Novel pyrrole inhibitors of s-nitrosoglutathione reductase as therapeutic agents

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole compounds of formula I or pharmaceutically acceptable salts thereof: I, where: Ar denotes phenyl, thiophenyl; R1 denotes imidazolyl, imidazolyl substituted with C1-C6alkyl, chlorine, bromine, fluorine, hydroxy group, methoxy group; R2 denotes H, CH3, Cl, F, OH, OCH3, OC2H5, propoxy group, carbamoyl, dimethylamino group, NH2, formamide group, CF3; X denotes CO and SO2. The compounds inhibit S-nitrosoglutathione reductase (GSNOR).

EFFECT: using the compound to produce a pharmaceutical composition and for treating asthma.

17 cl, 1 tbl, 14 dwg, 4 ex

 

Applications equivalents

This application is a continuation application of US 61/089,313, filed 15.08.2008, and bids US 61/116,982, filed 21.11.2008. Each of these applications are incorporated fully by reference.

The technical field to which the invention relates.

The present invention relates to novel pyrrole inhibitors of S-nitrosoglutathione, pharmaceutical compositions containing such inhibitors, and methods for their preparation and use.

The level of technology

The chemical compound nitric oxide is a gas with chemical formula NO. NO is one of the few gaseous signaling molecules known in biological systems, and plays an important role in the control of various biological processes. For example, endothelium uses NO to signal the surrounding smooth muscle in the walls of the arterioles relax, which leads to vasodilation and increased blood flow in hypoxic tissue. NO is also involved in the regulation of proliferation of smooth muscle, platelet function, neurotransmission, and plays a role in protecting the host. Although nitric oxide is highly reactive and has a lifetime of a few seconds, he can pass freely through the membrane and contact with many molecular targets. These properties make NO ideal signal molecule capable of controlling biological processes m is waiting for neighboring cells and in cells.

NO is a gas free radical, which makes it reactive and unstable, thus NO long exists in vivo, having a half-life period of 3-5 seconds under physiological conditions. In the presence of oxygen NO can unite with thiols with obtaining biologically important class of stable NO adducts, called S-nitrosothiols (SNO). This stable NO reserve, as it was installed, acts as a source of bioactive NO and as such is very important for health and disease, providing a Central place of NO in cellular homeostasis (article Stamler and others, Proc. Natl. Acad. Sci. USA, 1992, 89, cc.7674-7677). Protein SNO plays an important role in the function of the cardiovascular, respiratory, metabolic, gastrointestinal, immune and Central nervous systems (book Foster and others, 2003, Trends in Molecular Medicine, V.9, Issue 4, April 2003, cc.160-168). One of the most studied SNO in biological systems is a 5-nitrosoglutathione (GSNO) (article Gaston and others, Proc. Natl. Acad. Sci. USA, 1993, 90, cc.10957-10961)identified a key regulator of the transmission signal NO, because it is an effective TRANS-nitrotyrosine agent, and as it turned out, maintains balance with other S-nitrotyrosine proteins (article Liu and others, 2001) in the cells. Given this marginal position in NO-SNO continuum, GSNO provides therapeutically valuable target for consideration when the and NO modulation is pharmacologically justified.

In the light of the understanding that GSNO is a key regulator of NO homeostasis and cellular levels SNO, studies have focused on the study of endogenous production of proteins GSNO and SNO, which are found down along the way regarding producing NO radical enzymes synthetase of nitric oxide (NOS). Recently became clearer enzymatic catabolism of GSNO, which plays an important role in managing the available concentrations of GSNO, and therefore available NO and SNO.

In the centre of this study GSNO catabolism researchers recently identified a highly conservative 5-nitrosoglutathione (GSNOR) (article Jensen and others, Biochem J., 1998, 331, cc.659-668; Liu and others, Nature, 2001, 410, cc.490-494). GSNOR is also known as glutathione-dependent formaldehyde dehydrogenase (GS-FDH), alcoholdehydrogenase 3 (ADH-3) (book Uotila and Koivusalo, Coenzymes and Cofactors., edited by D. Dolphin., cc.517-551 (New York, John Wiley & Sons, 1989)), and alcoholdehydrogenase 5 (ADH-5). It is important that GSNOR shows greater activity against GSNO compared to other substrates (article Jensen and others, 1998; Liu and others, 2001), and as it turned out, mediates important protein and peptide dinitrogenase activity in bacteria, plants and animals. GSNOR, as it turns out, is the main GSNO-metabolizing enzyme in eukaryotes (article Liu and others, 2001). So, GSNO may accumulate in biological components in which the activity SNOR is low or absent (for example, the fluid of the respiratory tract) (article Gaston and others, 1993).

Yeast with GSNOR deficiency accumulate S-nitrotoluene proteins that are not substrates of the enzyme, which clearly suggests that GSNO exists in equilibrium with the SNO-proteins (article Liu and others, 2001). The exact enzymatic control ambient levels of GSNO, and thus SNO-proteins raises the possibility that GSNO/GSNOR can play a role in conjunction with physiological and pathological functions, including protection from nitrosative stress, where NO is produced in abundance from physiological levels. Indeed, GSNO in particular is involved in physiological processes, from digestion to breath (article Lipton and others, Nature, 2001, 413, cc.171-174), in the regulation of transmembrane regulator cystic fibrosis (article Zaman and others, Biochem Biophys Res Commun, 2001, 284, cc.65-70, in the regulation of vascular tone, thrombosis and platelet function (articles de Belder and others, Cardiovasc Res., 1994, May; 28(5), cc.691-4. (1994); Z. Kaposzta, And etc.. Circulation; 2002, 106(24), cc.3057-3062), as well as for protective forces of the body (article de Jesus-Berrios, etc., Curr. Biol., 2003, 13, cc.1963-1968). Other studies have shown that GSNOR protects yeast cells from nitrosative stress both in vitro (article Liu and others, 2001)and in vivo (article de Jesus-Berrios and others, 2003).

The overall data suggest that GSNOR is the primary physiological ligand for the enzyme S-nitrosoglutathione (GSNOR), the which catabolize GSNO, and therefore reduces the available SNO and NO in biological systems (article Liu and others, 2001), (article Liu and others, Cell, 2004, 116(4), cc.617-628) and (article Que and others, Science, 2005, 308, (5728), cc.1618-1621). As such, this enzyme plays a Central role in the regulation of local and systemic bioactive NO. Because impaired bioavailability of NO is associated with the pathogenesis of numerous diseases, including hypertension, atherosclerosis, thrombosis, asthma, gastrointestinal disorders, inflammation and cancer, agents that regulate the activity of GSNOR are candidate therapeutic agents for treatment of diseases associated with an imbalance of nitric oxide.

Currently there is a great need in the diagnosis, prevention, relief and treatment of medical conditions associated with increased NO synthesis and/or increased bioavailability of NO. In addition, there is a significant need for new compounds, compositions and methods of prevention, mitigation or cure NO other related disorders. The present invention satisfies these needs.

The invention

The present invention relates to novel pyrrole compounds useful as inhibitors of S-nitrosoglutathione ("GSNOR"). The present invention includes pharmaceutically acceptable salts, prodrugs and metabolites described GSNOR. The invention also includes pharmaceutical compositions containing at least one GSNOR inhibitor and at least one pharmaceutically acceptable carrier.

Compositions of the present invention can be obtained in any suitable pharmaceutically acceptable dosage form.

The present invention relates to a method of inhibiting S-nitrosoglutathione the subject, in need thereof. This method includes the introduction of pharmaceutical compositions containing at least one GSNOR inhibitor or its pharmaceutically acceptable salt, its prodrug or metabolite in a therapeutically effective amount, in combination with at least one pharmaceutically acceptable carrier. GSNOR inhibitor may be a new connection according to the invention, or they may be a known compound, which previously was not known as a GSNOR inhibitor.

The present invention also relates to a method for treating disorders, treatable NO-donor treatment for a subject, in need thereof. This method includes the introduction of pharmaceutical compositions containing at least one GSNOR inhibitor or its pharmaceutically acceptable salt, its prodrug or metabolite in a therapeutically effective amount, in combination with at least one pharmaceutically acceptable carrier. The inhibitor is m GSNOR may be a new connection according to the invention, or they may be a known compound, which previously was not known as a GSNOR inhibitor.

The present invention also relates to a method for treating cell proliferative disorders in a subject in need thereof. This method includes the introduction of pharmaceutical compositions containing at least one GSNOR inhibitor or its pharmaceutically acceptable salt, its prodrug or metabolite in a therapeutically effective amount, in combination with at least one pharmaceutically acceptable carrier. GSNOR inhibitor may be a new connection according to the invention, or they may be a known compound, which previously was not known as an inhibitor of GSNO.

The methods of the invention include the introduction of one or more secondary active agents. Such administration can be sequential or in combination composition.

Although methods and materials similar or equivalent described herein methods and materials can be used for the implementation or testing of the present invention, suitable methods and materials are described below. All these are publicly available publications, patent applications, patents, and other references are incorporated fully by reference. In the event of a conflict will prevail present description, including definitions.

Vysheizlozhennomu of the invention and the following detailed description are exemplary and explanatory, and are designed to provide other details of the claimed compositions and methods. Other objects, advantages and new features will be understood by a person skilled in the art from the foregoing detailed description.

A detailed description of the preferred embodiments

A. Overview inventions

Until recently it was known that 5-nitrosoglutathione (GSNOR) oxidizes formaldehyde glutathione adduct, S-hydroxymethylglutaryl. So GSNOR found in various bacteria, yeast, plants and animals, and is highly conservative. Proteins from E. coli, S. cerevisiae and mouse macrophages show the identity of the amino acid sequence of more than 60%. The GSNOR activity (i.e. the destruction of the S-nitrosoglutathione when NADH is present as a necessary cofactor) identified in E. coli, in mouse macrophages, endothelial cells mouse in cells of smooth muscles of mouse, yeast and HeLa human epithelial and monocytic cells. Information about the nucleotide GSNOR person and amino acid sequences can be obtained from the database of the National Center for Biotechnology Information (NCBI) under number M29872, NM_000671. Information about the nucleotide GSNOR and mouse amino acid sequences can be obtained from the NCBI database under the number NM_007410. In the nucleotide sequence of the starting area and is Onaway site are underlined. CDS has developed the coding sequence. SNP has developed single nucleotide polymorphism. Other related GSNOR nucleotide and amino acid sequences including nucleotide and amino acid sequences of other species can be found in the patent application US 2005/0014697.

In accordance with the present invention it was shown that GSNOR functions in vivo and in vitro for the metabolism of S-nitrosoglutathione (GSNO) and protein S-nitrosothiols (SNO) to modulate the biological activity of NO, by controlling the intracellular levels of low molecular weight NO-donor compounds and prevent the achievement of protein nitrotoluene toxic levels.

On this basis, it follows that inhibition of this enzyme potentional bioavailability of all diseases, which shows NO donor therapy, inhibits the proliferation of pathologically proliferating cells and increases the bioavailability of NO in diseases where it is beneficial.

The present invention relates to pharmaceutical agents that are potent inhibitors of GSNOR. In particular, the substituted pyrrole analogues, which are inhibitors of GSNOR structure below (formulas I and II), or their pharmaceutically acceptable salts, stereoisomers, or prodrugs.

,

Tizanidine pyrrole analogues are potent inhibitors of GSNOR. As used in this context, the term "analog" refers to a compound with similar chemical structure or function compounds of formulas I-II, which contain pyrrole ring.

Some of pyrrole analogues according to the invention can also exist in various isomeric forms, including configurational, geometric and conformational isomers, as well as existing in various tautomeric forms, particularly those at the point of attachment of a hydrogen atom. As used here, the term "isomer" is intended to include all isomeric forms of the compounds, including tautomeric forms of the compounds.

