen- C1-C12alkyl; C1-C12alkoxy; hydroxy; halogen- C1-C12alkoxy; nitro; amino; hydroxy- C1-C12alkyl; C1-C12alkoxyalkyl; hydroxy- C1-C12alkoxy; C1-C12alkylsulphonyl; cyano; heteroaryl representing a 5-members aromatic ring containing one, two or three heteroatoms selected from O, S and N which can be optionally substituted by a thio group, C1-C12alkyl or C1-C12alkylsulphonyl; heterocyclyl representing a 6-members saturated ring containing two heteroatoms N, one of which is substituted C1-C12alkylsulphonyl; -(CH2)m-(Z)n-(CO)-Rf or -(CH2)m-(Z)n-SO2-(NRg)n-Rf where each m and n independently represents 0 or 1, Z means NR8, Rf means C1-C12alkyl, hydroxy, amino or hydroxy- C1-C12alkyl, and Rg means hydrogen; R3 represents methoxy; R6 represents hydrogen; and one of radicals R7 and R8 represents hydrogen, and the other represents hydrogen, acetyl or phenyl.

EFFECT: also, the invention refers to a pharmaceutical composition and to an application of the compound of formula (I) for preparing a drug.

8 cl, 3 tbl, 70 ex

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