N3-alkylated benzimidazole derivatives as mek inhibitors

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N3-alkylated benzimidazole derivatives for preparing a drug used in inhibition of MEK activity. Invention describes benzimidazole compound of the formula (I): and its pharmaceutically acceptable salts and solvates wherein R1, R2, R9 and R10 are chosen independently from hydrogen atom, halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-, azido-group, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group; R3 is chosen from hydrogen atom, trifluormethyl group, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl group is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R' wherein R' is chosen independently from hydrogen atom, lower alkyl; R4 represents independently hydrogen atom or (C1-C6)-alkyl; R6 is chosen from trifluoromethyl group or (C1-C10)-alkyl, (C3-C10)-cycloalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R', -OR'; R7 is chosen from (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is chosen from -C(O)OR3, -C(O)NR3R4, -C(O)NROR3, -C(O)R4OR3, -C(O)(C3-C10)-cycloalkyl, -C(O)(C1-C10)-alkyl. Also, invention describes compositions used for inhibition of MEK activity, using such compounds for preparing a drug used in inhibition of MEK activity and preparing a drug used in cancer treatment.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 10 ex

 

The scope of the invention

This invention relates to a series of alkyl (1H-benzimidazole-5-yl)-(4-iodine-phenyl)-amine derivatives useful in the treatment of hyperproliferative diseases such as cancer and inflammation, in mammals. This invention also relates to a method for using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

A brief description of related prior art

Signaling in cells via receptors of growth factors and protein kinase is an important regulator of cell growth, proliferation and differentiation. Under normal cellular growth factors growth through activation of receptors (i.e. PDGF or EGF and other) triggers MAR-kinase pathway. One of the most important and most well-studied MAR-kinase pathways involved in normal and uncontrolled cell growth is a Ras/Raf-kinase pathway. Active GTP-bound Ras leads to activation and indirect phosphorylation of Raf kinase. Then Raf phosphorylates MEK and 2 on two serine residues (S218 and S222 for MAC and S222 and S226 for MAC) (Ahn ef at., Methods in Enzymology 2001, 332, 417-431). Next, activated MEK phosphorylates the only known substrates MAR-kinases ERK1 and 2. Phosphorylation of ERK by MEK PR is coming on Y204 and T for ERK1 and Y185 and T for ERK2 (Ahn et al., Methods in Enzymology 2001, 332, 417-431). Phosphorylated ERK dimerizes and then translocases into the nucleus, where its accumulation (Khokhlatchev et al., Cell 1998, 93, 605-615). In the nucleus ERK is involved in several important cellular functions, including nuclear transport, signaling, DNA repair, Assembly, and translocation of nucleosomes, processing and translation of mRNA, but not limited to (Ahn et al., Molecular Cell 2000, 6, 1343-1354). In General, treatment of cells with growth factors leads to activation of ERK1 and 2, which causes proliferation and, in some cases, differentiation (Lewis et al., Adv. Cancer Res. 1998, 74, 49-139).

When proliferative diseases, genetic mutations and/or overexpression of the receptors of growth factors and downstream signaling proteins or protein kinases involved in ERK kinase path that leads to uncontrolled cell proliferation and, eventually, to the formation of tumors. For example, in some malignant tumors have mutations that cause persistent activation of these pathways due to the continuous production of growth factors. Other mutations may cause a defect in deactivation of the activated complex of GTP-bound Ras, which again leads to activation of map-kinase pathway. Mutant oncogenic forms of Ras was detected in 50% of cases of colon cancer and >90% of cases of cancer of the pancreas, as well as many other types of malignant novokras the requirements (Kohl et al., Science 1993, 260, 1834-1837). Recently, mutations in skin disease were detected in more than 60% of cases of malignant melanoma (Davies, H. et al., Nature 2002, 417, 949-954). These mutations in skin disease lead to constitutive activation of map-kinase cascade. Studying samples of primary tumors and cell lines also showed constitutive or enhanced activation of map kinase path with cancer of the pancreas, colon, lung, ovary and kidney (Hoshino, R. et al., Oncogene 1999, 18, 813-822). Therefore, there is a strict relationship between malignant tumors and overactivity MAR-kinase path resulting from genetic mutations.

As constitutive or increased activation of map kinase cascade plays a crucial role in cell proliferation and differentiation, we believe that inhibition of this pathway will have a beneficial effect in hyperproliferative diseases. MEK-kinase is a key participant in this way, because it is located below Ras and Raf. In addition, she is an attractive therapeutic target, since the only known substrates of MEK phosphorylation are MAR-kinases ERK1 and 2. In some studies it has been shown that inhibition of MEK has potential therapeutic beneficial effect. For example, it was shown that discobolus the specific MEK inhibitors inhibit the growth of human tumors in xenografts Nude mice (Sebolt-Leopold et al., Nature Medicine 1999, 5 (7), 810-816; Trachet et al., AACR April 6-10, 2002 Poster #5426; Tecle, H.IBC 2ndInternational Conference of Protein Kinases, 9-10 September, 2002), block static allodynia in animals (WO 01/05390, published January 25, 2001), and also inhibit the growth of cells in acute myeloid leukemia (Milella et al., J.Clin. Invest. 2001, 108 (6), 851-859).

Small molecule inhibitors of MEK have been described. Over the last few years left at least thirteen patent applications: U.S. 5525625, filed January 24, 1995; WO 98/43960, published October 8, 1998; WO 99/01421, published January 14, 1999; WO 99/01426, published January 14, 1999; WO 00/41505, published on 20 July 2000; WO 00/42002, published on 20 July 2000; WO 00/42003, published on 20 July 2000; WO 00/41994, published on 20 July 2000; WO 00/42022, published on 20 July 2000; WO 00/42029, published on 20 July 2000; WO 00/68201, published on 16 November 2000; WO 01/68619 published 20 September 2001; and WO 02/06213, published January 24, 2002.

SUMMARY of the INVENTION

In this invention proposed alkylated (1H-benzimidazole-5-yl)-(4-iodine-phenyl)-amine compounds of the formula I and their pharmaceutically acceptable salts and prodrugs, which are useful in the treatment of hyperproliferative diseases. In particular, the present invention relates to compounds of formula I that act as inhibitorowo. In addition, the proposed preparations containing the compounds of formula I, and methods of using these compounds for treatment need in this patient. In addition, it describes how to get the inhibitory compounds of formula I.

Accordingly, the present invention relates to compounds of the formula I:

and their pharmaceutically acceptable salts, prodrugs and solvate, where:

R1, R2, R9and R10independently selected from hydrogen, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)R6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4and C1-C10of alkyl, C2-C10alkenyl,3-C10the quinil,3-C10cycloalkyl,3-C10cycloalkenyl, -S(O)j(C1-C6alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroaromatic, heterocyclyl, geterotsiklicheskikh, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4Rsup> 5)m-heterocyclyl and-NR4(CR4R5)m-heterocyclyl, where each alkyl, Alchemilla, Alchemilla, cycloalkyl, aryl, heteroaryl and heterocyclyl part possibly substituted by the groups in number from one to five independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

R3selected from hydrogen, trifloromethyl and C1-C10of alkyl, C2-C10alkenyl,3-C10the quinil,3-C10cycloalkyl,3-C10cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, heterocyclyl and geterotsiklicheskikh, where each alkyl, Alchemilla, Alchemilla, cycloalkyl, aryl, heteroaryl and heterocyclyl part possibly substituted by the groups in number from one to five independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR'r SO2R"", -SO2NR'R R", -C(O)R', -C(O)OR', -OC(O)R', -NR'R C(O)OR", -NR'r C(O)R", -C(O)R NR'r", -SR"", -S(O)R", -SO2R', -NR'r R", -NR'r C(O)NR"R'", -NR'r C(NCN)NR"R'", -OR', aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

R', R" and R'" are independently selected from hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl;

R"is selected from lower alkyl, lower alkenyl, aryl and arylalkyl;

or

any two of R', R", R'" or R" ' may be taken together with the atom to which they are attached, with the formation of 4-10-membered carbocyclic, heteroaryl or heterocyclic ring, each of which may substituted by the groups in the amount of from one to three, independently selected from halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, aryl, heteroaryl, arylalkyl, heteroallyl, heteroalkyl and geterotsiklicheskikh; or

R3and R4can be taken together with the atom to which they are attached, with the formation of 4-10-membered carbocyclic, heteroaryl or heterocyclic ring, each of which may substituted by the groups in the amount of from one to three, independently selected from halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR'r SO2R"", -SO2NR'r R", -C(O)R', -C(O)OR', -OC(O)R', -NR'r C(O)OR'",- NR'r C(O)R", -C(O)NR'r R", -SO2R"", -NR'r R", -NR'r C(O)NR"R'", -NR'r C(NCN)NR"R"', -OR', aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and gets the roccellaceae; or

R4and R5independently represent hydrogen or C1-C6alkyl; or

R4and R5can be taken together with the atom to which they are attached, with the formation of 4-10-membered carbocyclic, heteroaryl or heterocyclic ring, each of which may substituted by the groups in the amount of from one to three, independently selected from halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR'r SO2R"", -SO2NR'r R", -C(O)R", -C(O)OR', -OC(O)R', -NR'r C(O)OR", -NR'r C(O)R", -C(O)NR'r R", -SO2R"", -NR'r R", -NR'r C(O)NR"R'", -NR'r C(NCN)NR"R'", -OR', aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

R6selected from trifloromethyl and C1-C10of alkyl, C3-C10cycloalkyl, aryl, arylalkyl, heteroaryl, heteroaromatic, heterocyclyl and geterotsiklicheskikh, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl part possibly substituted by the groups in number from one to five independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR'r SO2R"", -SO2NR'r R", -C(O)R', -C(O)OR', -OC(O)R', -NR'r C(O)OR'",- NR'r C(O)R", -C(O)NR'r R", -SO2R"", -NR'r R', -NR'r C(O)NR"R"', -NR'r C(NCN)NR"R'", -OR', aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

R7selected from hydrogen and C 1-C10of alkyl, C2-C10alkenyl,2-C10the quinil,3-C10cycloalkyl,3-C10cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, heterocyclyl and geterotsiklicheskikh, where each alkyl, Alchemilla, Alchemilla, cycloalkyl, aryl, heteroaryl and heterocyclyl part possibly substituted by the groups in number from one to five independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR4SO2R8, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)R6, -NR4C(O)R3, -C(O)NR3R4, -SO2R6, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

W is selected from heteroaryl, heterocyclyl, -C(O)OR3-C(O)NR3R4, -C(O)NR4R3, -C(O)R4OR3-C(O)(C3-C10cycloalkyl), -C(O)(C1-C10alkyl), -C(O)(aryl), -C(O)(heteroaryl) and-C(O)(heterocyclyl), each of which may substituted by 1-5 groups independently selected from-NR3R4, -OR3, -R2and C1-C10of alkyl, C2-C10alkenyl and C2-C10the quinil, each of which in what can be substituted 1 or 2 groups independently selected from-NR3R4and-OR3;

m is 0, 1, 2, 3, 4, or 5; and

j equal to 1 or 2.

DETAILED description of the INVENTION

New compounds covered by this invention are compounds described by the above General formula I, and their pharmaceutically acceptable salts and prodrugs.

The present invention also suggested that the compounds of formula I in which R7represents a C1-C10alkyl, C3-C7cycloalkyl or3-C7cycloalkenyl, each of which may be substituted with 1-3 groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)R6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh.

The present invention also suggested that the compounds of formula I, where R9represents hydrogen or halogen, and R10represents hydrogen.

The present invention also suggested that the compounds of formula I, where W represents-C(O)OR3or C(O)NR 4OR3.

The present invention also suggested that the compounds of formula II:

where W, R1, R7, R9and R10are as defined above for formula I.