Illustrative of the compounds having asymmetric centers may exist in different enantiomeric and diastereomeric forms. The connection can be in the form of an optical isomer or diastereoisomer. Accordingly, the present invention includes compounds in the form of their optical isomers, diastereomers and mixtures, including racemic mixtures.

It should be noted that if there is a distinction between the structure and the name given to this structure, the advantage is the structure. In addition, if the stereochemistry of a structure or part of a structure not shown, for example, using bold, to nepodobnim or dashed lines, structure or part of a structure should be considered as encompassing all stereoisomers of the described connection.

In accordance with the invention, the levels of S-nitrosoglutathione in a biological sample can be determined by methods described in the patent application US 2005/0014697. The term "biological sample" includes, but is not limited to, blood samples (e.g. serum, plasma or whole blood), urine, saliva, sweat, breast milk, secret vaginal cavity, semen, hair follicles, skin, teeth, bones, nails or other secrets, body fluids, tissues or cells.

C. Definitions

As used here, the term "about" is understood to specialists in the art and will vary to some extent depending on the content in which it is used. If some use of the term, which is not understood by a person skilled in the art used in the context, "about" means plus or minus 10% of the particular term.

The term "acyl" includes compounds and groups that contain acetyl radical (CH3WITH-) or a carbonyl group to which is attached a linear or branched lower alkyl residue.

The term "alkyl" as used here denotes a linear or branched saturated hydrocarbon with the specified number of carbon atoms. the example (C1-C6)alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and neohexyl. The alkyl group can be unsubstituted or optionally substituted by one or more substituents, as described here.

The term "alkenyl" as used here denotes a linear or branched unsaturated hydrocarbon having the specified number of hydrogen atoms and at least one double bond. Examples (C2-C8) alkenylphenol groups include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-penten, 2-penten, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexane, 1-hepten, 2-hepten, 3-hepten, isoheptane, 1-octene, 2-octene, 3-octene, 4-octene and isooctane. Alchemilla group can be unsubstituted or optionally substituted by one or more substituents, as described here.

The term "quinil" as used here denotes a linear or branched unsaturated hydrocarbon having the specified number of hydrogen atoms and at least one triple bond. Examples (C2-C8) alkynylaryl groups include, but are not limited to, acetylene, Pronin, 1-butyn, 2-Butin, 1-penten, 2-pentyn, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyn, 2-heptyn, 3 leptin, 1-octyn, 2-actin, 3-OCTI and 4-octyn. Alchemilla group can be unsubstituted or optionally substituted by one or more substituents, as described here.

The term "alkoxygroup" as used here refers to-O-alkyl group containing the specified number of carbon atoms. For example, (C1-C6)alkoxygroup include-O-methyl, O-ethyl, O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, -O-hexyl, -O-isohexyl and-O-neohexyl.

The term "aminoalkyl" as used here refers to an alkyl group (typically containing from one to six carbon atoms, where one or more hydrogen atoms With1-C6alkyl groups substituted with the amine of formula-N(Rc)2where in each case Rcindependently represents-H or (C1-C6)alkyl. Examples aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2-, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2CH2CH2NH2, -CH2CH2CH2CH2CH2CH2NH2, -CH2CH2CH2N(CH3)2, tert-butylaminoethyl, isopropylaminomethyl and the like.

The term "aryl" as used here denotes a 5-14-membered monocyclic, bicyclic and is and tricyclic aromatic ring system. Examples of aryl groups include phenyl and naphthyl. The aryl group can be unsubstituted or optionally substituted by one or more substituents, as described here. Examples of aryl groups include phenyl or aryl heterocycles, such as pyrrole, furan, thiophene, thiazole, isothiazol, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazol, pyridine, pyrazin, pyridazine and pyrimidine, and the like.

As used here, the term "bioactivity" shows the effect on one or more cellular or extracellular processes (e.g., by binding, signal transduction, and so on), which may affect the physiological or pathophysiological processes.

The term "carbonyl" or "carboxypropyl" or "carboxyl" includes compounds and groups that contain a carbon atom linked by a double bond with an oxygen atom. Examples of groups containing carbonyl include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term "Cm-Cn" indicates the number of carbon atoms "m" to the number of carbon atoms "n". For example, the term "C1-C6" means one to six carbon atoms (C1C2With3With4C5or C6). The term "C2-C6includes from two to six carbon atoms (C2, 3C4C5or6). The term "C3-C6includes from three to six carbon atoms (C3With4C5or5).

The term "cycloalkyl" as used here denotes 3-14-membered saturated or unsaturated non-aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring system. In the data class included cycloalkyl group, which is condensed with the benzene ring. Examples cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, cycloheptyl, cycloheptenyl, 1,3-cycloheptadiene, 1,4-cycloheptadiene, -1,3,5-cycloheptatriene, cyclooctyl, cyclooctene, 1,3-cyclooctadiene, 1,4-cyclooctadiene, -1,3,5-cyclooctadiene, decahydronaphthalene, octahydronaphthalene, hexahydronaphthalen, octahedrons, hexahydrobenzene, tetrahydroindene, decahydronaphthalene, octahydrophenanthrene, hexahydrobenzylcarbonate, tetrahydrobenzaldehyde, dodecahydrate, decahydronapthalene, octahydronaphthalene, hexahydronaphthalen and tetrahydronaphthalen, (1s,3s)-bicyclo[1.1.0]butane, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[3.3.1]nonan bicyclo[3.3.2]decane, bicyclo[3.3]undecane, bicyclo[4.2.2]decane, bicyclo[4.3.1]decane. Cycloalkyl group can be unsubstituted or optionally substituted by one or more substituents, as described here.

The term "halogen" includes fluorine, bromine, chlorine, iodine, etc

The term "halogenated" as used here represents C1-C6alkyl group in which one or more hydrogen atoms of C1-C6alkyl group substituted by halogen atoms, which may be the same or different. Examples halogenating groups include, but are not limited to, trifluoromethyl, 2,2,2-triptorelin, 4-chlorobutyl, 3-bromopropyl, pentachloride and 1,1,1-Cryptor-2-bromo-2-chloroethyl.

The term "heteroalkyl" alone or in combination with another term, means, unless Oksana otherwise stated, a stable linear or branched alkyl or combinations thereof, consisting of carbon atoms and from 1-3 heteroatoms selected from the group consisting of O, N and S, and where the atoms of nitrogen and sulfur may not necessarily be oxidized, and the nitrogen heteroatom may not necessarily be stereoselectivity. Heteroatom (heteroatoms) O, N and S may be placed at any position heteroalkyl group. Examples include-CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-With the 2-S(O)-CH3, -CH2-CH2-S(O)2-CH3and CH2-CH=N-och3. Up to two heteroatoms can be consecutive, such as, -CH2-NH-co3. When the STB, such as (C2-C8), is used to denote heteroalkyl group, the number of carbon atoms from 2 to 8 in this example) also include heteroatoms. For example, With2-heteroalkyl group includes, for example, -CH2HE (one carbon atom and one heteroatom, replacing a carbon atom) and-CH2SH.

To further illustrate the definition heteroalkyl group where the heteroatom is an oxygen heteroalkyl group can be oxyalkylene group. For example, (C2-C5) oxyalkyl includes, for example, -CH2-O-CH3(C3-oxyalkylene group with two carbon atoms and one oxygen atom instead of a carbon atom), -CH2CH2CH2CH2HE, -och2CH2Och2CH2HE, -och2CH(OH)CH2OH and the like.

The term "heteroaryl" as used here refers to an aromatic heterocyclic ring containing from 5 to 14 members, and at least one heteroatom selected from nitrogen, kislorod and sulfur, and containing at least 1 carbon atom, including monocyclic, bicyclic, and three is ilycheskie ring system. Some heteroaryl are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thienyl (thiophenyl), benzothiazyl, chinoline, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolin, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnoline, phthalazine, hintline, pyrimidyl, azepine, oxepin, honokalani and oxazolyl. Heteroaryl group can be unsubstituted or optionally substituted by one or more substituents, as described here.

As used here, the term "heteroatom" includes oxygen (O), nitrogen (N) and sulfur (S).

As used here, the term "heterocycle" denotes a 3 to 14-membered ring system which is saturated, unsaturated or aromatic, and which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and where the heteroatoms nitrogen and sulfur may not necessarily be oxidized, and the nitrogen heteroatom may be optionally stereoselectivity, including monocyclic, bicyclic, and tricyclic ring systems. Bicyclic and tricyclic ring system may include a heterocycle or heteroaryl condensed with a benzene ring. The heterocycle may be attached via any heteroatom or carbon atom, helices and acceptable. Heterocycles include heteroaryl as defined above. Some examples of heterocycles include, but are not limited to, aziridinyl, oxiranyl, Triaryl, triazolyl, tetrazolyl, azirines, diaziridines, diazirines, oxazolidinyl, azetidine, azetidinone, oxetanyl, titanyl, piperidinyl, piperazinil, morpholinol, pyrrolyl, oxazinyl, triazinyl, diazines, dioxane, triazinyl, tetrazines, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furutani, pyridinyl, oxazolyl, benzoxazolyl, benzisoxazole, thiazole, benzthiazole, thienyl, pyrazolyl, triazolyl, pyrimidinyl, benzimidazolyl, isoindolyl, indazoles, benzodiazepin, benzotriazolyl, benzoxazolyl, benzisoxazole, purinol, indolyl, ethenolysis, chinoline and hintline. Heterocyclic group can be unsubstituted or optionally substituted by one or more substituents, as described here.

The term "heteroseksualci" alone or in combination with other terms, represents, unless otherwise stated, cyclic versions of "heteroalkyl". Optionally, a heteroatom can occupy the position in which the heterocycle is attached to the remainder of the molecule. Examples of geterotsiklicheskie include 1-(1,2,5,6-tetrahydropyridine), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-yl, tetrahydrothieno-2-yl, tetrahydrothieno-3-yl, 1-piperazinil, 2-piperazinil and the like.

The term "hydroxyalkyl" as used here refers to an alkyl group that contains the specified number of carbon atoms, where one or more hydrogen atoms in an alkyl group substituted-HE group. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH2CH2CH2CH2CH2OH, -CH2CH2CH2CH2CH2CH2OH and their branched version.

The term "hydroxy-group" or "hydroxyl" includes groups with-IT or-O-.

As here used, and unless otherwise specified, the term "stereoisomer" means one stereoisomer of a compound that is essentially free of other stereoisomers of the compound. For example, stereomono a pure compound with one chiral center is essentially free of the opposite enantiomer of the compound. Stereomono a pure compound with two chiral centers is essentially free of other diastereomers of the compounds. In some embodiments, implementation, stereomono net connection comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, e.g. the measures more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound.

As used here, "protein" is used interchangeably with "peptide", "polypeptide" or "peptide fragment". "Purified" polypeptide, protein, peptide or peptide fragment is essentially free of cellular material or other contaminating proteins from cells, tissue, or cell-free source of amino acid sequence, or substantially free from chemical precursors or other chemicals during chemical synthesis.

As used here, "modulate" means to raise or lower the levels of peptide or polypeptide, or to increase or decrease the stability or activity of the peptide or polypeptide. The term "inhibit" refers to lower levels of the peptide or polypeptide or decrease the stability or activity of the peptide or polypeptide. In preferred embodiments, implementation, modulating or inhibiting peptide is a S-nitrosoglutathione (GSNO) or protein-nitrosothiol (SNO).

As used here, the terms "nitrogen oxide" and "NO" indicates uncharged nitric oxide and charged species of nitric oxide, especially including nitrosonium ion (NO+and ion nitroxyl (NO-). Reactionary form of nitric oxide can be represented with gaseous nitric oxide. Compounds of structure X-NOywhere X represents a group releasing, delivering or transferring nitric oxide, including any and all such compounds that deliver nitric oxide in their area of intended actions in a form active for its intended purpose, and Y has a value of 1 or 2.

As used here, the term "pharmaceutically acceptable" means approved by a regulatory Agency of the Federal or state control or presents in the U.S. Pharmacopoeia or other generally recognized Pharmacopoeia for use in animals and, more specifically, to the people. The term "carrier" refers to a diluent, adjuvant, excipient or binder, which is suitable for therapeutic injection, and includes, but is not limited to such a sterile liquid, such as water and oil.

"Pharmaceutically acceptable salt" or "salt" of GSNOR inhibitor is a product of the described connections, which contains an ionic bond, and is typically obtained by the reaction described in connection with either acid or founded the eat, suitable for administration to a subject. Pharmaceutically acceptable salt may include, but are not limited to, an acid additive salt, including hydrochloride, hydrobromide, phosphates, sulphates, hydrosulfate, alkyl sulphonates, arylsulfonate, arylalkylamines, acetates, benzoate, citrine, maleate, fumarate, succinate, lactates and tartratami; alkali metal cations, such as salts with Li, Na, K, alkaline earth metal such as Mg or CA, or salt of an organic amine.

"Pharmaceutical composition" is a composition that includes the described compounds in a form suitable for administration to a subject. The pharmaceutical composition according to the invention preferably is designed for compatibility with the intended method of administration. Examples of routes of administration include, but are not limited to, oral and parenteral, e.g. intravenous, intradermal, subcutaneous, inhalation, local, transdermal, transmucosal and rectal administration.

The term "substituted" as used here means any one or more of the hydrogen atoms at the indicated atom substituted selected the indicated group, provided that the normal valency of the designated atom is not exceeded, and that the substitution leads to the formation of stable compounds. When a Deputy is ketogroup (t is there =O) then 2 of the hydrogen atom when the atom is substituted. The ring double bond, as used here, are double bonds that are formed between two adjacent ring atoms (for example, C=C, C=N or N=N).

The substituents for the groups identified as alkyl, heteroalkyl, alkylene, alkenyl, quinil, cycloalkyl, heteroseksualci, cycloalkenyl and geteroseksualen, can be selected from various groups, including-ORd', =O, =NRd', =N-ORd', -NRd'Rd", -SRd', -halogen, -SiRd'Rd"Rd"', -OC(O)Rd', -C(O)Rd', -CO2Rd', -CONRd'Rd", -OC(O)NRd'Rd", -NRd"C(O)Rd', -NRd"'C(O)NRd'Rd", -NRd"'SO2NRd'Rd"', -NRd"CO2Rd', -NHC(NH2)=NH, -NRd'C(NH2)=NH, -NHC(NH2)=NRd', -S(O)Rd', -SO2Rd', -SO2NRd'Rd"', -NRd"SO2Rd', -CN and-NO2in numerical value from zero to three, examples of these groups contain zero, one or two Deputy.

Rd', Rdand Rd"' each independently represents hydrogen, unsubstituted (C1-C8)alkyl, unsubstituted hetero(C1-C8)alkyl, unsubstituted aryl and aryl substituted by 1-3 substituents selected from halogen, unsubstituted al the sludge, unsubstituted of alkoxygroup, the unsubstituted toolcategory and unsubstituted aryl (C1-C4)alkyl. When Rd' and Rd" attached to the same nitrogen atom, they can be combined with the nitrogen atom to obtain 5-, 6 - or 7-membered ring. For example, -NRd'Rd" can represent a 1-pyrrolidinyl or 4-morpholinyl.

Typically, alkyl or heteroalkyl group contain from 0 to 3 substituents, examples of these groups contain two or more substituents of the present invention. Alkilany or heteroalkyl radical can be unsubstituted or monosubstituted. In some embodiments, implementation, alkyl or heteroalkyl radical is unsubstituted.

Examples of substituents for the alkyl and heteroalkyl radicals include, but are not limited to, -ORd', =O, =NRd', =N-ORd', -NRd'Rd", -SRd', -halogen, -SiRd'Rd"Rd"', -OC(O)Rd', -C(O)Rd', -CO2Rd', -CONRd'Rd", -OC(O)NRd'Rd", -NRd"C(O)Rd', -NRd"'C(O)NRd'Rd", -NRd"'SO2NRd'Rd"', -NRd"CO2Rd', -NHC(NH2)=NH, -NRd'C(NH2)=NH, -NHC(NH2)=NRd', -S(O)Rd', -SO2Rd', -SO2NRd'Rd"', -NRd"SO2 Rd', -CN and-NO2where Rd', Rd", Rd"' are as described above. Conventional substituents can be selected from: -ORd', =O, =NRd'Rd", -halogen, -OC(O)Rd', -CO2Rd', -C(O)NRd'Rd", -OC(O)NRd'Rd", -NRd"C(O)Rd', -NRd"CO2Rd', -NRd"'SO2NRd'Rd", -SO2Rd', -SO2NRd'Rd", -NRd"SO2Rd', -CN and-NO2.

Similarly, substituents for the aryl and heteroaryl groups are varied and are selected from: -halogen, -ORe', -OC(O)Re', -NRe'Re", -SRe', -Re', -CN, -NO2, -CO2Re', -C(O)NRe'Re", -C(O)Re', -OC(O)NRe'Re", -NRe"C(O)Re', -NRe"CO2Re', -NRe"'C(O)NRe'Re", -NRe"'SO2NRe'Re", -NHC(NH2)=NH, -NRe'C(NH2)=NH, -NH-C(NH2)=NRe', -S(O)Re', -SO2Re', -SO2NRe'Re", -NRe"SO2Re', -N3, -CH(Ph)2, performancebuy and PERFLUORO(C1-C4)alkyl, in a number ranging from 0 to the total number of open valences in the aromatic cyclic system.

Re', Reand Re"' are independently selected the C hydrogen, unsubstituted (C1-C8)alkyl, unsubstituted hetero(C1-C8)alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted aryl(C1-C4)alkyl, and unsubstituted, aryloxy(C1-C4)alkyl. Usually, aryl or heteroaryl group contains from 0 to 3 substituents, examples of these groups are groups with two or more substituents of the present invention. In one embodiment according to the invention, aryl or heteroaryl group is unsubstituted or monosubstituted. In another embodiment, aryl or heteroaryl group is unsubstituted.

Two Deputy when adjacent atoms of aryl or heteroaryl ring in the aryl or heteroaryl group as described herein optionally can be substituted by the Deputy of the formula-T-C(O)-(CH2)q-U, where T and U independently represent-NH-, -O-, -CH2or a simple bond, and q has the value from 0 to 2. Alternatively, two Deputy when adjacent atoms of aryl or heteroaryl ring optionally can be substituted by the Deputy of the formula-J-(CH2)r-K, where J and K independently represent-CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NRf'or a simple bond, and r has a value from 1 to 3. One of the simple relations of the new thus obtained is oliza optionally may be substituted double bond. Alternatively, two Deputy when adjacent atoms of aryl or heteroaryl ring optionally can be substituted by the Deputy of the formula -(CH2)s-X-(CH2)twhere s and t independently have a value from 0 to 3, and X represents-O-, -NRf'-, -S-, -S(O)-, -S(O)2- or-S(O)2NRa'-. Deputy Rf' in-NRf'- and-S(O)2NRf'is selected from hydrogen or unsubstituted (C1-C6) alkyl.

"Stable compound" and "stable structure" refers to a compound that is sufficiently robust to selection in a useful degree of purity from a reaction mixture, and the introduction of effective therapeutic agent.

As used here, the term "therapeutically effective amount" generally means the amount needed to alleviate at least one symptom prevent the breach, mitigate or cure, as described here. The phrase "therapeutically effective amount"attributable to GSNOR inhibitors of the present invention, refers to a dosage of GSNOR inhibitor that provides the specific pharmacological response for which the GSNOR inhibitor is administered in a significant number of subjects in need of such treatment. Assume that a therapeutically effective amount of GSNOR inhibitor, which impose specific subject is in a particular variant, not always effective for the treatment of these conditions/diseases, even though such dosage is therapeutically effective amount of a specialist in a given field of technology.

C. Inhibitors of S-nitrosoglutathione

1. Compounds according to the invention

In one of the embodiments the present invention relates to a compound of structural formula I or its pharmaceutically acceptable salt, stereoisomer or prodrug:

where:

Ar is selected from the group consisting of phenyl and thiophenyl;

R1selected from the group consisting of unsubstituted of imidazolyl, replaced imidazolyl, chlorine, bromine, fluorine, hydroxy-group and metoxygroup;

R2selected from the group consisting of hydrogen, methyl, chlorine, fluorine, hydroxy-group, metoxygroup, ethoxypropan, propoxylate, carbamoyl, dimethylaminopropyl, amino, formamido and trifloromethyl; and

X is selected from the group consisting of CO and SO2.

In another embodiment of the invention, suitable groups for R1include, but are not limited to, the unsubstituted imidazolyl and substituted imidazolyl. Suitable substituents for substituted imidazoline groups include, but are not limited to, C1-C6alkyl.

In another embodiment of the invention group is s ArR 1R2include, but are not limited to:

;;;

;

where R3selected from H, methyl and ethyl.

In another embodiment of the present invention ArR1include, but are not limited to, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 4-forfinal, 3-forfinal, 4-hydroxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-chlorothiophene-2-yl, 5-chlorothiophene-2-yl, 3-bromothiophene-2-yl, 4-bromothiophene-2-yl, 5-bromothiophene-2-yl and 5-bromothiophene-3-yl.

In one of the embodiments of the present invention describes a compound of structural formula II or its pharmaceutically acceptable salt, stereoisomer or prodrug:

where:

Ar is selected from the group consisting of phenyl and thiophenyl;

R4selected from the group consisting of unsubstituted of imidazolyl and replaced imidazolyl;

R5selected from the group consisting of hydrogen, fluorine, hydroxy-group and metoxygroup;

R6selected from the group consisting of hydrogen, chlorine, bromine and fluorine;

R7selected from the group consisting of hydrogen and methyl; and

R8selected from the group consisting of CONH2, SO2NH2and NHSO2CH3.

In another embodiment, implementation is tvline of the invention, suitable groups for ArR4R5include, but are not limited to:

;;v;

;

where R9selected from H, methyl and ethyl.

When the connection to the Deputy shows a cross link connecting two atoms in a ring, then such Deputy may be associated with any atom in the ring. When the Deputy is shown without indicating the atom with which such Deputy is connected with the remainder of the compounds mentioned formula, then such Deputy may be linked via any atom in such substituent. Combinations of substituents and/or variables are possible, but only if such combinations result in the formation of stable compounds.

These compounds may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. From prior art it is well known how to obtain optically active forms, such as the splitting of the racemic form or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds and the like may also be present in the compounds described herein, and all such camera is further isomers are included in the present invention. Described CIS - and TRANS - geometric isomers of the compounds of the present invention, and they can be allocated in the form of mixtures of isomers or in the form of individual isomeric forms. All chiral, diastereomeric, racemic and geometric isomeric forms of a structure are included, unless the specific stereochemistry or isomeric form. All tautomers shown or described compounds are also part of the present invention.

It should be understood that isomers due to the asymmetric (for example, all enantiomers and diastereomers) are included in the scope of the invention unless otherwise stated. Such isomers can be obtained essentially in pure form by classical separation techniques and stereochemical controlled synthesis. In addition, structures and other compounds and groups described in the present description, include their tautomers. Alkenes can include E - or Z-geometry, if possible.