The present invention also suggested that the compounds of formula II in which R7represents a C1-C10alkyl, C3-C7cycloalkyl or3-C7cycloalkenyl, each of which may be substituted with 1-3 groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh.

The present invention also suggested that the compounds of formula II, where R9represents hydrogen or halogen, and R10represents hydrogen.

The present invention also suggested that the compounds of formula II, where W represents-C(O)OR3or-C(O)NR4OR3.

The present invention also suggested that the compounds of formula III:

where R1, R2, R7and R9are as defined above for formula I, and a represents-OR3or-NR4C(O)R3where R3and R4are as defined above for formula I.

The present invention also suggested that the compounds of formula III in which R7represents a C1-C10alkyl, C3-C7cycloalkyl or3-C7cycloalkenyl, each of which may be substituted with 1-3 groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh.

The present invention also suggested that the compounds of formula III, where R9represents a hydrogen or halogen.

The present invention also suggested that the compounds of formula III, where R3represents hydrogen or lower alkyl when a is a-OR3; and R4represents hydrogen, a represents-NR 4C(O)R3.

The present invention also suggested that the compounds of formula IIIa:

where R1, R2, R7and R9are as defined above for formula I, and a represents-OR3or-NR4C(O)R3where R3and R4are as defined above for formula I.

The present invention also suggested that the compounds of formula IIIa, in which R7represents a C1-C10alkyl, C3-C7cycloalkyl or3-C7cycloalkenyl, each of which may be substituted with 1-3 groups independently selected from oxo, halogen, cyano, nitro, trifloromethyl, deformedarse, triptoreline, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh.

The present invention also suggested that the compounds of formula IIIa, where R9represents a hydrogen or halogen.

The present invention also suggested that the compounds of formula IIIa, where R3represents hydrogen or the Chille alkyl, when a represents-OR3; and R4represents hydrogen, a represents-NR4C(O)R3.

Except as specified otherwise, throughout this description, the following definitions of terms.

Under "C1-C10by alkyl", "alkyl" and "lower alkyl" in the present invention understand straight or branched alkyl group having 1-10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, mpem-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, heptyl, octyl and the like. Preferred alkyl radicals are C1-C6alkyl. More preferred alkyl radicals are C1-C3alkyl.

Under "C2-C10alkenyl", "lower alkenyl" and "alkenyl" see straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and at least one double bond, and they include ethynyl, propenyl, 1-but-3-enyl, 1-Penta-3-enyl, 1-Gex-6-enyl and the like. More preferred are the lowest of alkenyl having 3-5 carbon atoms.

Under "C2-C10the quinil", "lower quinil" and "quinil" see straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and at least od is the triple link, and they include ethinyl, PROPYNYL, butynyl, pentyn-2-yl and the like. More preferred are alkinyl having 3-5 carbon atoms.

The term "halogen" in the present invention understand fluorine, bromine, chlorine and iodine.

By "aryl" is understood aromatic carbocyclic group having a single ring (e.g. phenyl), multiple rings (e.g., biphenyl) or multiple condensed rings in which at least one is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl)which may be mono-, di - or tizamidine, for example, halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxy.

Under the "heteroaryl" understand comprising one or more than one aromatic ring systems of 5-, 6 - or 7-membered rings, which include condensed ring system in which at least one ring is aromatic) of 5 to 10 atoms, containing at least one heteroatom and up to four heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolin, pyrrolyl, chinoline, ethenolysis, indolyl, benzimidazolyl, benzofuranyl, indolinyl, ind who was Salil, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, oxadiazolyl, triazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzoxazole, hintline, honokalani, naphthyridines and properidine. Spirographic also included in the scope of this definition. Heteroaryl group possibly mono-, di - or tizamidine, for example, halogen, lower alkyl, lower alkoxy, halogenoalkanes, aryl, heteroaryl and hydroxy.

As it is used here, the term "carbocycle", "carbocyclic", "cycloalkyl" or "C3-C10cycloalkyl" refers to saturated carbocyclic radicals having three to ten carbon atoms. Cycloalkyl may be monocyclic or condensed polycyclic system and may be condensed with an aromatic ring. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Mentioned here cycloalkyl groups are unsubstituted or, if specified, substituted in one or more than one, replaced the position of different groups. For example, such cycloalkyl groups can be substituted, for example, With1-C6the alkyl, C1-C6alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)and is calamine, With2-C6alkenyl,2-C6the quinil, C1-C6halogenoalkanes,1-C6halogenoalkane, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, ilide(C1-C6)alkylamino(C1-C6)alkyl.

By "heterocycle" or "heterocyclyl" understand comprising one or more than one carbocyclic ring systems of 5-, 6 - or 7-membered rings, which include condensed ring system of 4 to 10 atoms, containing at least one heteroatom and up to four heteroatoms selected from nitrogen, oxygen, or sulfur, provided that the ring of this group does not contain two adjacent atom, O or S. the Condensed system can represent a heterocycle condensed with an aromatic group. Preferred heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothieno, tetrahydropyranyl, dihydropyran, tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, dioxane, piperazinil, homopiperazine, azetidine, oxetane, titanyl, homopiperazine, oxetanyl, tepanil, oxazepines, diazepines, thiazepines, 1,2,3,6-tetrahydropyridine, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, PI is Azzolini, ditional, dithiolane, dihydropyran, dehydration, dihydrofurane, pyrazolopyrimidines, imidazolidinyl, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes, azabicyclo[2.2.2]hexanal, 3H-indolyl, and finalizing. Spirographic also included in the scope of this definition. These groups, as follows from the above groups may be C-attached or N-attached where such is possible. For example, a group, a derivative of pyrrole, may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Next, the group, which is a derivative of imidazole, may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An example of a heterocyclic group, where 2 of the ring carbon atoms is substituted by an oxo-groups (=O)is 1,1-dioxo-thiomorpholine. Mentioned here heterocyclic groups are unsubstituted or, if specified, substituted in one or more than one, replaced the position of different groups. For example, such heterocyclic groups can be substituted, for example, With1-C6the alkyl, C1-C6alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino,2-C6alkenyl,2-C6the quinil, C1-C6halogenoalkanes, C -C6halogenoalkane, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl or di(C1-C6)alkylamino(C1-C6)alkyl.

The term "arylalkyl" means an alkyl group (as defined above), substituted by one or more than one aryl group (also defined above). More preferred arylalkyl radicals are aryl-C1-3-alkili. Examples include benzyl, phenylethyl and the like.

The term "heteroaromatic" means an alkyl group (as defined above), a substituted heteroaryl group (which is also defined above). More preferred heteroarylboronic radicals are 5 - or 6-membered heteroaryl-C1-3-alkili. Examples include oxazoline, pyridylethyl and the like.

The term "geterotsiklicheskikh" means an alkyl group (as defined above), a substituted heterocyclic group (which is also defined above). More preferred heterocyclisation radicals are 5 - or 6-membered heterocyclyl-C1-3-alkili. Examples include tetrahydropyranyl.

The term "cycloalkenyl" means an alkyl group (as defined above), substituted cycloalkyl group (which is the train defined above). More preferred cycloalkenyl radicals are 5 - or 6-membered cycloalkyl-C1-3-alkili. Examples include cyclopropylmethyl.

The term "Me" means methyl, "Et" means ethyl, "Bu" means butyl, and "AC" means acetyl.

The phrase "pharmaceutically acceptable(s) salt(s)"as it is used here, unless otherwise noted, includes salts of acidic or basic groups which may be represented as compounds of the present invention. Compounds of the present invention that are basic in nature are capable of forming large variety of salts with various inorganic and organic acids. Acids that can be used to obtain pharmaceutically acceptable salts accession acid such basic compounds of the present invention are acids which form non-toxic salts accession acid, i.e. salts containing pharmaceutically acceptable anions, such as acetate salt, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium salts, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edisylate, estolate, Eilat, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, salt geranamine, hydrobromide, hydrochloride, iodide, from tional, lactate, lactobionate, laurate, malate, maleate, mandelate, mesilate, methyl sulfate, mukat, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannat, tartrate, teoclate, tosylate, triethiodide and valerate. Because the individual connection of the present invention may include more than one acidic or basic groups, the compounds of the present invention may include mono-, di - or triple salt in the individual connection.

In the presence of acid groups in the compound of the present invention the salt can be formed by processing the compounds according to the present invention, the basic compound, in particular an inorganic base. Preferred inorganic salts are salts formed with alkali and alkaline-earth metals such as lithium, sodium, potassium, barium and calcium. Preferred salts of organic bases include, for example, ammonium salts of dibenzylamine, benzylamine, 2-hydroxyethylamine, bis(2-hydroxyethyl)ammonium, phenylethylenediamine, dibenzyl-Ethylenediamine and the like salts. Other salts of acid groups may include, for example, such salts formed with procaine, quinine and N-methylglucamine, and salts formed the basic amino acids, such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. Especially preferred salt is the sodium or potassium salt of the compounds of the present invention.

As for the main groups, the salt form by treating the compounds of the present invention the acid compound, in particular an inorganic acid. Preferred inorganic salts of this type may include, for example, salts of hydrochloric, Hydrobromic, idiscovered, sulfuric, phosphoric acid or the like. Preferred organic salts of this type may include, for example, salts formed with formic, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, holeva, pambou, mucus, D-glutamic, D-camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, methanesulfonic, benzosulfimide, paratoluenesulfonyl, sorbic, purine, benzoic, cinnamic and like organic acids. Particularly preferred salt of this type of salt is the hydrochloride or sulfate compounds of the present invention.

In the compounds of the present invention, when used terms such as (CR4R5)mor (CR4R5)t, R4and R5can vary with each REP the d m or t above 1. For example, if m or t is 2, the terms (CR4R5)mor (CR4R5)tmay be-CH2CH2- or-CH(CH3)C(CH2CH3)(CH2CH2CH3) - or any number of similar groups that fall within the scope of the definitions for R4and R5.

Some compounds of the present invention may have asymmetric centers and therefore exist in different enantiomeric forms. It is believed that all optical isomers and stereoisomers of the compounds of the present invention and their mixtures are within the scope of this invention. As for the compounds of the present invention, the invention encompasses the use of a racemate, one or more than one enantiomeric forms, one or more than one diastereomeric forms or their mixtures. In addition, the compounds of the present invention may exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.

The object of the invention also includes labeled isotopes compounds that are identical to the compounds described in this invention, but with the fact that one or more than one atom is replaced by an atom having an atomic mass or mass number different from the usually occurring atomic the mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N18Oh,17Oh,31R32R35S18F and36Cl, respectively. Compounds of the present invention, their prodrugs and pharmaceutically acceptable salts of these compounds either of these prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Some labeled isotopes of the compounds of the present invention, for example those compounds in which incorporated such radioactive isotopes, as3H and14With, useful in the analysis of the distribution of drugs and/or substrate tissue. Particularly preferred tritium isotopes3N, and carbon-14, that is,14Since, because of the ease of their production and detection. In addition, the substitution of heavier isotopes such as deuterium, i.e2H may provide some therapeutic advantages resulting from increased metabolic stability, for example, requirements are increased half-life in vivo or reduced dosage, and hence may be preferred in some EAC is aethelstan. Usually labeled with isotopes of the compound of the present invention and prodrugs can be obtained by performing the procedures described in the Schemes and/or in the Examples and Preparatory stages, by the replacement of the reagent is not labeled isotopes, readily available reagent, labeled isotopes.