2. Some inhibitors of GSNOR

Table 1 below shows some of the new pyrrole analogs of formula I and formula II which are useful as inhibitors of GSNOR according to the invention. Methods of synthesis that can be used for each connection, shown in more detail below in table 1 (scheme 1, scheme 2, and so on). In some cases, if the source material or the intermediate connection scheme is not comm is Ronski available then the appropriate method describes the synthesis of this starting material or intermediate compounds (that is, method 1, method 2, etc). Table 1 shows the number of schemes, some source materials shown on the drawings, and if necessary, the number of the method that corresponds to the detailed synthesis of the intermediate or starting material. Confirming the data of mass spectrometry for each connection are also included in table 1. Inhibiting activity GSNOR determined using the analysis described in example 2, and the obtained values IC50. Connection-GSNOR inhibitors 1-70 in table 1 are the values of the IC50about <15 μm. Connection-GSNOR inhibitors 1-12, 14-15, 17-19, 22-36, 38-42, 44-56, 58-69 in table 1 are the values of the IC50less than 1.0 μm.

D. pharmaceutical compositions containing the GSNOR inhibitor

The present invention includes pharmaceutical compositions containing at least one described here GSNOR inhibitor and at least one pharmaceutically acceptable carrier. Suitable carrier materials are described in the book "Remington: The Science and Practice, Twentieth Edition," published by Lippincott Williams & Wilkins, which is incorporated by reference. Pharmaceutical compositions in accordance with the invention can also include one or more non-GSNOR inhibiting active agents.

The pharmaceutical compositions according to the invention may include new described here GSNOR inhibitors, pharmaceutical compositions may include known compounds that have not been previously known as the GSNOR inhibitors, or combinations thereof.

The GSNOR inhibitors can be used in any pharmaceutically acceptable dosage form, including, but not limited to, injectable dosage forms, liquid dispersions, gels, aerosols, ointments, creams, liofilizovannye formulations, dry powders, tablets, capsules, controlled release formulations, fast consumable compositions, compositions with delayed release, long visual the statement, compositions with a pulsed-release formulations, mixed immediate release and controlled release, etc. Specifically described here GSNOR inhibitors can be formulated: (a) for administration selected from the group consisting of oral, pulmonary, intravenous, intraarterial, intrathecal, intraocular, rectal, ophthalmic, colonic, parenteral, intracisternal, endovaginal, intraperitoneal, local, buccal, nasal and local administration; (b) in a unit dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, tablets, sachets and capsules; (C) in a unit dosage form selected from the group consisting of liofilizovannyh formulations, dry powders, quickly consumable compositions, compositions with controlled release compositions with delayed release formulations of extended release formulations with a pulsed release and compositions mixed immediate release and controlled release.

For respiratory infections inhalation composition can be used to achieve high local concentrations. Formulations suitable for inhalation include dry powder or aerosol or sprayable solutions, dispersions or suspensions, are able to spread the inhaler Il is a nebulizer in endobronchial or nasal cavity of infected patients for the treatment of bacterial infections of the upper and lower respiratory tract.

Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include one or more of the following components: (1) a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; (2) antibacterially agents such as benzyl alcohol or methylparaben; (3) antioxidants, such as ascorbic acid or sodium bisulfite; (4) chelating agents such as ethylenediaminetetraacetic acid; (5) buffers, such as acetates, citrates or phosphates; and (5) agents for regulating toychest, such as sodium chloride or dextrose. The pH value can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral composition can be included in ampoules filled syringes or vessels with multiple doses of glass or plastic.

Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (water soluble) or dispersions and sterile powders for obtaining before applying sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline solution, bacteriostatics the th water Cremophor EL (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that it can be easy to fill the syringe. The pharmaceutical composition should be stable under conditions of manufacture and storage and must be protected from undesirable action of microorganisms, such as bacteria and fungi.

The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol, and the like), and suitable mixtures. The desired fluidity can be achieved, for example, using a coating such as lecithin, by the provision of the necessary size of the particles for dispersion and with the help of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases, they preferably include isotonic agents, for example, sugar, polyalcohol, such as mannitol or sorbitol, inorganic salts such as sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by inclusion in the composition of agents, which semelee the absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be obtained by introducing the active reagent (for example, the GSNOR inhibitor) in the required amount in an appropriate solvent with one or more ingredients listed above, if necessary, with subsequent filtration sterilization. Typically, the dispersion is produced by introduction of at least one of GSNOR inhibitor in a sterile medium, which contains the basic dispersion medium and any other necessary ingredients. For sterile powders for obtaining sterile injection solutions, approximate methods of production include vacuum drying and drying, freezing, which can lead to powder GSNOR inhibitor plus any additional desired ingredient from a previously sterile-filtered solution.

Oral compositions generally include an inert diluent or edible carrier. They can be included, for example, gelatin capsules or pressed into tablets. For oral therapeutic administration GSNOR inhibitor may be formulated with excipients and used in the form of tablets, pellets or capsules. Oral compositions can also be obtained by using a liquid medium for use as a solution for rinsing the oral cavity, where the connection in the LM is whom the carrier is used for oral and washed off and sprawyvaetsya or eaten. Pharmaceutically compatible binding agents and/or adjuvants can be included in the composition.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable gas propellant is used, for example, a gas such as carbon dioxide, aerosol liquid or dry powder of a suitable device. For transmucosal or TRANS-dermal composition are substances that promote penetration, suitable for penetration through the barrier. Such substances that promote infiltration, usually known from the prior art, and include, for example, for transmucosal introduction, detergents, salts of bile acids and derivatives of fuseboy acid. Transmucosally introduction can be carried out through the use of nasal sprays or suppositories. For TRANS-dermal active reagents are in ointments, salves, gels, or creams, known from the prior art. The reagents can also be obtained in the form of suppositories (e.g., with the usual bases for suppositories, such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, inhibitors of GSNOR get with carriers that protect from quick races is alinia in the body. For example, there may be used a composition with controlled release formulation, including implants and microencapsulation delivery system. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyarteritis and polylactic acid. Methods for such compounds is clear to a person skilled in the technical field.

Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. They can be obtained in accordance with methods known to the person skilled in the technical field, for example as described in patent US 4,522,811.

Additionally, suspensions of GSNOR inhibitors can be obtained as appropriate oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or synthetic fatty acid esters, such as etiloleat, triglycerides, or liposomes. Non-lipid poly-aminopolymers can also be used for delivery. Optionally, the suspension may also include suitable stabilizers or agents to increase the solubility of the compounds and obtain highly concentrated Rast the Directors.

Especially preferred for making oral or parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used here refers to physically discrete units suitable as unitary dosages for treatable entity; each unit contains a predetermined quantity of GSNOR inhibitor, designed to obtain a desired therapeutic effect in a mixture with the required pharmaceutical carrier. List of unit dosage forms according to the invention is prescribed and directly depends on the specific characteristics of the GSNOR inhibitor and achieved specific therapeutic actions, and restrictions known from the prior art for preparation, such as an active agent for the treatment of patients.

Pharmaceutical compositions in accordance with the invention, containing at least one GSNOR inhibitor may include one or more pharmaceutical excipients. Examples of such excipients include, but are not limited to, binders, fillers, lubricants, suspendresume agents, sweeteners, fragrances, preservatives, buffers, moisturizing agents, leavening agents, agents to obtain a frothy mixture and other excipients. Such excipients are known from the prior ur is VNA technology. Exemplary excipients include: (1) binding agents, which include various cellulose and cross crosslinked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102, microcrystalline silicon cellulose (ProSolv SMCC™), the resin tragakant and gelatin; (2) fillers such as various starches, lactose, lactose monohydrate and anhydrous lactose; (3) disintegrating agents such as alginic acid, Primogel, corn starch, light cross-linked polyvinylpyrrolidone, potato starch, corn starch and modified starches, croscarmellose sodium, cross-povidone, nitroglicerine starch and mixtures thereof; (4) lubricants, including agents that act on the flowability spressovyvanie powder include magnesium stearate, colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, calcium stearate and silica gel; and (5) glidant, such as colloidal silicon dioxide; (6) preservatives such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or Quaternary compounds such as benzalkonium chloride; (7) diluents such as pharmaceutically acceptable inert fillers, so is e as microcrystalline cellulose, lactose, discouny calcium phosphate, saccharides, and/or mixtures of any of the foregoing; examples of diluents include microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102; lactose such as lactose monohydrate, anhydrous lactose, and Pharmatose® DCL21; discouny calcium phosphate such as Emcompress®; mannitol; starch; sorbitol; sucrose and glucose; (8) sweeteners, including any natural or artificial sweetener, such as sucrose, saccharin, xylitol, saccharin, sodium cyclamate, aspartame and Acesulfame; (9) odorants, such as peppermint, methyl salicylate, orange flavoring, Magnasweet® (trademark MAFCO), flavoring chewing gum, fruit odorants and the like; and (10) agents to obtain a frothy mixture, including connections to obtain effervescent mixtures, such as organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic and alginic acid, and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium carbonate, sodium glycine carbonate, L-lysine, and arginine carbonate. Alternatively, it may be only a component of sodium bicarbonate in combination to obtain effervescent mixtures.

That is, the set that includes the computer is a stand according to the invention

The present invention also includes kits containing a composition according to the invention. Such kits can include, for example, (1) at least one GSNOR inhibitor; and (2) at least one pharmaceutically acceptable carrier, such as a solvent or diluent. Additional components of the kit optionally can include, for example: (1) any of these pharmaceutically acceptable excipients, such as stabilizers, buffers, etc., (2) at least one container, vessel, or similar device for storage and/or mixing the components of the set; and (3) a delivery device, such as an inhaler, nebulizer, syringe, etc.

F. Methods of obtaining inhibitors of GSNOR

The GSNOR inhibitors according to the invention can be easily synthesized by known methods of synthesis or modification of known methods of synthesis. Specialist in the art will understand that the following methods allow the synthesis of pyrrole with different substituents. Exemplary methods of synthesis described below in the examples.

In accordance with one method of synthesis, the reaction of 2-furaldehyde with appropriately substituted acetophenone followed by treatment in a strong acid to yield the appropriately substituted 1,4,7-trione. Cyclization of Triana in the appropriate 1,2,5-triple-substituted pyrrole easily dostigaet the reaction triona with the primary amine in the presence of p-toluensulfonate acid. In one embodiment, the present invention can easily perform further derivatives of phenyl rings in C5 pyrrole, for example, different cross-reactions of condensation. For example, the synthesis trisemester pyrrole reaction of 1-(4-chlorophenyl)ethanone and 2-furaldehyde leads to obtain the desired pyrrole with 4-chloraniline group at C5. From artilharia can be obtained derivative by reaction with boric acid under the reaction conditions of the condensation Suzuki. Such conventional methods of obtaining derivatives allow you to quickly obtain a library of compounds for studies of inhibition of GSNOR in vitro. Various additional methods described in example 1 of this document.

If necessary, further purification and separation of enantiomers and diastereomers can be carried out by standard methods known from the prior art. For example, the separation of the enantiomers of the compounds can be carried out using chiral HPLC and similar chromatographic techniques. The diastereomers can be separated similarly. In some embodiments, however, the diastereomers can simply be physically separated, for example, controlled by precipitation or crystallization.

The method according to the invention, in the implementation as described here, may conveniently be carried out at temperatures which are used in esults in the prior art. In one embodiment, the method is carried out at a temperature in the range from about 25°to about 110°C. In another embodiment, the temperature maintained within the range from about 40°to about 100°C. In another embodiment, the temperature maintained within the range from about 50°to about 95°C.

Phase synthesis using the Foundation carried out using any conventional organic or inorganic bases. Typically, the base is not nucleophilic. Thus, in one embodiment, the base is selected from carbonates, phosphates, hydroxides, alkoxides, salts disilanes and tertiary amines.

The method according to the invention, in the implementation as described here, can essentially be finished in a few minutes or a few hours depending on the nature and quantity of the reagents and the reaction temperature. Determining that the reaction is essentially over, can usually be assessed by standard methods known from the prior art, such as, for example, HPLC, LCMS, TLC and1H NMR.

G. Method of treatment

The present invention relates to methods for prevention or treatment (for example, facilitate one or more symptoms) medical conditions by applying one or more of the described compounds. The methods include the introduction and is hibitor GSNOR in therapeutically effective amounts to a patient, who needs this. The composition of the invention may also include the use of preventive therapy.

GSNOR inhibitor used in the methods of treatment in accordance with the invention, may be: (1) described here a new GSNOR inhibitor or its pharmaceutically acceptable salt, its prodrug or metabolite; (2) connection, which was known prior to the present invention, but it was not known as a connection-GSNOR inhibitor or its pharmaceutically acceptable salt, its prodrug or metabolite; or (3) a compound which was known prior to the present invention, and was known as connection-GSNOR inhibitor, but where it was not known that the compound useful for these treatments, or its pharmaceutically acceptable salt, its prodrug or metabolite.

The patient can be any animal, domestic, cattle or wild animal, including, but not limited to, cats, dogs, horses, pigs and cattle, and preferably humans. As used here, the terms patient and the subject may be used interchangeably.

Subjects with extremely high levels of GSNOR or GSNOR activity, modulation may be achieved, for example, by introducing one or more of the described compounds, which violate or further regulate the function of GSNOR, or red eye reduction is jut level of GSNOR. These compounds can be administered with other agents-GSNOR inhibitors, such as anti-GSNOR antibodies or fragments of antibodies, entomologie GSNOR and-RNA or a low molecular weight molecules, or other inhibitors, alone or in combination with other agents described herein in more detail.

The present invention relates to a method of treatment of a subject suffering from a disorder, facilitate donor therapy N0. This method includes the introduction to a subject a therapeutically effective amount of a GSNOR inhibitor.

As used here, "treatment" means the management and protection of the patient in order to save from the disease, condition, or disorder and includes the introduction of compounds of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition or violation. More specifically, "treatment" includes alteration, mitigation, relief, reducing, suppressing or stopping at least one adverse symptom or disease (disorder), disease, the pathogen (e.g. bacteria or viruses) or other disturbed condition. The treatment lasts as long as improve symptoms and/or pathology.

Violations can include pulmonary disorders associated with hypoxemia is/or contraction of smooth muscles in the lungs and/or pulmonary infection and/or lung injury (for example, pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung disease, cystic fibrosis, COPD), cardiovascular disease and heart disease, including conditions such as hypertension, ischemic coronary syndromes, atherosclerosis, glaucoma, diseases characterized by angiogenesis (e.g., coronary artery disease), disorders in which there is a risk of thrombosis disorders in which there is a risk of restenosis, chronic inflammatory diseases (for example, AID dementia and psoriasis), disorders in which there is a risk of development of apoptosis (e.g., heart failure, atherosclerosis, heart failure, degenerative neurological disorders, arthritis and liver injury (ischemic or alcohol)), impotence, obesity, caused by food, need for food, stroke, reperfusion injury (e.g., traumatic muscle injury in cardiac or pulmonary injury or damage by crushing) and the violations beforehand protection NO heart or brain against subsequent ischemic attacks.

In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts or prodrugs or metabolites can be entered in combination donor NO. The donor gives NO nitrous oxide or related types of reduction-oxidation, and usually provide the bioactivity of nitric oxide, which is identical to nitric oxide, for example, vasorelaxation or stimulation or inhibition of a protein receptor, for example, a ras protein, adrenergic receptor, NFκB. Useful NO donors, including S-nitroso-, O-nitroso-, S-nitroso - and N-nitroso compounds and their nitro-derivatives and complexes of NO with metal, but not excluding other compounds that generate NO bioactivity described in the book "Methods in Nitric Oxide Research," edited by Feelisch and others, s-115 (J.S., John Wiley & Sons, New York, 1996), which is incorporated by reference. The NO donors, which are C-nitroso compounds, where nitrosopropane attached to a tertiary carbon atom, which are useful include donors, as described in patent US 6,359,182 and international patent application WO 02/34705. Examples of S-nitrosoguanidine, including useful S-nitrosothiol include, for example, S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine, S-microsocieties and its ethyl ester, S-nitrosalicylic, S-nitroso-gamma-methyl-L-homocysteine, S-nitroso-L-homocysteine, S-nitroso-gamma-thio-L-leucine, S-nitroso-Delta-thio-L-leucine and S-nitrotoluene. Examples of other useful NO-donors are sodium nitroprusside (nipride), amylnitrite, isosorbide, nitroglycerin, SIN 1, which represents assidoman, furoxemide, N-hydroxy (N-s) and perperoglou, which is saturated with NO, or hydrophobic donor NO.

The combination of GSNOR inhibitor with R(+) enantiomer of amlodipine, a known substance, releasing NO (article Zhang X.P and others, 2002, J. Cardiovascular Pharmacology, 39, SS-214) is also the embodiment of the present invention.

The present invention also relates to a method of treatment of a subject suffering from pathologically proliferating cells, which includes the introduction of a specified subject of GSNOR inhibitor in a therapeutically effective amount. The GSNOR inhibitors are the above compounds or their pharmaceutically acceptable salts, or prodrugs or metabolites, in combination with a pharmaceutically acceptable carrier. Treatment continued so long as alleviated the symptoms and/or pathology.

In another embodiment, the pathologically proliferating cells can be pathologically proliferating microbes. Microbes can be microbes that GSNOR is to protect the microbe from nitrosative stress, or in which cells of a patient infected with the microbe, Express the enzyme, thereby protecting the organism from nitrosative stress. The term "pathologically proliferating microbes" as used here refers to a pathological microorganisms, including, what about the not limited to, pathological bacteria, pathological viruses, pathological chlamydia, pathological protozoa, pathological Rickettsia, pathological fungi and pathological mycoplasmata. A more detailed description of the microbes listed in columns 11 and 12 of the patent US 6,057,367. The term "host cells infected with pathologic microbes", includes not only mammalian cells infected with pathologic viruses, but also mammalian cells containing intracellular bacteria or protozoa, for example, macrophages containing Mycobacteriwn tuberculosis, Mycobacterium leper (leprosy) or Salmonella typhi (typhoid fever).

In another embodiment, the pathologically proliferating cells can be pathologic helminths. The term "pathologic helminths" is used here to refer to the pathological nematodes, pathological trematodes and pathological tisted. More detail on the use of worms, see column (12) patent US 6,057,367.

In another embodiment, the pathologically proliferating cells can be pathologically proliferating mammalian cells. The term "pathologically proliferating mammalian cells" as used here refers to mammalian cells, which increase in size or number in the specified mammal, providing junk on mammalian Il is its agencies. The term includes, for example, pathologically proliferating or growing cells, causing restenosis, pathologically proliferating or growing cells causing benign prostatic hypertrophy, pathologically proliferating cells, causing hypertrophy of the myocardium, and proliferating cells in sites of inflammation, such as synovial cells with arthritis or cells associated with a cell proliferative disorder.

As used here, the term "cell proliferative violation" means a condition in which unregulated and/or abnormal growth of cells can lead to the development of an unwanted condition or disease which may be cancerous or non-cancerous, for example, psoriatic condition. As used here, the term "psoriatic condition" means violations, including hyperproliferative keratinocytes, infiltration of inflammatory cells and formation of cytokines. The cell proliferative disorder may be a precancerous condition, or cancer. Cancer can be a primary cancer or metastatic cancer, or both.

As used here, the term "cancer" includes solid tumors, such as tumors of the lung, breast, colon, ovary, pancreas, prostate, adenocarcinoma, squamous cell carcinoma, sarcoma, malignant g is of IOM, leiomyosarcoma, hepatoma, head and neck cancer, malignant melanoma, non-melanoma skin cancers, as well as hematologic tumors and/or cancer, such as leukemia, children's leukemia and lymphoma, multiple myeloma, Hodgkin's disease, lymphoma limfotsitov and cutaneous origin, acute and chronic leukemia such as acute lymphoblastoma, acute melozitna or chronic melozitna leukemia, neoplasm plasma cells, lymphoid neoplasm and cancers associated with AIDS.

In addition to psoriatic conditions, types of proliferative diseases that can be cured compositions of the present invention, are epidermal and dermoid cyst, lipoma, adenoma, capillary and skin hemangioma, lymphangioma, injury nevus, teratoid tumors, nephroma, myofibromatosis, osteogenic tumors and other dysplastic masses and the like. In one embodiment, the proliferative disease include dysplasia and other disorders.

In one embodiment, the cancer treatment involves reducing the size of the tumor, reducing tumor, stopping tumor growth, reduction of metastatic sites in other tissues or organs distant from the primary site of the tumor, improving the viability of the patient or improving the quality of life of the patient, and the at least two of the foregoing.

In another embodiment, the treatment of cell proliferative disorders include decreased rate of cell proliferation, decrease in the proportion of proliferating cells, reducing the size of the area or zone of cellular proliferation or reducing the number or proportion of cells with disrupted appearance or morphology, or at least two of the foregoing.

In another embodiment, the compounds of the present invention or their pharmaceutically acceptable salts, prodrugs or metabolites can be administered in combination with a second chemotherapeutic agent. In another embodiment, the second chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin, carboplatin, paclitaxel, cyclophosphamide, lovastatin, mimosine, gemcitabine, Aras, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristine, vinblastine, nocodazole, teniposide, etoposide, epothilone, navelbine under maintenance Protocol, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin, idarubitsina, imatinib, epitimia, erlotinib, sorafenib, malate of sunitinib, trastuzumab, rituximab, cetuximab and involving bevacizumab

In another embodiment, the compounds of the present invention or the pharmacist who Cesky acceptable salt, their prodrugs or metabolites can be administered in combination with an agent that cause nitrosative or oxidative stress. Agents for selective caused nitrosative stress for inhibition of proliferation of pathologically proliferating cells in the combination therapy described by GSNOR inhibitors and dosages and methods of their administration include those described in the incorporated patent US 6,057,367. Auxiliary agents for inducing oxidative stress (i.e. agents that increase the ratio of GSSG (oxidized glutathione) relative to GSH (glutathione) or the ratio of NAD(P) with respect to NAD(P)H or derivatives increase thiobarbiturate acid) in combination therapy with the described inhibitors of GS-FDH include, for example, L-buthionine-3-sulfoximine (BSO), an inhibitor of glutathione reductase (e.g., BCNU), inhibitors or substances, separating mitochondrial respiration, and drugs that increase species reactive oxygen species (ROS), for example, adriamycin, standard doses with standard techniques.

The GSNOR inhibitors also can be co-administered with a phosphodiesterase inhibitor (e.g., rolipram, cilomilast, roflumilast, Viagra (sildenafil citrate), Cialis® (tadalafil), Levitra® (vardenafil) etc.), β-agonist, steroid, or an antagonist of leukotriene (LTD4). The Bank is in the art can easily determine a suitable therapeutically effective amount depending on treatable diseases.

The GSNOR inhibitors can be used as a means to improve β-adrenergic transmission signal. In particular, the GSNOR inhibitors alone or in combination with β-agonists could be used to treat or protect against heart disease and other vascular disorders such as hypertension and asthma. The GSNOR inhibitors can also be used to modulate receptors associated with G-protein (GPCR) by potentiation Gs G-protein, resulting in relaxation of smooth muscles (e.g., blood vessels, Airways and blood vessels), and reduced Gq G-protein, thereby preventing the reduction of smooth muscles (e.g., blood vessels, Airways and blood vessels).