Additionally, this invention encompasses pharmaceutical compositions and methods of treating proliferative disorders, or abnormal cell growth through the introduction of prodrugs of the compounds of the present invention. Compounds of the present invention, having a free amino group, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds where the amino acid residue or a polypeptide chain of two or more than two (e.g., two, three or four) amino acid residues, covalently joined through an amide or ether bond to a free amino group, the hydroxy-group or the carboxylic acid group of compounds of the present invention. Amino acid residues include the 20 existing in nature, amino acids, usually indicated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demazin, isodesmosine, 3-methylhistidine, Norvaline, beta-alanine, gamma-aminobutyric acid is the one the citrulline, homocysteine, homoserine, ornithine and methanesulfonic, but are not limited to them. Also included are additional types of prodrugs. For example, can be obtained from derivatives of free carboxyl groups to form amides or alilovic esters. Can be obtained from derivatives of free hydroxyl groups in the form of groups, including hemisuccinate, phosphate esters, diethylaminoacetate and phosphorylethanolamine, but not limited to them, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Also included urethane prodrugs of hydroxy groups and amino groups, as representing the carbonate prodrugs, sulfate esters and sulfate esters of hydroxy groups. Also includes derivatives of the hydroxy groups in the form (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group can be alkilany ester, possibly substituted groups include functional groups, ethers, amines or carboxylic acids, but not limited by them, or where the acyl group is an ester of the amino acids as described above. Prodrugs of this type is described in J.Med.Chem. 1996, 39, 10. In addition, can be obtained from derivatives of free amines in the form of amides, sulfonamides or phosphoramidon. All these proletarienne groups which may be incorporated group, including functional groups, ethers, amines or carboxylic acids, but not limited to.

It should be understood that in the case of use in a row of two or more than two of the radicals to determine attached to the structure of the Deputy, the first named radical is considered to be a limit, called the last radical is attached to the structure. For example, the radical arylalkyl attached to the structure via an alkyl group.

This invention also relates to pharmaceutical compositions for the treatment of hyperproliferative disorders in a mammal containing a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically acceptable carrier. In one embodiment of specified pharmaceutical composition intended for the treatment of cancer such as cancer of the brain, lung, squamous cells, bladder, stomach, pancreas, breast, head, neck, kidney, ovarian, prostate, colon and rectal, esophageal, testicular, gynecological or thyroid cancer. In another embodiment of specified pharmaceutical composition intended for the treatment of hyperproliferative disorders of the e cancerous nature, such as benign hyperplasia of the skin (e.g. psoriasis), restenosis or hyperplasia of the prostate (e.g., benign prostatic hypertrophy (national Department of standardization)).

In addition, this invention relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and induced diabetes renal disease), or pain in a mammal containing a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically acceptable carrier.

In addition, this invention relates to a pharmaceutical composition for the prevention of implantation of blastocytes the mammal containing a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically acceptable carrier.

In addition, this invention relates to a pharmaceutical composition for the treatment of diseases associated with vasculogenesis or angiogenesis in a mammal containing a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically pickup is acceptable carrier. In one embodiment of specified pharmaceutical composition intended for the treatment of diseases selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retrolateral fibroplasia, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast cancer, lung, pancreas, prostate, colon and epidermoid cancer.

This invention also relates to a method of treatment of hyperproliferative disorders in a mammal, wherein the specified mammal is administered a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate. In one embodiment of this method relates to the treatment of cancer such as cancer of the brain, lung, squamous cells, bladder, stomach, pancreas, breast, head, neck, kidney, ovarian, prostate, colon and rectal, esophageal, testicular, gynecological or thyroid cancer. In another embodiment of this method the relative who are getting ready for the treatment of hyperproliferative disorders not cancerous nature, such as benign hyperplasia of the skin (e.g. psoriasis), restenosis or hyperplasia of the prostate (e.g., benign prostatic hypertrophy (national Department of standardization)).

This invention also relates to a method of treatment of hyperproliferative disorders in a mammal, wherein the specified mammal is administered a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate in combination with an antitumor agent selected from the group consisting of inhibitors of mitosis, alkylating agents, antimetabolites, intercalating antibiotics, inhibitors of growth factors, inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors and anti-androgens.

In addition, this invention relates to a method of treating pancreatitis or kidney disease, or pain in a mammal, wherein the specified mammal is administered a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate.

In addition, this invention relates to a method of preventing implantation of blastocytes in a mammal, when cotromoxazole the mammal is administered a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate.

In addition, this invention relates to a method of treatment of diseases associated with vasculogenesis or angiogenesis in a mammal, wherein the specified mammal is administered a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate. In one embodiment the method is for treatment of a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases, such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retrolateral fibroplasia, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast cancer, lung, pancreas, prostate, colon and epidermoid cancer.

Patients who can be treated with compounds of the present invention or pharmaceutically acceptable salts, prodrugs and hydrates of these compounds in accordance with the methods according to this invention, include, for example, patients diagnosed with psoriasis, restenosis, atherosclerosis, national Department of standardization, lung cancer, bone cancer, chronic myeloma iitary leukemia (CMML), pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular tumor, gynecological (such as sarcoma of the uterus, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system (e.g., cancer of the thyroid, parathyroid glands or adrenal glands), sarcomas of soft tissues, cancer the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumor in children, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis) or neoplasm Central nervous system (e.g., primary CNS lymphoma, tumors of the spine, gliomas of the brainstem or pituitary adenomas).

This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal, comprising a number of compounds of the present invention or its pharmaceutically acceptable salt or MES or prodrug in combination with the drug amount, and the number of connections, salt, Sol is wool or prodrugs and chemotherapeutic are together effective in inhibiting abnormal cell growth. Currently in the art will know of many chemotherapeutic agents. In one embodiment of the chemotherapeutic agent selected from the group consisting of inhibitors of mitosis, alkylating agents, antimetabolites, intercalating antibiotics, inhibitors of growth factors, inhibitors of the cell cycle, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors and anti-androgens.

In addition, this invention relates to a method of inhibiting abnormal cell growth in a mammal or treating a proliferative disorder, wherein the mammal is administered an amount of the compound of the present invention or its pharmaceutically acceptable salt or MES or prodrug in combination with radiation therapy, and the number of connections, salt, MES or prodrug in combination with radiation therapy are effective in inhibiting abnormal cell growth or treating a proliferative disorder in a mammal. Techniques of radiation therapy known in the art, and these techniques can be used in combination therapy described herein. Introduction compounds according to this invention in such combination therapy can be defined as the description is about here.

Suppose that the compounds of the present invention can make abnormal cells more sensitive to treatment with radiation for purposes of cell lysis and/or inhibiting the growth of such cells. Accordingly, this invention also relates to a method of increasing the sensitivity of abnormal cells in a mammal to treatment with radiation, wherein the mammal is administered an amount of the compound of the present invention or its pharmaceutically acceptable salt or MES or prodrug, which is effective to increase the sensitivity of abnormal cells to treatment with radiation. The number of compounds, salts or MES in this way can be determined according to techniques of identifying effective amounts of such compounds, are described here.

This invention also relates to a method and pharmaceutical composition for inhibiting abnormal cell growth in a mammal, which contains a number of compounds of the present invention or its pharmaceutically acceptable salt or MES, its prodrugs or its isotope labeled derivative and one or more than one substance selected from antiangiogenetic agents, inhibitors of signal transduction and antiproliferative agents.

Antiangiogenesis agents, such as hibitory MMP-2 (matrix metalloproteinase 2), inhibitors of MMP-9 (matrix metalloproteinase 9) inhibitors SOH-II (cyclooxygenase II), can be used in combination with the compound of the present invention and pharmaceutical compositions described herein. Examples of useful inhibitors SOH-II include CELEBREX™ (elecoxib), valdecoxib and rofecoksib. Examples of useful inhibitors of matrix metalloproteinases described in WO 96/33172 (published 24 October 1996), WO 96/27583 (published March 7, 1996), the application for the European patent No. 97304971.1 (filed July 8, 1997), the application for the European patent No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published 26 February 1998), WO 98/03516 (published 29 January 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published 6 August 1998), WO 98/30566 (published July 16, 1998), the publication of the European patent 606046 (published 13 July 1994), the publication of the European patent 931788 (published July 28, 1999), WO 90/05719 (published may 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published 17 June 1999), international PCT application number PCT/V/01113 (filed July 21, 1998), the application for the European patent No. 99302232.1 (filed March 25, 1999), the application for a patent of great Britain No. 9912961.1 (filed with the Oh June 3, 1999), the provisional application U.S. No. 60/148464 (filed August 12, 1999), U.S. patent 5863949 (issued January 26, 1999), U.S. patent 5861510 (issued January 19, 1999) and the publication of the European patent 780386 (published June 25, 1997), all of which are included in this description in its entirety by reference. Preferred inhibitors of MMP-2 and MMP-9 are inhibitors have little activity against inhibition of MMP-1 or no such activity. More preferred are inhibitors that selectively inhibit MMP-2 and/or MMP-9 compared to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13).

Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830.

The term "abnormal cell growth" and "hyperproliferative disorder" are used in this application interchangeably.

"Abnormal cell growth", as it is used here, unless otherwise noted, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). It includes, for example, an abnormal growth of: (1) tumor cells (tumors)that have proliferated through ekspressirovali mutated Tyr is sincinaty or overexpression of the receptor tyrosine kinase; (2) benign or malignant cells of other proliferative diseases in which there is aberrant activation of tyrosine kinase; (3) any tumors that proliferate by receptor tyrosinekinase; (4) any tumors that proliferate by aberrant activation of the serine/trionychinae; and (5) a benign or malignant cells of other proliferative diseases in which there is aberrant activation of the serine/trionychinae.

The term "treatment"as used here, unless otherwise stated, means reversing, alleviating, suppressing development or preventing the disorder or condition to which to apply such a term, or one or more than one symptom of such disorder or condition. The term "treatment"as used here, unless otherwise noted, refers to the act of treatment per se, as it is directly defined above.

Representative compounds of the present invention, which are covered by the present invention include compounds of the examples and their pharmaceutically acceptable salts accession acids or bases, or their prodrugs, but they are not limited.

The examples below are intended to illustrate specific embodiments of the present invention in any manner and on the ohms are not intended to limit the scope of the description or the claims.

Illustration of obtaining compounds of the present invention are shown in Schemes 1-3.

Scheme 1 - N alkyla iodo

Scheme 2 - N-amino alkyl iodo

Figure 3 - example of heterocyclic oxadiazole

General methods of synthesis, which may be relevant to certain of the compounds of the present invention proposed in published PCT application number WO 00/42022 (published 20 July 2000). The above-mentioned patent application are included in this description of the invention by reference in its entirety.

The examples below are intended to illustrate specific embodiments of the present invention and are in no way intended to limit the scope of the description or the claims.

Illustration of obtaining compounds of the present invention are shown in Schemes 1-3.

Scheme 1 illustrates the synthesis of compounds of the present invention. In stage 1 carry out the nitration acid using standard conditions, preferably fuming nitric acid (H2SO4. In stage 2 receive aniline by substitution of fluoride using NH4OH, at room temperature in water with subsequent careful acidified with concentrated mineralogically to a pH of about 0. At stage 3 receive ester using standard methods, including Fisher esterification (Meon, H2SO4and interaction with TMSCHN2in suitable organic solvents, such PhMe/MeOH or THF/MeOH, but not limited to. In stage 4 receive dianilinoethane by heating (60 to 200° (C) this complex ester with an excess of the corresponding pure aniline or in an organic solvent type xylenes. For example, when R1=Me and R2=N, the preferred method is the mixing of ester with 10 equivalents of aniline in xylene at the temperature of reflux distilled until the reaction is completed. Stage 5 nitroarene restore with getting diamine using standard conditions recovery, including H2and Pd/C or Pd(OH)2/C or Raney Nickel in an organic solvent like EtOH or THF, Fe in the Asón, Zn in the Asón or Zn, NH4Cl (VOD.) in Meon, but not limited to. At stage 6 the diamine is subjected to cyclization by heating with pure formic acid or formamidines in an appropriate solvent like EtOH. Alternatively, when R1or R2not is halogeno, nitroarene can be directly converted into a benzimidazole stage 7 by heating in formic acid with Pd(OH)2/C or other source of palladium,such Pd/C. On stage 8 is injected iodide using standard methods, including NIS and para-TsOH in organic co-solvents like THF and Meon, or designed dichlorotin and ZnCl2in the Asón, but not limited to. On stage 9 of benzimidazole alkylate, which gives almost equal mixture of N1 - and N3-products, which can be separated by standard techniques, including, for example, chromatography and rubbing. The alkylation is carried out by use of an alkylating agent, such alkylhalogenide, and bases like NaH or2CO3, in a suitable organic solvent like DMF or THF, at temperatures varying in the range from 0 to 80°C. R7may be further modified by using different methods of synthesis known in the art, as illustrated in the examples below. On stage 10 ester hydrolyzing using standard methods of saponification. Then the acid is transformed into the desired hydroxamate on stage 11 using standard procedures combinations, including EDCl, HOBt, or Rumor and the appropriate hydroxylamine in suitable organic solvents like DMF, THF or methylene chloride, but not limited to.