A therapeutically effective amount for treatment of a subject suffering from a disorder, relieved NO-donor therapy, is an inhibitory GSNOR number in vivo, which causes the relief curable breach or protect against the risk associated with the violation. For example, for asthma a therapeutically effective amount is effective bronchodilator number; for cystic fibrosis therapeutically effective amount is an effective amount, relieving the obstruction of the respiratory tract; for ARDS therapeutically effective amount is an effective amount, facilitate the it hypoxemia; for heart disease a therapeutically effective amount is an effective amount, debilitating angina or inducing angiogenesis; for hypertension a therapeutically effective amount is an effective amount for reducing blood pressure; coronary coronary disorders a therapeutically effective amount is an effective amount, which increases the flow of blood; for atherosclerosis a therapeutically effective amount is an effective amount, stopping endothelial dysfunction; for glaucoma therapeutically effective amount is an effective amount for reducing intraocular pressure; for diseases characterized by angiogenesis, therapeutically effective amount is an effective amount, inhibiting angiogenesis; for disorders in which there is a risk of thrombosis, a therapeutically effective amount is effective the number that prevents thrombosis; for disorders in which there is a risk of restenosis a therapeutically effective amount is an effective amount, inhibiting restenosis; chronic inflammatory diseases of therapeutically effective amount is an effective amount for reducing inflammation; for violations in which the substance is t the risk of apoptosis therapeutically effective amount is an effective amount for preventing apoptosis; for impotence therapeutically effective amount is an effective amount, causing or prolonging an erection; for obesity therapeutically effective amount is an effective amount, causing a feeling of fullness; for a stroke a therapeutically effective amount is an effective amount, which increases the flow of blood or protecting TIA; reperfusion injury a therapeutically effective amount is an effective amount, increasing function; and for pre-treatment of the heart and brain therapeutically effective amount is an effective amount, protects the cell, for example, when measuring tripolina or IBS.

A therapeutically effective amount for treatment of a subject suffering from pathologically proliferating cells indicates inhibitory GSNOR number in vivo, which is an antiproliferative effective amount. Such antiproliferative effective amount as used here refers to the amount that causes a decrease in the rate of proliferation by at least 20%, at least 10%, at least 5% or at least 1%.

Usually the dose that is therapeutically effective is the quantity is in the range from 1 μg to 10 g/kg, and often in the range of 10 μg to 1 g/kg, or from 10 μg to 100 mg/kg body weight curable patient, per day.

N. Other applications

Compounds of the present invention or their pharmaceutically acceptable salts or prodrugs or metabolites can be used in a variety of vehicles in circumstances where the presence of such compounds is desirable. Such device may be any device or tank, for example, the implantable device, in which the GSNOR inhibitor can be used to cover surgical openings or cardiovascular stent prior to implantation into the patient. The GSNOR inhibitors of the present invention can also be used for various devices for in vitro or kulturarbeit cells.

Compounds of the present invention or their pharmaceutically acceptable salts or prodrugs or metabolites can also be used as an agent for development, selection or purification of binding partner compounds of GSNOR inhibitors, such as antibodies, natural ligands, and the like. Specialist in the art will easily determine a similar application for the compounds of the present invention.

Examples

The following examples are given to illustrate the present invention. It should be noted, is arranged, however, that the invention is not limited to the specific conditions or details described in these examples. In the description of any and all references to publicly available documents, including U.S. patents, incorporated specifically by reference.

Example 1: General and specific methods of obtaining new pyrrole inhibitors of GSNOR

This example describes the schema of receipt of GSNOR inhibitors described in table 1. Some schemes are specific to a particular connection, while others are General schemes, which include the approximate method of obtaining a representative connection. Next on the schemes presented in ways that reveal the intermediate compounds used in the selected schema.

Scheme 1: General scheme for inhibitors of GSNOR patterns 1D

Approximate methods for scheme 1: Synthesis of 3-[1-(4-carbarnoyl-2-were)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propanoic acid

Stage 1: Synthesis of (E)-3-furan-2-yl-1-(4-methoxyphenyl)propenone. A solution of 2-furaldehyde (5,85 g, 60,92 mmole) was added to a methanol solution (120 ml) of 4-methoxyacetophenone (8.5 g, 56.6 mmole)was then added sodium methoxide (3.1 g, 56.6 mmole). The reaction mixture was stirred at room temperature for 16 h, then the solvent was removed in vacuum. The resulting mixture was diluted with water (130 ml) and EXT who was agarawala with ethyl acetate (350 ml). The aqueous layer was re-extracted with ethyl acetate (100 ml). The combined organic layers were dried anhydrous Na2SO4, and the solvent was removed in vacuum to obtain the product (E)-3-furan-2-yl-1-(4-methoxyphenyl)propenone as an orange solid (12,6 g, 97%).

Stage 2: Synthesis of 1-(4-methoxyphenyl)Decan-1,4,7-trione. Conc. HCl (59 ml) was added to a solution of (E)-3-furan-2-yl-1-(4-methoxyphenyl)propenone (12,6 g, 55,2 mmole) in ethanol (237 ml). The reaction mixture was heated at the boil under reflux for 16 h, concentrated and diluted with dichloromethane (250 ml)and the resulting organic layer was washed with water (25 ml). After phase separation the organic layer was dried anhydrous Na2SO4, and the solvent was removed in vacuum to obtain the crude mixture, which was purified accelerated by chromatography on silica gel to obtain 1-(4-methoxyphenyl)Decan-1,4,7-trione (6,89 g, 43%).

Stage 3: Synthesis of ethyl ester of 3-[1-(4-carbarnoyl-2-were)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propanoic acid. 4-Amino-3-methylbenzamide (180 mg, 1.2 mmole) was added to a solution of 1-(4-methoxyphenyl)Decan-1,4,7-trione (350 mg, 1.2 mmole) in ethanol (6 ml), then added monohydrate p-toluensulfonate acid (reducing TsOH or TsOH) (23 mg, 0.12 mmole). The reaction mixture was heated at the boil under reflux for 16 h, and the solvent was removed in vacuum the floor is the group of crude product, after purification accelerated by chromatography on silica gel resulted in the receipt of ethyl ester of 3-[1-(4-carbarnoyl-2-were)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propanoic acid (147 mg, 30%).

Stage 4: Synthesis of 3-[1-(4-carbarnoyl-2-were)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propanoic acid. Ethyl ester of 3-[1-(4-carbarnoyl-2-were)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propanoic acid (86 mg, 0,216 mmole) was dissolved in ethanol (4 ml). Was added water (0.5 ml) to the ethanol solution, and then was added 1N NaOH (0.51 ml, of 0.51 mmole). The reaction mixture was stirred at room temperature for 1 h and then at 45°C for another hour. After removal of solvent in vacuo, the residue was diluted with water (6 ml) and was extracted with ethyl acetate (2×6 ml). The pH value of the aqueous layer was brought to 2 with 1N HCl, and then extracted with ethyl acetate (6 ml). The combined organic layers were dried anhydrous Na2SO4, and the solvent was removed in vacuo to obtain 3-[1-(4-carbarnoyl-2-were)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propanoic acid as a product (68 mg, 85%).

Scheme 1A: Alternative conditions

The exemplary method of figure 1A, alternative conditions: Synthesis of 3-[1-(4-carbamoylmethyl-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-spropvalue acid

Stage 3: Synthesis of ethyl ester of 3-[1-(4-carbamoylmethyl-2-yl)-5-(4-m is toxigenic)-1H-pyrrol-2-yl]propionic acid (compound 1C, R1=4-carbamoylmethyl-2-yl, R2=4-methoxyphenyl): To a solution of ethyl ester of 7-(4-methoxyphenyl)-4,7-dioxaheptyl acid (0.5 mmole), see scheme 1, in ethanol (2 ml) was added amine (1.5 equiv.) and monohydrate p-toluensulfonate acid (0.5 equiv.). The reaction was carried out using a Biotage Initiator Microwave for 1-3 hours at 150°C. the Solvent was removed in vacuum to obtain the crude mixture, which was purified preparatoria on the plate with silica gel to obtain the final product (70 mg, 38%).

Stage 4: Synthesis of 3-[1-(4-carbamoylmethyl-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propionic acid (compound 1D, R1=4-carbamoylmethyl-2-yl, R2=4-methoxyphenyl): ethyl ether, 3-[1-(4-carbamoylmethyl-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propionic acid (0.15 mmole) in a mixture 2:1 methanol/THF was added 2M LiOH (0.30 mmole). The reaction mixture was stirred for 24 hours. The solvent was removed in vacuum. The residue was diluted with water (2 ml) and was extracted with ethyl ether. The pH value of the aqueous layer was brought to 2 with 1N HCl. The resulting suspension was filtered; the solid was washed with water and dried to obtain the final compounds. Yield: 36 mg, 69%.

Scheme 2 scheme 4 intentionally missed.

Figure 5: General scheme for inhibitors of GSNOR patterns 5E

An exemplary method of scheme 5: Synthesis of 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl the-2-were)-1H-pyrrol-2-yl)propanoic acid (compound 5E, Ar1=4-carbarnoyl-2-were, R=H)

Stage 1: Synthesis of 1-(4-bromophenyl)-3-(furan-2-yl)prop-2-EN-1-she (compound 5A). To a solution of 4-brompheniramine (112,6 g, 570 mmol) and furan-2-carbaldehyde (58.5 g, 610 mmol) in methanol (1.5 l) was added CH3ONa (31 g, 570 mmol) for 10 min, and the reaction solution was stirred at room temperature overnight. The reaction mixture was neutralized conc. HCl until pH=7, and the solvent was removed under reduced pressure. To the obtained residue was added to the EA and water. The aqueous layer was extracted with EA for 3 times. The combined layers were washed with a saturated solution of sodium chloride, dried MgSO4concentrated and was purified column chromatography on silica gel (PE (petroleum ether): EA (ethyl acetate)=10:1) to give 1-(4-bromophenyl)-3-(furan-2-yl)prop-2-EN-1-she (compound 5A) as a yellow solid (90,2 g, 65%).

Stage 2: Synthesis of ethyl 7-(4-bromophenyl)-4,7-dioxopentanoate (compound 5B). To a solution of compound 1-(4-bromophenyl)-3-(furan-2-yl)prop-2-EN-1-she (compound 5A) (20,0 g, 72.2 mmole) in ethanol (160 ml) was added HBr (48% in water, 40 ml). The resulting mixture was stirred at the boil under reflux for 8 h and then the reaction solution was concentrated in vacuum. To the residue was added to feast upon. NaHCO3to pH=7 and extracted with EA. The combined organic layers were washed with a saturated solution of CHL is reed sodium, dried MgSO4concentrated and was purified column chromatography on silica gel (PE:EA=5:1) to obtain ethyl 7-(4-bromophenyl)-4,7-dioxopentanoate (compound 5B) as a yellow solid (7.0 g, 28%).

Stage 3: Synthesis of ethyl 3-(5-(4-bromophenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoate (compound 5C, Ar1=4-carbarnoyl-2-were). To a solution of ethyl 7-(4-bromophenyl)-4,7-dioxopentanoate (compound 5B) (3,41 g, 10 mmol) and 4-amino-3-methylbenzamide (1.65 g, 11 mmol) in 50 ml of ethanol was added TsOH·H2On (570 mg, 3 mmole). The reaction solution was stirred at the boil under reflux overnight, and then concentrated in vacuum. The obtained residue was neutralized the feast upon. NaHCO3and were extracted with ethyl acetate. The organic layers were washed with a saturated solution of sodium chloride, concentrated and was purified column chromatography on silica gel (DHM:PE=1:1) to obtain ethyl 7-(4-bromophenyl)-4,7-dioxopentanoate as a pale solid (2,80 g, 61%).

Stage 4: Synthesis of ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoate (compound 5D, Ar1=4-carbarnoyl-2-were, R=H). To a mixture of ethyl 7-(4-bromophenyl)-4,7-dioxopentanoate (4,54 g, 10 mmol) and imidazole (2,04 g, 30 mmol) in DMSO (50 ml) was added L-Proline (0,345 g, 3 mmole), CuI (1,14 g, 6 mmol) and K2CO3(2.76 g, 20 mmol). The resulting mixture AC is stirred in N 2at 100°C overnight, cooled to room temperature, was filtered and concentrated in vacuum. The residue was dissolved in ethyl acetate, and added a saturated aqueous solution of NaHCO3to pH=8,5. The mixture was filtered, and the resulting aqueous layer was extracted with EA (5 times). The combined organic layers were washed with a saturated solution of sodium chloride, dried MgSO4concentrated and was purified column chromatography on silica gel (DHM:Meon=30:1-20:1) to obtain 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoate as a pale solid (1.6 g, 36%).

Stage 5: Synthesis of 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid (compound 5E, Ar1=4-carbarnoyl-2-were, R=H). To a solution of compound 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoate (22,0 g, 48.3 mmole) in a mixture of THF/H2O (V/V=1/1, 220 ml) was added LiOH·H2O (4.15 g, 96,6 mmole). The reaction solution was stirred at room temperature for 5 hours THF was removed under reduced pressure, and the aqueous solution was acidified with 10% HCl to pH=5. The solid was filtered and recrystallized from THF and water [1:1 (V/V)] to obtain 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid as a yellow solid substances is TBA (11,35 g, 55%).

Figure 6: General scheme for inhibitors of GSNOR patterns 6N

An exemplary method of scheme 6: Synthesis of 3-(5-(benzo[(1][1,thioxo-5-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid

Stage 1: Synthesis of 3-methyl-4-(1H-pyrrol-1-yl)benzamide (compound 6A). 2.5-Dimethoxytetrahydrofuran (106 g, 80 mmol) was added to a solution of 4-amino-3-methylbenzamide (100 g, 66.7 mmole) in Asón (300 ml). The mixture was stirred at 80°C for 1.5 h, and then cooled to room temperature. Was added dropwise a solution of Na2CO3at 0°C, and three times were extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of sodium chloride, dried Na2SO4concentrated and washed with petroleum ether. The obtained solid was filtered and dried to obtain 3-methyl-4-(1H-pyrrol-1-yl)benzamide as a pale solid (89,7 g, yield 67%).

Stage 2: Synthesis of 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile (compound 6B). POCl3(65 g, 427 mmol) was added to DMF (34 ml) at 0°C for 30 minutes After addition the mixture was stirred at room temperature for 1.5 h, and then cooled to 0°C. was Added a solution of 3-methyl-4-(1H-pyrrol-1-yl)benzamide (compound 6A) (42.7 g, 213,5 mmole) in DMF (150 ml) at 0°C, and the resulting mixture was stirred at room temperature for 20 m is h, and then was heated at 80°C for 1 h the Solution was cooled to room temperature, and then was added to feast upon. a solution of Na2CO3at 0°C. until pH=8. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed a feast upon. a solution of NaHCO3and a saturated solution of sodium chloride, dried Na2S04, concentrated and purified column chromatography on silica gel (PE:EA=10:1) to obtain 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile in the form of a yellow solid (30.5 g, yield 68%).

Stage 3: Synthesis of ethyl 3-(1-(4-cyano-2-were)-1H-pyrrol-2-yl)acrylate (compound 6C).

Method a: a Mixture of 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile (15 g, 71.4 mmole) and (carletonville)triphenylphosphorane (27.5 g, 78,6 mmole) in toluene was heated at 100°C during the night. Then the mixture was cooled to room temperature, concentrated and purified column chromatography on silica gel (PE:EA=5:1) to obtain ethyl 3-(1-(4-cyano-2-were)-1H-pyrrol-2-yl)acrylate as a yellow oil (19,8 g, 98%).

Method B: To a mixture of 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile (24.5 g, of 116.7 mmole), DMAP (2.9 g, with 23.3 mmole) and monoethylamine potassium (99,2 g, 583,3 mmole) in DMF (600 ml) was added Asón (35,0 g, 583,3 mmole) and piperidine (29,8 g, 350 mmol). The resulting mixture was heated at 80°C and was stirred for 48 hours the Reaction mixture was poured into chilled water and ek who was tragically with ethyl acetate (800 ml × 3). The combined organic layers were washed a feast upon. a solution of NaHCO3and a saturated solution of sodium chloride, dried Na2SO4concentrated and was purified column chromatography on silica gel (PE:EA=5:1) to obtain ethyl 3-(1-(4-cyano-2-were)-1H-pyrrol-2-yl)acrylate as a yellow oil (21.8 g, 67%).

Stage 4: Synthesis of ethyl 3-(1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate (compound 6D). To a solution of ethyl 3-(1-(4-cyano-2-were)-1H-pyrrol-2-yl)acrylate (compound 6C) (8.0 g, 28.6 mmole) in ethanol was added 10% Pd/C (0.8 g). The mixture was stirred under 1 ATM of H2for 30 min at room temperature and was filtered. The obtained filtrate was concentrated to dryness to obtain a crude product of ethyl 3-(1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate (7.5 g)which was used in the next stage without further purification: LC-MS m/z 283,0 [M+H]+the purity of 68%.

Stage 5: Synthesis of ethyl 3-(5-bromo-1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate (compound 6E). NBS (4,76 g, 1 equiv.) portions were added to a solution of ethyl 3-(1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate in DMF at 0°C for 45 minutes After the addition the mixture was stirred at room temperature for 30 min, then poured into water, and three times were extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of sodium chloride, dried Na2SO 4concentrated and was purified column chromatography on silica gel (PE:EA=15:1) to obtain ethyl 3-(5-bromo-1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate in the form of a white solid.

Step 6: Synthesis of ethyl 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate. To a suspension of ethyl 3-(5-bromo-1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate (400 mg, 0,665 mmole), 3,4-methylenedioxyphenylacetic acid (143 mg, 0,864 mmole), sodium bicarbonate (560 mg, 5,32 mmole) in solvent (4 ml) was added Pd(PPh3)4(60 mg, 0,199 mmole). The reaction mixture was degirolami and was heated at the boil under reflux for 5 hours TLC showed that the reaction was completed. Was added water (4 ml)and the mixture was extracted with ethyl acetate (5 ml × 3). The combined organic layers were dried with magnesium sulfate, was filtered and was evaporated to obtain a brown oil, which was purified column chromatography on silica gel to obtain ethyl 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate in the form of a colorless oil (308 mg, 69%).

Stage 7 and stage 8: Synthesis of 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid. To a mixture of ethyl 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate (100 mg, 0,249 mmole) and potassium carbonate (52 mg, 0,373 mmole) in DMSO (1 ml) was added 30% aqueous p is the target H 2O2(of 28.2 mg, 0,249 mmole). The resulting mixture was stirred at room temperature for 2 hours TLC showed that the reaction was completed. Was added water (7 ml), and precipitated white solid. The suspension was centrifuged, and the aqueous phase was discharged. The obtained solid was dried in vacuum to obtain amide intermediate compound as a white solid (85 mg, yield 81%). To a mixture of this intermediate compound in N2About (0.6 ml) and THF (0.6 ml) was added LiOH·H2About (10 mg, 0,238 mmole). The reaction mixture was stirred at room temperature overnight. THF was evaporated in vacuum. The residue was acidified to pH=4 with 5% hydrochloric acid, centrifuged and dried to obtain 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid as a white solid (46 mg, total yield 47%).

Scheme 7 scheme 8 intentionally missed.

Scheme 9a: General scheme for inhibitors of GSNOR patterns 9a-With

An exemplary method of scheme 9: Synthesis of 3-[1[(4-carbarnoyl-2-were)-5-(4-(pyrazole-1-yl)-1H-pyrrol-2-yl]propionic acid

Synthesis of ethyl ester of 3-[1-(4-carbarnoyl-2-were)-5-(4-(pyrazole-1-ylphenyl)-1H-pyrrol-2-yl]propionic acid (compound 9a-B, Ar=1H-pyrazole-1-yl). N,N-Dimethylcyclohexane-1,2-diamine (11 mg, 0.08 mmole) dissolve the Yali in DMSO and was degirolami by passing argon through the solution for 2 minutes. The resulting solution was then added to a mixture of ethyl ester of 3-[1-(4-carbarnoyl-2-were)-5-(4-itfinal)-1H-pyrrol-2-yl]propionic acid (which was obtained in accordance with the first 3 stages of scheme 1, R2=4-iopener, and R1=4-carbarnoyl-2-were) (150 mg, 0.29 to mmole), pyrazole (500 mg, 7.5 mmole), copper iodide (11 mg, 0.06 to mmole) and potassium carbonate (86 mg, and 0.61 mmole)and the resulting reaction mixture was again degirolami within 2 minutes by passing argon through the solution. The reaction mixture was then subjected to microwave radiation for 30 minutes at 120°C. the Reaction mixture is then added to water (10 ml), was extracted into ethyl acetate (3×10 ml). An ethyl acetate extracts were combined, washed with water (5 ml) and then saturated sodium chloride solution (5 ml). The organic layer was then dried MgSO4. Chromatography (cartridge with 5 g of silica gel sep-pak) with dichloromethane, then 1% methanol in dichloromethane resulted in obtaining pure intermediate compound ethyl ester 3-[1[(4-carbarnoyl-2-were)-5-(4-(pyrazole-1-yl)-1H-pyrrol-2-yl]propionic acid (26 mg, 20%).

Synthesis of 3-(5-(4-(1H-pyrazole-1-yl)phenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid (compound 9a-C, Ar=1H-pyrazole-1-yl). Ethyl ester of 3-[1-(4-carbarnoyl-2-were)-5-(4-(pyrazole-1-ylphenyl)-1H-pyrrol-2-yl]propionic acid (24 mg, 0.06 to mmole) was subjected to hydrolysis by the method described above on to the final stage of scheme 1 to obtain specified in the connection header, 3-[1[(4-carbarnoyl-2-were)-5-(4-(pyrazole-1-yl)-1H-pyrrol-2-yl]propionic acid (18 mg, 75%).

Scheme 9b: General scheme for inhibitors of GSNOR patterns 9b-

An exemplary method of scheme 9b: Synthesis of 3-[1-(4-carbarnoyl-2-were)-5-(5-imidazol-1-althofen-2-yl)-1H-pyrrol-2-yl]propionic acid

Synthesis of ethyl ester of 3-[1-(4-carbarnoyl-2-were)-5-(5-imidazol-1-althofen-2-yl)-1H-pyrrol-2-yl]propionic acid. Received, using the same technique as in stage 1 scheme 9a, except that started with ethyl 3-(5-(5-bromothiophene-2-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoate (which was obtained in accordance with the first 3 stages of scheme 1, R2=5-bromothiophene-2-yl, and R1=4-carbarnoyl-2-were).

Synthesis of 3-[1-(4-carbarnoyl-2-were)-5-(5-imidazol-1-althofen-2-yl)-1H-pyrrol-2-yl]propionic acid. Ethyl ester of 3-[1-(4-carbarnoyl-2-were)-5-(5-imidazol-1-althofen-2-yl)-1H-pyrrol-2-yl]propionic acid was subjected to hydrolysis in accordance with procedure described in the first stage of scheme 1, to obtain specified in the title compound 3-[1-(4-carbarnoyl-2-were)-5-(5-imidazol-1-althofen-2-yl)-1H-pyrrol-2-yl]propionic acid.