Figure 2 illustrates the receiving N3-alkyl-amino-benzimidazole derivatives. In stage 1 terminal alkene N3 alkylated benzimidazole guide is oxamate dihydroxyaryl using a suitable oxidant, such OsO4in a suitable solvent, or KMnO4or I2, AgOAc, Asón, water. This diol then further oxidized in stage 2, using NaIO4or Pb(SLA)4in a suitable biphasic mixture that gives the aldehyde. Alternative (stage 3), the alkene can be directly converted to the aldehyde using standard methods, including ozone/IU2S, NaIO4/OsO4or KMnO4but they are not limited to. In stage 4 receive amine by reductive amination, using standard methods, such as Na(CN)NR3, Na(SLA)3NR, NMe4NR(SLA)3in the presence or in the absence of Asón in a suitable solvent, such as methylene chloride, acetonitrile or THF. Preferred reductive amination relates to the handling of the aldehyde with the amine, Me4MVN(SLA)3and acetic acid in MeCN at room temperature.

Scheme 3 illustrates the formation of compounds of the present invention, where W is a heterocycle. In stage 1 methyl ester converted into the hydrazide by mixing with hydrazine in a suitable solvent like ETOH, at a temperature from 50 to 100°C. the Desired heterocyclic derivative is then processed by cyclization with an appropriate reagent. To obtain oxadiazole 18 hydrazide treated orthoformiate is, like triethylorthoformate, and acid catalyst, such pair-TsOH, in a suitable organic solvent like ETOH, at elevated temperatures (50 to 100°). To obtain hydroxymidazolam 19 hydrazide can be cycletour using phosgene or equivalent of phosgene, such triphosgene or carbonyldiimidazole in a suitable organic solvent such as toluene, at temperatures varying in the range from 50 to 120°s Mercaptoimidazole 20 can be obtained by the interaction with carbon disulfide and a base like KOH, in a suitable organic solvent like ETOH, at elevated temperatures (50 to 100°). Aminoimidazole 21 can be obtained by interaction with Enrichment and base, such NaHCO3in a suitable bi-phase solvent system such as dioxane and water at room temperature. And finally, substituted aminoimidazole 22 can be obtained by first communicating with the corresponding hydrazide by isothiocyanates in a suitable organic solvent like DMF or THF, at temperatures varying in the range from 25 to 100°C. the Intermediate compound may be isolated or may be cyklinowanie directly by processing EDCl or other carbodiimide in a suitable organization of the organic solvent, like THF or DMF, at temperatures varying in the range from room temperature to 80°C.

Compounds of the present invention may have asymmetric carbon atoms. Diastereomer mixture can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to experts in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by turning the enantiomeric mixture in diastereomer mixture by interaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolysis) the individual diastereomers to the corresponding pure enantiomers. It is believed that all such isomers, including diastereomeric mixtures and pure enantiomers, are part of this invention.

The active compounds according to the present invention can be determined using the following procedure. 6 His-tagged N-end constitutive active MEK (2-393) Express in E. coli and the protein purified by conventional methods (Ahn et al., Science 1994, 265, 966-970). Activity MEK assessed by measuring the incorporation γ-33R-phosphate of γ-33P-ATP in the His-tagged N-end ERK2, which Express in E. coli and purify traditional the methods in the presence of MEK. The analysis is performed in 96-well polypropylene plate. The incubation mixture (100 μl) contains 25 mm Hepes, pH of 7.4, 10 mm MgCl2, 5 mm β-glycerol, 100 μm Na-orthovanadate, 5 mm DTT, 5 nm MEK and 1 μm ERK2. Inhibitors suspended in DMSO and all of the reaction mixture, including controls, are prepared at a final concentration of 1%DMSO. The reaction initiated by addition of 10 μm ATP (0.5 µci γ-33P-ATP/well) and incubated at ambient temperature for 45 minutes. To stop the reaction and precipitate proteins add an equal volume of 25%TCA. Precipitated precipitated proteins are separated on a glass fiber filter plates of a type and In an excess of labeled ATP washed using harvester Tomtec MACH III. Tablets leave to be dried in the air before adding Packard Microscint 20 at the rate of 30 ál/well, and tablets read using a Packard TopCount. In this assay, compounds of this invention demonstrate the value of the IC50less than 50 micromoles.

The following compounds are given as examples of such activity.

Connection #
11a
11b
11S
11d
11th
11f
11g
11h
11i
11j

Introduction compounds of the present invention (hereinafter referred to as "active(s) compound(I)may be carried out by any method that enables delivery of the compounds to the site of action. These methods include oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

The number of active connections will depend on being treated of the subject, the severity of the disorder or condition, rate of administration, availability of connections available and at the discretion of the attending physician. However, an effective dosage is in the range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day, in single or divided doses. For a person weighing 70 kg, this amount will be from about 0.05 to 7 g/day, preferably from about 0.05 to about 2.5 g/day. In some cases, the levels of dosages lower than the lower limit of the above interval may be more than sufficient at that time to the to in other cases, there may be used higher doses, not cause any harmful side effects, provided that such higher dose initially divided into several small doses for administration throughout the day.

The active compound can be applied as a sole therapy or one or more other anti-tumor substance, for example, is selected, for example, inhibitors of mitosis, for example vinblastine; alkylating agents, for example CIS-platinum, carboplatin and cyclophosphamide; antimetabolites, for example 5-fluorouracil, citizenoriented and hydroxyacetone or, for example, one of the preferred antimetabolites described in the application for European patent application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoindole-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; inhibitors of growth factors, inhibitors of cell cycle; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and antihormones such as antiestrogens, such as NolvadexTM (tamoxifen)or, for example anti-androgens such as CasodexTM (4'-cyano-3-(4-perpenicular)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propion-anilide). This combined treatment can be achieved by simultaneous, sequential or separate introduction of individual components of the treatment.

The pharmaceutical composition may be, nab is emer, in a form suitable for oral administration in the form of tablets, capsules, pills, powders, drugs, continuous release, solution, suspension; for parenteral injection as a sterile solution, suspension or emulsion; for topical administration in the form of ointments or creams; or for rectal administration in the form of a suppository. The pharmaceutical composition may be in a standard dosage forms suitable for single injection exactly certain dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and connection in this invention as the active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, and so on.

Typical forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, for example aqueous solutions of propylene glycol or dextrose. Such dosage forms may be appropriately buffered.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. If desired, the pharmaceutical compositions can be added to additional ingredients, such accordignly, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as citric acid, may be used in conjunction with various leavening agents, such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and Arabic gum. In addition, it is often very useful for tabletting are lubricants such as magnesium stearate, sodium lauryl sulfate and talc. In addition, the solid compositions of a similar type can be used in soft and hard filled gelatin capsules. Therefore, preferred materials include lactose or milk sugar and glycols of high molecular weight. If oral administration is desired aqueous suspensions or elixirs, the active compound can be combined with various sweetening or korrigentami, colouring matter or dyes and, if desired, emulsifying agents or suspendresume agents, together with such diluents as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of preparing various pharmaceutical compositions with a specific number of active compounds known or will be apparent to experts in this region, the STI technique. See, for example Remington''s Pharmaceutical Sciences. Mack Publishing Company, Ester, Pa., 15thEdition (1975).

Examples and preparatory, below, further illustrate the compounds of the present invention and methods for producing such compounds. It should be understood that the scope of the present invention is in no way limited to the scope of the following examples and preparation stages. In the following examples of molecules with a single chiral center unless specified otherwise, exist as racemic mixtures. The same molecule with two or more than two chiral centers, unless otherwise noted, are in the form of a racemic mixture of diastereomers. Individual enantiomers/diastereomers can be obtained using methods known to experts in this field of technology.

The descriptions in this application all articles and references, including patents, incorporated by reference.

This invention is further illustrated by the following examples, which should not be construed as limiting the invention in scope or entity described in specific procedures.

Raw materials and various intermediate compounds can be purchased from commercial sources, obtained from commercially available organic compounds or obtained using well known the different methods of synthesis.

Representative examples of methods for obtaining the intermediate compounds according to this invention is set forth below.

Examples

Example 1

Cyclopropylmethoxy-amide 7-fluoro-6-(4-iodine-2-methyl-phenylamino)-3-methyl-3H-benzimidazole-5-carboxylic acid (11a)

Stage A: 2,3,4-Cryptor-5-nitro-benzoic acid

In a three-neck round bottom flask with a capacity of 3 liters of load 125 ml H2SO4. Added fuming nitric acid (8,4 ml, 199 mmol) and the mixture is gently stirred. In continuation of 90 minutes add 2,3,4-triptoreline acid (25 g, 142 mmol) in portions for 5, Dark brownish-yellow solution is stirred for 60 min, during which the reaction is finished. The reaction mixture is poured into 1 liter of a mixture of ice/water and extracted with diethyl ether (3×600 ml). The combined organic extracts dried (MgSO4) and concentrate under reduced pressure to obtain solid yellow color. The solid is suspended in hexano and stirred for 30 min, and then filtered to obtain 29 g (92%) transparent expected product in the form of a solid yellowish color.

Stage b: 4-amino-2,3-debtor-5-nitro-benzoic acid

A solution of ammonium hydroxide (˜30% in water) (35 ml, 271 mmol) are added to a solution of 2,3,4-Cryptor-5-nitro-benzoic key is lots (15 g; 67.8 mmol) in 30 ml of water at 0°With stirring. Upon completion of the addition of ammonium hydroxide, the reaction mixture was warmed to room temperature with stirring. After 2.5 h the reaction mixture was cooled to 0°and carefully add concentrated HCl up until the pH of the reaction mixture reaches approximately 0. The reaction mixture was diluted with water (30 ml) and extracted with diethyl ether (3×50 ml). The combined organic extracts dried (MgSO4) and concentrate under reduced pressure to obtain 14 g (95%) of the expected pure product.

Stage C: methyl ester of 4-amino-2,3-debtor-5-nitro-benzoic acid

2M Solution of TMS-diazomethane in hexano (6,88 ml; of 13.75 mmol) are added to a suspension of 4-amino-2,3-debtor-5-nitro-benzoic acid (2.00 g; 9,17 mmol) in 25 ml of a mixture of 4:1 THF/MeOH at 0°C in nitrogen atmosphere. After the addition was finished the reaction mixture is heated to room temperature. After 0.5 h the excess TMS-diazomethane neutralized by careful addition of acetic acid. The reaction mixture was then concentrated under reduced pressure and dried in vacuo to obtain 1,95 g (92%) of the expected pure product.

Stage D: methyl ester of 4-amino-3-fluoro-5-nitro-2-ortho-triaminobenzene acid

Methyl ester of 4-amino-2,3-debtor-5-nitro-benzoic acid (12.0 g; of 51.7 mmol) suspended in xylene is (60 ml) and add ortho-toluidine (55,2 ml; 517 mmol). The reaction mixture is heated with stirring to a temperature of reflux distilled in a nitrogen atmosphere. After 36 h, the reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with 10%aqueous HCl solution. Water washing is extracted with diethyl ether. The combined organic extracts are concentrated under reduced pressure. The residue is dissolved in methylene chloride and filtered through silica gel in fittowindow funnel, rinsing with methylene chloride. Get three fractions. The first (2 liters) is close to the net. The second (1 liter) and third (1 liter) faction only partially clean. The first fraction is concentrated under reduced pressure and triturated with diethyl ether to obtain 11.2 g (68%) of the expected pure product in the form of a solid bright yellow.

Stage E: methyl ester of 7-fluoro-6-ortho-tolylamino-1H-benzimidazole-5-carboxylic acid

Methyl ester of 4-amino-3-fluoro-5-nitro-2-ortho-triaminobenzene acid (1,57 g; to 4.92 mmol), formic acid (25 ml; of 26.5 mmol) and 20%Pd(OH)2/C (1,57 g; 2,95 mmol) in 25 ml of ETOH is heated with stirring to 95°C. After 16 h, the reaction mixture was cooled to room temperature and add 0.5 g of 20%Pd(OH)2/C and 10 ml of formic acid. The reaction mixture is heated to 95°With stirring. After 16 h, the reaction mixture was cooled to room t is mperature and filtered through celite, washing EtOH. The filtrate is concentrated under reduced pressure up until the expected product precipitates. The expected product is collected by filtration. The filtrate is again concentrated until an additional amount of the expected product precipitates. The product is collected by filtration. Repeat the ETOH concentration, filtration of the product several times. Received 1,09 g (74%) of the expected pure product.

Stage F: methyl ester of 7-fluoro-6-(4-iodine-2-methyl-phenylamino)-1H-benzimidazole-5-carboxylic acid

Methyl ester of 7-fluoro-6-ortho-tolylamino-1H-benzimidazole-5-carboxylic acid (1.47 g; to 4.92 mmol) is suspended in a mixture of 1:1 THF/MeOH (44 ml) and cooled to -78°C in nitrogen atmosphere. Add a solution of NIS (1.66 g; 7,39 mmol) in THF (2 ml) followed by a solution of TsOH·H2O (1,87 g; 9,84 mmol) in Meon (2 ml). After 30 min the reaction mixture is heated to 0°and add 1 ml of methylene chloride. The reaction mixture was left to slowly warm to room temperature with stirring continued for 16 hours, the Reaction mixture was quenched by adding 10%aqueous solution of Na2S2O4. The reaction mixture was diluted with water and ethyl acetate and the layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts dried (Na2SO4) and concentrate under reduced pressure. Polucen the e solid is triturated with Meon to obtain 1.45 g (69%) of the expected pure product.

Stage G: methyl ester of 7-fluoro-6-(4-iodine-2-methyl-phenylamino)-3-methyl-3H-benzimidazole-5-carboxylic acid

Methyl ester of 7-fluoro-6-(4-iodine-2-methyl-phenylamino)-1H-benzimidazole-5-carboxylic acid (100 mg; 0,235 mmol) suspended in DMF (2.5 ml) and cooled to 0°C in nitrogen atmosphere. Add NaH (95%) (6 mg; 0,238 mmol). After 10 minutes add MeI (15 μl; 0,238 mmol). After 45 min the reaction mixture is heated to room temperature (kg). After 1.5 h, the reaction mixture was quenched with water and diluted with ethyl acetate and brine solution. The layers are separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts dried (Na2SO4) and concentrate under reduced pressure. The crude mixture of products is cleaned by FCC (10:1 methylene chloride/ethyl acetate) to give 36 mg (36%) of the expected methyl-N3-product and 43 mg (43%) of methyl-N1-product.

Stage H: 7-fluoro-6-(4-iodine-2-methyl-phenylamino)-3-methyl-3H-benzimidazole-5-carboxylic acid

Methyl ester of 7-fluoro-6-(4-iodine-2-methyl-phenylamino)-3-methyl-3H-benzimidazole-5-carboxylic acid (34 mg; 0,077 mmol) is suspended in a mixture of 1:1 THF/MeOH (2 ml) and add 20%NaOH (500 μl). After 16 h, the reaction mixture was cooled to 0°and added dropwise 1M solution of HCl to pH 1-2. The reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic layer is washed with brine, dried (MgSO4 ) and concentrate under reduced pressure to obtain 33 mg (100%) of the expected product in the form of a solid white color.

Stage I: cyclopropylmethoxy-amide 7-fluoro-6-(4-iodine-2-methyl-phenylamino)-3-methyl-3H-benzimidazole-5-carboxylic acid

7-Fluoro-6-(4-iodine-2-methyl-phenylamino)-3-methyl-3H-benzimidazole-5-carboxylic acid (30 mg; 0,071 mmol) suspended in DMF (1 ml) and added HOBt (11 mg; of 0.085 mmol) followed by the addition of triethylamine (22 μl; rate £ 0.162 mmol). Add cyclopropylmethyl-hydroxylamine hydrochloride (10 mg; of 0.085 mmol) (WO 0042022) then add EDCl (18 mg; 0,092 mmol). After 16 h, the reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic layer was washed with saturated NH4Cl, salt solution, saturated NaHCO3, water and salt solution. The organic layer is dried (MgSO4) and concentrate under reduced pressure. The crude reaction mixture was purified using FCC, elwira a mixture of 20:1 methylene chloride/Meon to obtain 21 mg (61%) of the expected pure product (11a) in a solid beige color; found: MS APCI (+) m/z 495 (M+1); found: MS APCI (-) m/z 493 (M-1);1H NMR (400 MHz; DMSO-d6) δ 11.62 (s, 1H), 8.38 (s, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.43 (d, 1H), 7.25 (dd, 1H), 6.12 (dd, 1H), 3.89 (s, 3H), 3.58 (d, 2H), 2.23 (s, 3H), 1.01 (m, 1H), 0.47 (m, 2H), 0,19 (m, 2H);19F NMR (376 MHz; DMSO-d6) δ - 133.71 (s).

Example 2

Cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid (11b)

Stage A: methyl ester of 4-amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid

Methyl ester of 4-amino-2,3-debtor-5-nitro-benzoic acid (23,48 g; 101,1 mmol) suspended in xylene (125 ml) and added aniline (92 ml; 1011 mmol). The reaction mixture was stirred at 125°C for 16 hours in an atmosphere of N2. The reaction mixture is cooled to room temperature, and the solids precipitate out of solution. The solids are collected by filtration and washed with xylene and then diethyl ether. Received 22,22 g (72,78 mmol) solid yellow color represent the expected pure product. The filtrate is concentrated under reduced pressure, re-dissolved in methylene chloride and quickly passed through the packing silica gel with elution with methylene chloride. The desired fractions are concentrated under reduced pressure to obtain solid brown color, which is triturated with diethyl ether, receiving vs. 5.47 g (17,91 mmol) solid yellow, which represents the expected net produktami the product yield is 27,69 g (90%); found: MS APCI (-) m/z 304 (M-1).

Stage b: methyl ester of 7-fluoro-6-phenylamino-3H-benzimidazole-5-carboxylic acid

Methyl e is Il-4-amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid (16,70 g; 54,71 mmol), formic acid (250 ml; 6,63 mol) and 20%Pd(OH)2/C (9.00 g; 16,91 mmol) in ethanol (250 ml) was stirred at 40°C for two hours in an atmosphere of N2and then at 95°C for 16 hours. The reaction mixture is cooled to room temperature and filtered through celite, washing with ethyl acetate. The filtrate is concentrated under reduced pressure, obtaining a solid yellow color. The solid is triturated with diethyl ether to obtain 13,47 g (86%) of the expected product in the form of a solid yellow-brown color; found: MS APCI (+) m/z 286 (M+1); found: MS APCI (-) m/z 284 (M-1).

Stage C: methyl ester of 7-fluoro-6-(4-iodine-phenylamino)-3H-benzimidazole-5-carboxylic acid

Methyl ester of 7-fluoro-6-phenylamino-3H-benzimidazole-5-carboxylic acid (1.47 g; 4,91 mmol) is suspended in a mixture of 1:1 THF/MeOH (40 ml) and cooled to -78°C. Add solid Lara-TsOH monohydrate (1.5 g, 7.4 mmol) followed by the addition after 5 min NIS (1.2 g; 5.2 mmol). After 15 min the reaction mixture is heated to 0°and then slowly heated to K.T. for 16 hours, the Reaction mixture was quenched by adding 10%NaHSO3. After 30 min the reaction mixture was poured into a separating funnel and the layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts washed with water and with brine, dried (Na2SO4and Konz is tryout under reduced pressure. The residue is triturated with methylene chloride to obtain 1.47 g (69%) of the expected pure product in the form of a solid substance of a reddish colour; found: LC/MS ESI (+) m/z 412 (M+1).

Stage D: methyl ester of 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid

Methyl ester of 7-fluoro-6-(4-iodine-phenylamino)-3H-benzimidazole-5-carboxylic acid (1.4 g; 3.5 mmol) dissolved in DMF (60 ml) and added NCS (470 mg; 3,51 mmol). The reaction mixture is stirred for 144 h at K.T. and then heated to 60°C. After 40 h at 60°the reaction mixture is cooled to K.T., quenched with 10%NaHSO3and diluted with diethyl ether. The layers are separated and the organic layer washed with water, dried (Na2SO4) and concentrate under reduced pressure to obtain 1.24 g (80%) of the expected product in the form of a solid brown color:1H NMR (400 MHz; DMSO-d6) δ 8.50 (s, 1H), 7.97 (s, 1H), 7.78 (d, 1H), 7.42 (dd, 1H), 6.1 (bs, 1H), 3.82 (s, 3H).

Stage E: methyl ester of 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid

Methyl ester of 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid (205 mg; 0.46 mmol) dissolved in DMF (3 ml) and added To the2CO3(76 mg, 0.55 mmol) followed by addition of MeI (36 μl; of 0.58 mmol). After 2 h the reaction mixture is concentrated almost to dryness under reduced pressure. The residue is dissolved in e is racette, washed with saturated NaHCO3and with brine, dried (Na2SO4) and concentrate under reduced pressure. Cleaning with FCC with elution with a mixture of 9:1 methylene chloride/MeCN gives 35 mg (17%) of the expected product:1H NMR (400 MHz, MeOH-d4) δ 8.38 (s, 1H), 8.17 (s, 1H), 7.67 (d, 1H), 7.39 (dd, 1H), 6.40 (dd, 1H), 3.98 (s, 3H), 3.93 (s, 3H);19F NMR (376 MHz; MeOH-d4) δ - 133.8 (s).

Stage F: cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid

Methyl ester of 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid is further treated as described in Example 1, obtaining 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid, cyclopropylmethoxy-amide (11b):1H NMR (400 MHz; acetone-d6) δ 8.24 (s, 1H), 7.79 (s, 1H), 7.68 (d, 1H), 7.45 (dd, 1H), 6.41 (dd, 1H), 4.01 (s, 3H), 3.75 (m, 2H), 1.09 (m, 1H), 0.51 (m, 2H), 0.23 (m, 2H).

Example 3

Cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-methoxy-ethyl)-3H-benzimidazole-5-carboxylic acid (11C)

Cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-methoxy-ethyl)-3H-benzimidazole-5-carboxylic acid (11C) is obtained from the methyl ester of 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid and 1-bromo-2-methoxy-ethane and further treated as described above:1H NMR (400 MHz; Meon-d4) δ 8.32 (s, 1H), 7.72 (s, 1H), 7.63 (m, 1H), 7.33 (dd, 1H), 6.27 (m, 1H), 4.50 (t, 2H), 3.77 (t, 2H), 3.61 (dd, 2H), 3.37 (s, 3H), 1.06 (m, 1H), 0.51 (m, 2H), 0.22 (m, 2H);19F NMR (376 MHz; MeOH-d4) δ -134.91 (s).

Example 4

Cyclopropylmethoxy-amide 3-(4-chloro-butyl)-6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid (11d)

Cyclopropylmethoxy-amide 3-(4-chloro-butyl)-6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid (11d) is obtained from the methyl ester of 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid and 1-bromo-4-chloro-butane and further treated as described above; detected; MS APCI (-) m/z 589, 591, 593 (M-, Cl-form).

Example 5

Cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(4-(morpholine-4-yl-butyl)-3H-benzimidazole-5-carboxylic acid (11th)

Cyclopropylmethoxy-amide 3-(4-chloro-butyl)-6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid (11d) (45 mg; 0,076 mmol) dissolved in DMF (0.5 ml) in a reactor under pressure and add NaI (19 mg, 0.12 mmol) followed by the addition of the research (22 μl; 0.25 mmol). The reaction mixture is blown with nitrogen, sealed and heated to 65°With stirring for 16 hours the Reaction mixture was concentrated under reduced pressure and the residue diluted with ethyl acetate. The organic phase is washed with water and with brine, dry the up (Na 2SO4) and concentrate under reduced pressure. Purification by FCC with elution with a mixture of 95:5 CH3CN/Meon give 36 mg (66%) of the expected product (11th) in the form of solids; found: MS APCI (-) m/z. 640, 642 (N-, Cl-form);1H NMR (400 MHz, MeOH-d4) δ 8.37 (s, 1H), 7.71 (s, 1H), 7.63 (m, 1H), 7.33 (dd, 1H), 6.27 (m, 1H), 4.38 (t, 2H), 3.65 (m, 6N), 2.41 (m, 6N), 1.96 (m, 2H), 1.56 (m, 2H), 1.05 (m, 1H), 0.50 (m, 2H), 0.22 (m, 2H).

Example 6

Cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-[4-(3-hydroxy-azetidin-1-yl)-butyl]-3H-benzimidazole-5-carboxylic acid (11f)

Cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-[4-(3-hydroxy-azetidin-1-yl)-butyl]-3H-benzimidazole-5-carboxylic acid (11f) receive, as described above, using toilet azetidin-3-ol and potassium carbonate; found: MS APCI (-) m/z 626, 628 (N-, Cl-form);1H NMR (400 MHz, MeOH-d4) δ 8.34 (s, 1H), 7.72 (s, 1H), 7.63 (m, 1H), 7.34 (dd, 1H), 6.27 (m, 1H), 4.34 (m, 3H), 3.61 (m, 3H), 3.38 (m, 2H), 2.86 (m, 2H), 2.54 (m, 2H), 1.95 (m, 2H), 1.41 (m, 1H), 1.06 (m, 1H), 0.51 (m, 2H), 0.22 (m, 2H);19F NMR (376 MHz; MeOH-d4) δ - 133.38 is awaited (s).

Example 7

(2-Hydroxy-ethoxy)-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(4-(morpholine-4-yl-butyl)-3H-benzimidazole-5-carboxylic acid (11g)

Stage A: (2-vinyloxy-ethoxy)-amide 3-(4-chloro-butyl)-6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid

3-(4-Chloro-butyl)-6-(2-chloro-4-iodine-phenyl) - Rev. Mino)-7-fluoro-3H-benzimidazole-5-carboxylic acid (70 mg; 0,134 mmol) suspended in DMF (1 ml) under nitrogen atmosphere and add triethylamine (44 μl; 0.32 mmol) followed by addition of NEWT (25 mg; 0.16 mmol). After 5 min add O-(2-vinyloxy-ethyl)-hydroxylamine (WO 0206213) (17 mg; 0.16 mmol) followed by addition of EDCI (31 mg, 0.16 mmol). After 16 h, the reaction mixture was diluted with a mixture of 1:1 ethyl acetate/THF. The organic layers washed with saturated NaHCO3saturated NH4Cl and saline solution, dried (Na2SO4) and concentrate under reduced pressure. Purification by trituration with methylene chloride gives 80 mg (98%) of the expected product; found: MS APCI (-) m/z 605, 607, 609 (N-, Cl-form).

Stage b: (2-vinyloxy-ethoxy)-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(4-(morpholine-4-yl-butyl)-3H-benzimidazole-5-carboxylic acid

(2 Vinyloxy-ethoxy)-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(4-(morpholine-4-yl-butyl)-3H-benzimidazole-5-carboxylic acid is obtained from (2-vinyloxy-ethoxy)-amide 3-(4-chloro-butyl)-6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid as described above: MS APCI (-) m/z 656, 658 (N-, Cl-form).

Stage C: (2-hydroxy-ethoxy)-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(4-(morpholine-4-yl-butyl)-3H-benzimidazole-5-carboxylic acid

(2 Vinyloxy-ethoxy)-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(4-(morpholine-4-yl-butyl)-3H-benzimidazole-5-carboxylic acid (24 mg; being 0.036 mmol) suspended in THF (1 ml) and add recipients who have to 1.0 N. a solution of HCl (0,18 ml; of 0.182 mmol). After 16 h, the reaction mixture was diluted with ethyl acetate and neutralized with saturated solution of NaHCO3. The organic layer is washed with brine, dried over MgSO4and concentrate under reduced pressure. The crude reaction mixture was purified by FCC, elwira a mixture of 10% MeOH/DCM, to obtain 12 mg (52%) of the expected pure product (11g) in the form of a solid white; found: MS APCI (-) m/z 630, 632 (N-, Cl-form);1H NMR (400 MHz, MeOH-d4) δ 8.39 (s, 1H), 7.74 (s, 1H), 7.63 (m, 1H), 7.33 (dd, 1H), 6.26 (m, 1H), 4.38 (t, 2H), 3.92 (t, 2H), 3.66 (m, 6N), 2.41 (m, 6H), 1.97 (m, 2H), 1.56 (m, 2H);19F NMR (376 MHz; Meon-d4) δ - 135.94 (s).

Example 8

Cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzimidazole-5-carboxylic acid (11h)

Stage A: methyl ester of 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzimidazole-5-carboxylic acid

Methyl ester of 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid (220 mg; 0,494 mmol) dissolved in a mixture of 1:1 THF/DMF (2 ml) under nitrogen atmosphere and add To the2CO3(69 mg; 0,499 mmol) followed by the addition of methylphenylsulfonyl (51 μl; 0,592 mmol). After 16 h, the reaction mixture was concentrated under reduced pressure and the residue is dissolved in ethyl acetate. The organic layers washed with saturated is NaHCO 3and with brine, dried (Na2SO4) and concentrate under reduced pressure. Purification by FCC with elution with a mixture of 1:1 methylene chloride/MeCN give 122 mg (45%) of the expected product in the form of a solid whitish color.

Stage: cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzimidazole-5-carboxylic acid

The hydrolysis and the combination, as described above, to give the expected product (11h); found: MS APCI (-) m/z 605, 607 (N-, Cl-form);1H NMR (400 MHz; acetone-d6) δ 10.95 (bs, 1H), 8.37 (s, 1H), 8.21 (bs, 1H), 7.92 (s, 1H), 7.70 (d, 1H), 7.46 (dd, 1H), 6.44 (m, 1H), 4.93 (t, 2H), 3.85 (t, 2H), 3.75 (dd, 2H), 2.98 (s, 3H), 1.09 (m, 1H), 0.44 (m, 2H), 0.24 (m, 2H);19F NMR (376 MHz; acetone-d6) δ-132.31 (s).

Example 9

The following compounds get analogously using the corresponding acceptor Michael (Michael) and hydroxylamine.

(2-Hydroxy-ethoxy)-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzimidazole-5-carboxylic acid (11i): found: MS APCI (-) m/z 595, 597 (M-, Cl-form);1H NMR (400 MHz; Meon-d4) δ 8.39 (s, 1H), 7.78 (s, 1H), 7.64 (d, 1H), 7.34 (dd, 1H), 6.28 (m, 1H), 4.87 (t, 2H), 3.93 (m, 2H), 3.79 (t, 2H), 3.67 (m, 2H), 2.98 (s, 3H);19F NMR (376 MHz; MeOH-d4) δ - 134.00 (s).

Cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-pyridin-2-yl-ethyl)-3H-benzimidazol-carboxylic acid (11j): found: MS APCI (+) m/z 606, 608 (M+, Cl-form); found: MS APCI (-) m/z 604, 606 (M-, Cl-form);1H NMR (400 MHz, MeOH-d4) δ 8.47 (d, 1H), 8.13 (s, 1H), 7.65 (dt, 1H), 7.62 (m, 2H), 7.35 (dd, 1H), 7.26 (dd, 2H), 7.20 (d, 1H), 6.25 (dd, 1H), 4.75 (t, 2H), 3.62 (d, 2H), 3.39 (t, 2H), 1.09 (m, 1H), 0.51 (m, 2H), 0.25 (m, 2H);19F NMR (376 MHz; MeOH-d4) δ - 134.62 (s).

Example 10

An example of a pharmaceutical composition and manufacture of a pharmaceutical preparation in the form of tablets.

Ingredientsmg tablet
1. The MEK inhibitor of formula (I)10,0
2. Cellulose microcristalline57,0
3. Phosphate calcium15,0
4. Sodium starch glycolate5,0
5. Silicon dioxide, colloidal0,25
6. Magnesium stearate0,75

The MEK inhibitor is mixed with the ingredients 2, 3, 4 and 5 for about 10 minutes. Then add the magnesium stearate and the mixture is stirred for approximately 2 minutes and pressed into tablet form.

Now this invention, and the manner and process of its creation and use are described in full, clear, concise and exact terms that enables any person skilled in the art to which it pertains, slipped the t and apply all the same. It should be understood that the above describes the preferred embodiment of the present invention, and there may be changes within the essence and scope of the present invention are set forth in the claims. In order especially to pay attention and to articulate the object is regarded as the invention, this description ends with the following forth by the claims.

1. Benzimidazole compound of the formula

and its pharmaceutically acceptable salt and solvate,

where R1, R2, R9and R10independently selected from hydrogen, halogen, trifloromethyl, deformedarse, triptoreline, azido, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3and C1-C10of alkyl, C3-C10cycloalkyl,3-C10cycloalkenyl, where each alkyl and cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptoreline;

R3selected from hydrogen, trifloromethyl and C1-C10of alkyl, C3-C10cycloalkyl,3-C10cycloalkenyl, where each alkyl and cycloalkyl part possibly substituted by the groups in number from one to five independently selected is from halogen, trifloromethyl, deformedarse, triptoreline, -C(O)R', -C(O)OR', -OC(O)R', -OR';

R' is independently selected from hydrogen, lower alkyl;

R4independently represents hydrogen or C1-C6alkyl;

R6selected from trifloromethyl or C1-C10of alkyl, C3-C10cycloalkyl, where each alkyl, cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptoreline, -C(O)R', -C(O)OR', -OC(O)R', -OR';

R7selected from C1-C10of alkyl, C3-C10cycloalkyl,3-C10cycloalkenyl, where each alkyl and cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptoreline, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

W is selected from-C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3-C(O)(C3-C10cycloalkyl), -C(O)(C1-C10alkyl),

where heteroaryl represents consisting of one or more than one aromatic ring system, a 5 - or 6-membered rings containing at least one is heteroatom and up to two heteroatoms, selected from nitrogen, oxygen and sulfur, and heterocyclyl is azetidin or consisting of one or more than one carbocyclic ring system, a 5 - or 6-membered rings containing at least one heteroatom and up to two heteroatoms selected from nitrogen, oxygen, or sulfur, provided that the ring of this group does not contain two adjacent atom O or S.

2. Benzimidazole compound of the formula

and its pharmaceutically acceptable salt and solvate,

where R1, R9and R10independently selected from hydrogen, halogen, trifloromethyl, deformedarse, triptoreline, azido, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3and C1-C10of alkyl, C3-C10cycloalkyl,3-C10cycloalkenyl, where each alkyl and cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptoreline;

R3selected from hydrogen, trifloromethyl and C1-C10of alkyl, C3-C10cycloalkyl,3-C10cycloalkenyl, where each alkyl and cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triforma is hydroxy, -C(O)R', -C(O)OR', -OC(O)R', -OR';

R' is independently selected from hydrogen, lower alkyl;

R4and R5independently represent hydrogen or C1-C6alkyl;

R6selected from trifloromethyl and C1-C10of alkyl, C3-C10cycloalkyl, where each alkyl and cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptoreline, -C(O)R', -C(O)OR', -OC(O)R', -OR';

R7selected from C1-C10of alkyl, C3-C10cycloalkyl,3-C10cycloalkenyl, where each alkyl, cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptoreline, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

W is selected from-C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3-C(O)(C3-C10cycloalkyl), -C(O)(C1-C10alkyl),

where heteroaryl represents consisting of one or more than one aromatic ring system, a 5 - or 6-membered rings containing at least one heteroatom and up to two heteroatom is s, selected from nitrogen, oxygen and sulfur, and heterocyclyl is azetidin or consisting of one or more than one carbocyclic ring system, a 5 - or 6-membered rings containing at least one heteroatom and up to two heteroatoms selected from nitrogen, oxygen, or sulfur, provided that the ring of this group does not contain two adjacent atom O or S.

3. Benzimidazole compound of the formula

and its pharmaceutically acceptable salt and solvate,

where R1, R2and R9independently selected from hydrogen, halogen, trifloromethyl, deformedarse, triptoreline, azido, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3and C1-C10of alkyl, C3-C10cycloalkyl,3-C10cycloalkenyl, where each alkyl and cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptoreline;

R3selected from hydrogen, trifloromethyl and C1-C10of alkyl, C3-C10cycloalkyl,3-C10cycloalkenyl, where each alkyl, cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptime the si, -C(O)R', -C(O)OR', -OC(O)R', -OR';

R' is independently selected from hydrogen, lower alkyl;

R4independently represents hydrogen or C1-C6alkyl;

R6selected from trifloromethyl or C1-C10of alkyl, C3-C10cycloalkyl, where each alkyl, cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptoreline, -C(O)R', -C(O)OR', -OC(O)R', -OR';

R7selected from C1-C10of alkyl, C3-C10cycloalkyl,3-C10cycloalkenyl, where each alkyl and cycloalkyl part possibly substituted by the groups in number from one to five independently selected from halogen, trifloromethyl, deformedarse, triptoreline, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

And selected from-OR3or-NR4OR3,

where heteroaryl represents consisting of one or more than one aromatic ring system, a 5 - or 6-membered rings containing at least one heteroatom and up to two heteroatoms selected from nitrogen, oxygen and sulfur, and

heterocyclyl is azetidin or consisting of one the or more than one carbocyclic ring system, a 5 - or 6-membered rings, containing at least one heteroatom and up to two heteroatoms selected from nitrogen, oxygen, or sulfur, provided that the ring of this group does not contain two adjacent atom O or S.

4. The compound according to claim 3 having the formula

5. The compound according to claim 4,

where R7represents a C1-C10alkyl, C3-C7cycloalkyl,3-C7cycloalkenyl, each of which may be substituted with 1-3 groups independently selected from halogen, trifloromethyl, deformedarse, triptoreline, -C(O)R3, -C(O)OR3, -OC(O)R3, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

R9represents hydrogen or halogen; and

R1represents lower alkyl or halogen.

6. The compound according to claim 5, where R9represents fluorine.

7. The connection according to claim 6, where R1represents methyl or chlorine.

8. The compound according to claim 5, where a represents a-NR4OR3.

9. The compound according to claim 1,

where R7represents a C1-C10alkyl, C3-C7cycloalkyl,3-C7cycloalkenyl, each of which may be substituted with 1-3 groups independently selected from halogen, trifloromethyl, deformedarse, three is timetake, -C(O)R3, -C(O)OR3, -OC(O)R3, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

R9represents hydrogen or halogen;

R10represents hydrogen; and

W represents-C(O)OR3or-C(O)NR4R3.

10. The connection according to claim 9, where W represents-C(O)NR4OR3.

11. The compound according to claim 2,

where R7represents a C1-C10alkyl, C3-C7cycloalkyl,3-C7cycloalkenyl, each of which may be substituted with 1-3 groups independently selected from halogen, trifloromethyl, deformedarse, triptoreline, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, -OR3, aryl, heteroaryl, arylalkyl, heteroallyl, heterocyclyl and geterotsiklicheskikh;

R9represents hydrogen or halogen;

R10represents hydrogen; and

W represents-C(O)OR3or-C(O)NR4OR3.

12. Connection to item 11, where W represents-C(O)NR4OR3.

13. The compound according to claim 1, selected from

cyclopropylmethoxy-amide 7-fluoro-6-(4-iodine-2-methyl-phenylamino)-3-methyl-3H-benzimidazole-5-carboxylic acid;

cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-methyl-3H-benzoni the azole-5-carboxylic acid;

cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-methoxy-ethyl)-3H-benzimidazole-5-carboxylic acid;

cyclopropylmethoxy-amide 3-(4-chloro-butyl)-6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3H-benzimidazole-5-carboxylic acid;

cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(4-(morpholine-4-yl-butyl)-3H-benzimidazole-5-carboxylic acid;

cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-[4-(3-hydroxy-azetidin-1-yl)-butyl]-3H-benzimidazole-5-carboxylic acid;

(2-hydroxy-ethoxy)-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(4-(morpholine-4-yl-butyl)-3H-benzimidazole-5-carboxylic acid;

cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzimidazole-5-carboxylic acid;

(2-hydroxy-ethoxy)-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzimidazole-5-carboxylic acid; and

cyclopropylmethoxy-amide 6-(2-chloro-4-iodine-phenylamino)-7-fluoro-3-(2-pyridin-2-yl-ethyl)-3H-benzimidazole-5-carboxylic acid.

14. Composition for inhibiting the activity of MEK containing compound according to claim 1 and a pharmaceutically acceptable carrier.

15. Composition for inhibiting the activity of MEK (kinase mitogenactivated or regulated by extracellular signal kinase)containing the compound according to item 13 and pharmaceutically priemel the range of the media.

16. The use of compounds according to claim 1 in the manufacture of medicaments for the inhibition of the activity of MEK.

17. The use of compounds according to claim 1 in the manufacture of drugs for cancer treatment.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine.

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

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel carboxylic acid amides of the general formula (I):

wherein R1 represents hydrogen atom (H); R2 represents a linear or branched (C1-C8)-alkyl possibly substituted with phenyl; or R1 and R2 in common with nitrogen atom (N) represent a 5-membered heterocyclic residue or a 6-membered heterocyclic residue comprising oxygen atom additionally; n = 0, 1. Method involves heating a mixture of 5-amino-1,2,4-triazol-3-ylcarboxylic acid ester of the general formula (II):

wherein R3 represents (C1-C4)-alkyl group; n = 0, 1, amine of the general formula (III):

wherein R1 and R2 have value given above and tertiary aliphatic amine of the formula (IV) given in the invention description at temperature 70-130°C wherein components are taken in the ratio (II) : (III) : (IV) = 1.0:(1.1-2.5):(1.0-3.0), respectively. Method provides decreasing the cost of compounds of the formula (I) based on using the more inexpensive raw, reducing duration of the process and enhancing safety of the process. Synthesized compounds can be used in synthesis of biologically active substances and dyes.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I): or its pharmaceutically acceptable salt wherein X is chosen from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S) atoms; Z represents nitrogen atom (N); Y is chosen from the group consisting of =O, =S or their tautomers; SPU means a spacer element providing distance d between Z and N atom wherein -SPU- represents bi-radical -(CR6R7)n- wherein n means 1, 2, 3, 4 or 5; N atom in common with R1 and R2 forms heterocyclic ring wherein indicated heterocyclic ring is chosen from the group consisting of piperidine and 8-azabicyclo[3.2.1]octane and wherein heterocyclic ring is substituted with one or more substitutes R4 chosen from the group consisting of hydrogen atom, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkylidene, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkyloxyimino-group each of them is substituted optionally with a substitute R5 and wherein at least with one of indicated substitutes R4 is represented by R4' chosen from the group consisting of (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkylidene wherein each of them is substituted optionally with a substitute R5 wherein R5 is chosen from the group consisting of hydrogen, halogen atom, hydroxy-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl; RX can absent or can be chosen from the group consisting of hydrogen atom and optionally substituted (C1-C8)-alkyl; R3 can be represented in 0-4-fold range and chosen from the group consisting of halogen atom, optionally substituted (C1-C8)-alkyl and (C1-C8)-alkoxy-group; each R6 and R7 is chosen optionally and independently among the group consisting of hydrogen atom, hydroxy-group and optionally substituted (C-C8)-alkyl. Also, invention relates to a pharmaceutical composition possessing the selective activity with respect to M and/or M4-subtypes of muscarinic receptors and antagonism with respect to D2-dopamine receptors and comprising compound of the formula (I) by claim 1 in common with pharmaceutically acceptable carriers or excipients. Also, invention relates to a method for enhancing activity of cholinergic receptor comprising interaction of cholinergic receptor and system comprising cholinergic receptor with the effective amount of at least one compound of the formula (I) by claim 1. Also, invention relates to using the compound according to any claim among 1-11 or its pharmaceutically acceptable salt, or pharmaceutical composition containing any base for preparing a medicinal preparation used in prophylaxis aim or treatment of psychosis or for attenuation of symptoms associated with psychosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to novel derivatives of imidazolidine and describes compound of the formula (I): wherein R1 is chosen from the group consisting of (C1-C9)-alkyl, (C1-C2)-alkyl-Ar; R2 is chosen from the group consisting of phenyl, (C1-C4)-alkyl-Ar', -NC(O)R4, (C2-C4)-alkyl-NR3R4, (C1-C3)-alkyl-C(O)-Ar'; R3 is chosen from the group consisting of hydrogen atom (H), (C1-C2)-alkyl-Ar and Ar; R4 represents R3, or R4 can be taken in common with R3 and nitrogen atom to which they are bound for formation of morpholinyl; Ar is chosen from the group consisting of phenyl that can be optionally substituted with one, two or three substitutes chosen from the group consisting of F, Cl, Br and J; Ar' is chosen from the group consisting of phenyl, biphenyl, benzofuranyl and benz[b]thiophene that can be optionally substituted with one, two or three substitutes chosen from the group consisting of (C1-C6)-alkyl, -(CH2)0-5CO2R1, F, Cl, Br, J and COOH; A is chosen from -C(O)NHOH or -N(CHO)OH; X means -NH if Y means -C(O), or its pharmaceutically acceptable salt. Also, invention describes a method for treatment of bacterial infection based on compounds of the formula (I). Invention provides preparing novel compounds possessing the useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds.

4 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

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

7 cl, 47 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new type of compounds representing crown-containing styryl dyes with ammonium group at N-substitute of heterocyclic residue that can be used as photo- and thermosensitive compounds. Invention describes new crown-containing styryl dyes with ammonium group at N-substitute of a heterocyclic residue. Also, invention describes two variants of the method for their preparing. The first method is based on the interaction of a heterocyclic base quaternary salt with formyl derivative of the corresponding crown-compound, and the second method involves quaternization reaction of crown-containing heteroarylphenylethylene at heterocycle nitrogen atom. Proposed crown-containing styryl dyes are prepared from available raw with high yield and represent compounds of the new type able to stereospecific reactions [2 + 2], i. e. photocyclo-addition and possessing thermochromism properties.

EFFECT: improved preparing methods, valuable properties of dyes.

4 cl, 4 dwg, 16 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

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

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinone of the general formula (VI): wherein R1, R2, R3 and R4 are chosen independently from group consisting of hydrogen atom (H) and halogen atom; each R5 means independently (C1-C12)-alkyl; R6 means -NR8-(CH2)mR9, -NR10R11 under condition that from 1 to 4 groups -CH2- can be substituted optionally with -OH; R8 means H; R9 means -NR10R11 wherein R10 and R11 mean (C1-C12)-alkyl, or R10 and R11 in common with nitrogen atom to which they are bound can form a heterocyclic group chosen from morpholinyl, pyrrolidinyl and piperidinyl under condition that the heterocyclic group can be substituted optionally with morpholino-group; J means -NH; L means carbon atom (C), and group -C(O)R6 is bound with L; K and M means -CR5; m = 1, 2, 3 or 4; p = 2. Method for synthesis of these compounds involves the addition reaction of compound of the general formula (III): wherein R* means R with compound of the formula (IV): wherein values R1, R2, R3 and R4 are given above with amine of the general formula (V): HR6 (V) wherein R6 is given above to form indolinone of the general formula (VI). Method provides synthesis of indolinone derivatives with the yield 25-85%.

EFFECT: improved method of synthesis.

20 cl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel carboxylic acid amides of the general formula (I):

wherein R1 represents hydrogen atom (H); R2 represents a linear or branched (C1-C8)-alkyl possibly substituted with phenyl; or R1 and R2 in common with nitrogen atom (N) represent a 5-membered heterocyclic residue or a 6-membered heterocyclic residue comprising oxygen atom additionally; n = 0, 1. Method involves heating a mixture of 5-amino-1,2,4-triazol-3-ylcarboxylic acid ester of the general formula (II):

wherein R3 represents (C1-C4)-alkyl group; n = 0, 1, amine of the general formula (III):

wherein R1 and R2 have value given above and tertiary aliphatic amine of the formula (IV) given in the invention description at temperature 70-130°C wherein components are taken in the ratio (II) : (III) : (IV) = 1.0:(1.1-2.5):(1.0-3.0), respectively. Method provides decreasing the cost of compounds of the formula (I) based on using the more inexpensive raw, reducing duration of the process and enhancing safety of the process. Synthesized compounds can be used in synthesis of biologically active substances and dyes.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 6 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of N-triazolylmethylpiperazine of the general formula (I): , wherein R1 means hydrogen atom or (lower)-alkyl; R2 means (lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, cycloalkyl with 5-6 carbon atoms in cycle, pyridinyl-(lower)-alkyl, possibly bi-substituted phenyl-(lower)-alkyl, phenyloxy-(lower)-alkyl substituted with halogen atom in phenyl ring; R3 means (lower)-alkyl, (lower)-alkyloxycarbonyl-(lower)-alkyl or (C5-C6)-cycloalkyl, or both R2 and R3 in common with nitrogen atom to which they are bound form substituted pyrrolidine ring or cyclic group of the formula (a): , wherein A means nitrogen, oxygen atom, methylene or methylidene group wherein its double bond is formed in common with adjacent carbon atom at position 3 of the group (a), and if A means nitrogen atom then this nitrogen atom has substitute R4', and in this case n means 2 or 3, and R4' means (lower)-alkyl, possibly substituted phenyl-(lower)-alkyl, possibly substituted pyridyl, pyridyl-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, pyrimidyl-(C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(lower)-alkyl or morpholinyl-(lower)-alkyl; R4 and R5 mean hydrogen atom and in all cases n means a whole number from 1 to 2; R4 means hydrogen atom, (lower)-alkyl, (lower)-alkoxy-(lower)-alkyl, (lower)-alkoxycarbonyl, (lower)-alkoxycarbonyl-(lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, phenyl, pyrrolidinyl, pyrrolidinyl-(lower)-alkyl, pyridyl or piperidinyl, cyclohexyl, cyclohexyl-(lower)-alkyl, phenyl-(lower)-alkyl, pyridyl monosubstituted with (lower)-alkyl, phenyl-(lower)-alkyl monosubstituted with (lower)-alkyl, pyrimidyl, pyridyl-(lower)-alkyl, morpholinyl-(lower)-alkyl; R5 means hydrogen atom, (lower)-alkyl or (lower)-alkoxy-(lower)-alkyl, or R4 and R5 taken in common mean spiroethylenedioxy-group bound with carbon atom of the group (a), (C3-C4)-alkylene bound with two adjacent atoms of the group (a) or phenyl anellated by two adjacent carbon atoms of the group (a), and their physiologically acceptable acid-additive salts also. Also, invention relates to methods for synthesis of these compounds, a medicinal agent based on thereof and intermediate compound in synthesis of novel compounds. Novel compounds are antagonists of neurokinin receptors and display effect in peripheral region preferably and can be used in treatment of functional and inflammatory disorders of digestive tract.

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

10 cl, 4 tbl, 4 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted pyrazoles of general formula I , wherein X, Y, Z are nitrogen or R12C; R1 is, halogen, alkoxy, alkyl, alkenyl, haloalkyl, cyano nitro, R9R10N, R9OC=O, R10R11NC=O or R10R11NSO2; R2 is hydrogen, halogen, alkoxy, alkyl, alkenyl, haloalkyl, cyano or R48R49N; R3, R4, R5, R6 are hydrogen or alkyl. Pharmaceutical composition and method for inhibiting of S. cathepsin also are disclosed.

EFFECT: agents useful in treatment of autoimmune diseases mediated by S. cathepsin.

43 cl, 312 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) wherein radicals R1, R2 and alk have values given in claim 1 of the invention claim. Compounds prepared by a method by claim 6 are important antagonists of 5-HT2A-receptors and can be sued in treatment psychosis, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's diseases, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's chorea, nutritional disturbances, such as bulimia, nervous-psychic anorexia, premenstrual syndrome and/or for the positive effect on obsessive-compulsive disorder.

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

12 cl, 12 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (1): and their pharmaceutically acceptable salts wherein represents a double bond; Z1 represents nitrogen atom (N), -CR5 wherein R5 represents hydrogen atom (H), (C1-C6)-alkyl, hydroxy-group (OH),(C1-C6)-alkoxy-group or halogen atom; Z2 at position 2 represents CR1 and at position it represents CA wherein each R1 means independently (C1-C6)-alkyl; A represents -Wi-COXjY wherein Y means -COR2 wherein R2 means -OR, -NR2, -NRNR2 or -NROR wherein each R represents independently hydrogen atom (H), (C1-C6)-alkyl, or (C5-C6)-heteroaryl comprising one or two heteroatoms in ring chosen from atoms N, O and S wherein each of them is substituted with one or some groups chosen from -NR'2, -OR', -COOR', (C1-C6)-alkyl, -CN, =O, and -SR' wherein each R' represents hydrogen atom (H) or (C1-C6)-alkyl and wherein two R or R' jointed to the same nitrogen atom (N) can form 3-8-membered ring chosen from the group comprising piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring and wherein indicated ring can be substituted additionally with (C1-C6)-alkyl or -COO-(C1-C6)-alkyl; X represents unsubstituted (C1-C6)-alkylene, or Y means imidazole substituted with methyl group; i = 0; j = 0 or 1; R7 means hydrogen atom (H) or (C1-C6)-alkyl, -SOR, -SO2R, -RCO, -COOR, (C1-C6)-alkyl-COR, -CONR2, -SO2NR2,-CN, -OR, (C1-C6)-alkyl-SR, (C1-C6)-alkyl-OCOR, (C1-C6)-alkyl-COOR, (C1-C6)-alkyl-CN, or (C1-C6)-alkyl-CONR2 wherein each R represent independently hydrogen atom (H), (C1-C6)-alkyl or aryl that is substituted optionally with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; or R7 represents methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R3 represent independently halogen atom, (C1-C6)-alkyl, -OR, -SR or -NR2 wherein R represents hydrogen atom (H) or (C1-C6)-alkyl; n = 0-3; L1 means -CO; L2 means (C1-C4)-alkylene optionally substituted with one or two groups of (C1-C4)-alkyl; each R4 is chosen independently from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2, -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl; or R4 represents =O; m = 0-4; Ar means aryl group substituted with from 0 to 5 substitutes chosen from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2 and -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl. Compounds of the formula (I) possess the inhibitory activity with respect to p38-α kinase that allows their using as components of the pharmaceutical composition.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

63 cl, 3 tbl, 9 sch, 16 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperazine oxime of the general formula (I): wherein X means phenyl or pyridyl substituted with 1 or 2 substitutes; Y means 2- or 3-indolyl, phenyl, 7-azaindole-3-yl, 3-indazolyl, 2-naphthyl, 3-benzo[b]thiophenyl or 2-benzofuranyl that can be substituted; n = 0-3; m = 0-2; R1 means -NH2, morpholino-, thiomorpholino-group, 2-, 3- or 4-pyridyl or 4-CH3-piperazinyl. Compounds possess antagonistic activity with respect to neurokinine receptors and can be used in treatment of anxiety states. Also, invention describes a pharmaceutical composition based on compounds of the formula (I), method for its preparing and using.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 16 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of sulfonylpyrrolidine of the formula (I): wherein R1 means aryl optionally substituted with halogen atom; R2 means aryl optionally substituted with halogen atom or (lower)-alkyl; R3 means -OR', cyano-group, halogen atom, N-hydroxyamidino-group, -C(O)-OR, -C(O)NR'R'', -N(R')-C(O)-R4, -N(R')-S(O)2-R, -N(R')-C(S)-NR'R, or 5- or 6-membered heteroaryl group comprising from 1 to 4 heteroatoms one of that represents oxygen atom and others represent nitrogen atom, or all heteroatoms represent nitrogen atom only and optionally substituted with (lower)-alkyl or (C3-C7)-cycloalkyl; R4 means (C3-C7)-cycloalkyl, phenyl or (lower)-alkyl that are optionally substituted with halogen atom; R means (lower)-alkyl; R' means hydrogen atom (H), (lower)-alkyl or (C3-C7)-cycloalkyl-(lower)-alkyl being independently of one another if above one R' presents; R'' means H, (lower)-alkyl; n means a whole number from 0 to 5, and to their pharmaceutically acceptable salts under condition that 1-[4-(methylphenyl)sulfonyl]-5-phenylpyrrolidinemethanol is excluded. Compounds of the formula (I) possess affinity to metabotropic glutamate receptors of group I that allows their using as a medicinal agent in treatment, prophylaxis of acute and/or chronic neurological disturbances and states that result to development of glutamate insufficiency taken among the following disorders: damage of spinal cord, head trauma, hypoxia caused by pregnancy, hypoglycemia, Alzheimer's disease, Huntington chorea, amyotrophic lateral sclerosis, disturbance in cognitive ability, memory disturbance and chronic and acute pain, schizophrenia, idiopathic parkinsonism and parkinsonism caused by medicinal agents, convulsions, anxiety (fear) and depressions.

EFFECT: valuable medicinal properties of compounds.

21 cl, 6 sch, 1 tbl, 153 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of cyclic amine of the general formula (1): , their pharmaceutically acceptable salts or hydrates wherein each among R1, R2 and R3 represents independently hydrogen atom, halogen atom, hydroxy-group, (C1-C8)-alkoxy-group; each among W1 and W2 represents independently nitrogen atom (N) or -CH; X represents oxygen atom (O), -NR4, -COONR4 or -NR4CO; R4 represents hydrogen atom, (C1-C8)-alkyl, (C3-C6)-alkynyl, substituted or unsubstituted phenyl, unsubstituted benzyl, unsubstituted indanyl wherein substitute(s) of phenyl represent(s) 1-3 groups or atoms chosen from (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkoxy-group substituted with 1-3 halogen atoms, (C1-C8)-alkylthio-group, (C1-C8)-alkylsulfonyl, halogen atom, trifluoromethyl group and (C1-C3)-alkylenedioxy-group; each among l, m and n represents number 0 or 1. Proposed compounds possess inhibitory effect on cell adhesion and/or cell infiltration and can be used as a medicinal agent and pharmaceutical composition based on thereof.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 439 ex

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