Diagram 10 diagram 18 intentionally missed.

Scheme 19: General scheme for inhibitors of GSNOR patterns 19F

An approximate method is Hemi 19: Synthesis of 3-[5-benzothiazol-6-yl-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl]propionic acid (compound 19F, Ar2=benzothiazol-6-yl)

Synthesis of benzothiazole-6-carbonylchloride (compound 19A, Ar2=benzothiazol-6-yl). In nitrogen atmosphere benzothiazole-6-carboxylic acid (1,014 registered g, 5.6 mmole) was dissolved in methylene chloride (25 ml). Added five drops of N,N-dimethylformamide. Was slowly added oxalicacid (0.5 ml, 5.6 mmole). After 2 h the reaction mixture was heated at 30°C for 16 hours the Reaction mixture was concentrated in vacuum to obtain benzothiazole-6-carbonylchloride (1,665 g, Quant., light yellow powder).

Synthesis of 7-(benzothiazole-6-carbonyl)-1,4-dioxaspiro[4.5]decane-8-she (compound 19C, Ar2=benzothiazol-6-yl). In nitrogen atmosphere hexamethyldisilazide lithium (2.4 ml, 2.4 mmole) was mixed with THF (5 ml). The reaction mixture was cooled to -78°C. Via an addition funnel was slowly added monoethyleneglycol 1,4-cyclohexandione (374 mg, 2.4 mmole), dissolved in THF (2 ml). The reaction mixture was stirred for 20 min at -78°C. the Mixture was then transferred by pipette into the flask, was cooled to -78°C benzothiazole-6-carbonylchloride (498 mg, 2,52 mmole) was dissolved in THF (5 ml). After the addition the reaction mixture was stirred at -78°C for 1 h, and then left to warm to room temperature. After 12 h was added water (30 ml) and was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with 10% citric acid solution (20 ml), water (20 ml), bicarbonate is m sodium (20 ml) and a saturated solution of sodium chloride (20 ml). The mixture was then dried Na2SO4that was filtered and concentrated in vacuum. The crude material was purified on a column of silica gel (1:1 EtOAc/hexane) to give 7-(benzothiazole-6-carbonyl)-1,4-dioxaspiro[4.5]decane-8-she (271 mg, 35%, light yellow solid).

Synthesis of ethyl ester of 3-[2-(3-benzothiazol-6-yl-3-oxopropyl)-[1,3]dioxolane-2-yl]propionic acid (compound 19S, Ar2=benzothiazol-6-yl). In nitrogen atmosphere 7-(benzothiazole-6-carbonyl)-1,4-dioxaspiro[4.5]decane-8-he (271 mg, of 0.85 mmole) was dissolved in ethanol (1 ml). Added 2,43 M solution ethoxide sodium (0.01 ml, 0.03 mmole). After 12 h the reaction mixture was concentrated in vacuum. The residue was diluted with 10 ml EtOAc/5 ml 10% citric acid. The layers were separated. The aqueous layer was then extracted with EtOAc (3×3 ml). The combined organic layers were washed with water (5 ml) and a saturated solution of sodium chloride (5 ml), dried Na2SO4that was filtered and concentrated in vacuum. The crude material was purified on a column of silica gel (40% EtOAc/hexane) to give the ethyl ester of 3-[2-(3-benzothiazol-6-yl-3-oxopropyl)-[1,3]dioxolane-2-yl]propionic acid (100 mg, 38%, light yellow oil).

Synthesis of ethyl ester of 7-benzothiazol-6-yl-4,7-dioxaheptyl acid (compound 19D, Ar2=benzothiazol-6-yl). In nitrogen atmosphere ethyl ester of 3-[2-(3-benzothiazol-6-yl-3-oxopropyl)-[1,3]dioxolane-2-yl]propionic acid (compound 19 (C) (100 mg, of 0.28 mmole) was dissolved in THF (1 ml). Added 3N HCl and stirred at room temperature. After 12 h the reaction mixture was diluted with water and was extracted with EtOAc (3 times). The combined organic layers were washed with a saturated solution of sodium chloride, dried Na2SO4that was filtered and concentrated in vacuo to obtain ethyl ester 7-benzothiazol-6-yl-4,7-dioxaheptyl acid (52 mg, 58%, dark red solid; 2/3 in the form of ethyl ester, 1/3 in the form of carboxylic acid).

Synthesis of ethyl ester of 3-[5-benzothiazol-6-yl-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl]propionic acid (compound 19TH, Ar2=benzothiazol-6-yl). In a flask with a volume of 4 ml, saturated with nitrogen, ethyl ester of 7-benzothiazol-6-yl-4,7-dioxaheptyl acid (52 mg, 0.16 mmole) was dissolved in 2 ml ethanol. Added p-toluensulfonate acid (pTSA) (9,9 mg, 0.05 mmole) and 4-amino-3-methylbenzamide (37 mg, 0.24 mmole). The vessel was tightly closed and heated at 80°C in oil bath. After 12 h the reaction mixture was cooled and concentrated in vacuum. The crude material was dissolved in N,N-dimethylformamide (1 ml). Was added potassium carbonate (44 mg, of 0.32 mmole). Then added Iodate (0.01 ml, 0,17 mmole). The reaction mixture was stirred at room temperature for 12 hours, the Reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed the ode, a saturated solution of sodium chloride and dried Na2SO4that was filtered and concentrated in vacuum. The crude product was purified on a column of silica gel (5% IPA/CH2Cl2) to give the ethyl ester of 3-[5-benzothiazol-6-yl-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl]propionic acid (compound 19TH, Ar2=benzothiazol-6-yl) (42 mg, 73% with 2 stages, red solid).

Synthesis of 3-[5-benzothiazol-6-yl-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl]propionic acid (compound 19F, Ar2=benzothiazol-6-yl). Ethyl ester of 3-[5-benzothiazol-6-yl-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl]propionic acid (compound 19TH) (42 mg, 0.10 mmole) was subjected to hydrolysis in accordance with the methodology described above in the final stages of scheme 4, to obtain specified in the title compound 3-[5-benzothiazol-6-yl-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl]propionic acid (23 mg, 59%, light yellow-brown powder).

Diagram 20: the General scheme of receipt of GSNOR inhibitors patterns 20C

An exemplary method of scheme 20: Synthesis of 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid (compound 20C, Ar2=4-(1H-imidazol-1-yl)phenyl)

Synthesis of 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-amino-2-were)-1H-pyrrol-2-yl)propanoic acid (compound 20B, Ar2=4-(1H-imidazol-1-yl)phenyl). 3-(5-(4-(1H-Imidazol-1-yl)Hairdryer is l)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid (compound 20A, obtained in accordance with scheme 5, Ar2=4-carbarnoyl-2-were) (3.88 g, 9,37 mmole) was added to aq. the NaOH solution (4.12 g, 103,09 mmole dissolved in 50 ml). Then was added dropwise 11% aq. NaClO (28,83 g, 42,17 mmole). The resulting mixture was stirred at 0~10°C for 1 h, at 35°C for 1 h and at 75°C for 30 minutes After cooling to room temperature the reaction mixture was acidified with 10% hydrochloric acid to pH=7,0, and was filtered to remove solid impurities. The filtrate was then acidified with 10% hydrochloric acid to pH=5,0, and a new precipitate. The precipitate was filtered and dried to obtain compound 20B, Ar2=4-(1H-imidazol-1-yl)phenyl, in the form of a grey powder (3,20 g, 88%).

Synthesis of 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid (compound 20C, Ar2=4-(1H-imidazol-1-yl)phenyl). To a solution of pyridine (2 ml) and CH3SO2Cl/DHM (V/V=1/100, 5 ml) was added a solution of 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-amino-2-were)-1H-pyrrol-2-yl)propanoic acid (compound 20B) (250 mg, of 0.74 mmole) in pyridine (2 ml) at 0°C. the Mixture was stirred at room temperature for 1 h the Solvent was removed under reduced pressure and the resulting solid was acidified with 10% hydrochloric acid until pH=5,0. The precipitate was isolated by centrifuge, promyvaiut, was dried under reduced pressure to obtain compound 20C, Ar2=4-(1H-imidazol-1-yl)phenyl, in the form of a brown powder (40 mg, 13%).

Diagram 21 diagram 32 intentionally missed.

Scheme 33: General scheme for inhibitors of GSNOR patterns 33

An exemplary method of scheme 33: Synthesis of 3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid (compound ZZS, R1=4-carbarnoyl-2-were, R2=4-chloro, R3=methyl)

Synthesis of ethyl 3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-hydroxyphenyl)-1H-pyrrol-2-yl)propanoate (compound 33A, R1=4-carbarnoyl-2-were, R2=4-chloro). Received in accordance with scheme 1 for 1C, R1=4-carbarnoyl-2-were, R2=4-chloro-2-hydroxyphenyl.

Synthesis of ethyl 3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoate (compound 33B, R1=4-carbarnoyl-2-were, R2=4-chloro, R3=methyl). Ethyl 3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-hydroxyphenyl)-1H-pyrrol-2-yl)propanoate (300 mg, 0,704 mmole) was dissolved in acetone. Was added potassium carbonate (146 mg, 1,056 mmole) and methyl iodide (299 mg, 2,112 mmole), and stirred at room temperature overnight. When TLC showed that the reaction was completed, the mixture was filtered, evaporated in a vacuum. The residue was separated between ethyl acetate (20 ml) and water (5 ml). The organic phase was dried with magnesium sulfate, was filtered and was concentrated with receipt is m connection 33B, R1=4-carbarnoyl-2-were, R2=4-chloro, R3=methyl in the form of a yellow oil (295 mg, yield 95%).

Synthesis of 3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid (compound ZZS, R1=4-carbarnoyl-2-were, R2=4-chloro, R3=methyl). The hydrolysis was performed using end-stage circuit 5 with obtaining specified in the connection header.

Scheme 34: General scheme for inhibitors of GSNOR structure 34C

An exemplary method of scheme 34: Synthesis of 3-(1-(4-carbarnoyl-2-were)-5-(4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid (compound 34C. Ar1-X=4-bromophenyl, Ar2 represents a 2-cyclopropyl-1H-imidazol-1-yl, R1=4-carbarnoyl-2-were)

Synthesis of ethyl 3-(5-(4-bromophenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoate (compound 34A, R1=4-carbarnoyl-2-were, Ar1-X=4-bromophenyl). Received in accordance with scheme 1, stage 1-3.

Synthesis of ethyl 3-(1-(4-carbarnoyl-2-were)-5-(4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoate (compound 34B, Ar1-X=4-bromophenyl, Ar2 represents a 2-cyclopropyl-1H-imidazol-1-yl, R1=4-carbarnoyl-2-were. To a mixture of compound 34A (Ar2=4-bromophenyl) (455 mg, 1.0 mmol) and 2-cyclopropyl-1H-imidazole (see method 14 for synthesis) (324 mg, 3.0 mmole, 3.0 equiv.) in NMP (4 ml) was added 8-hydroxyquinolin (22 mg, 0.15 mmole, 0.15 equiv.), Cu2O (282 mg, 0.1 mmole) and K2CO32subjected to microwave radiation at 128°C for 6.0 h, cooled to room temperature and diluted with THF (10 ml) and water (10 ml). The mixture was filtered, and the resulting aqueous layer was extracted with EA (30 ml × 5). The combined organic layers were washed with a saturated solution of sodium chloride (20 ml), dried MgSO4that was filtered, concentrated and purified column chromatography on silica gel (Meon:CH2Cl2=1:15) to give the target compound as a yellow solid (190 mg, yield 39%).

Synthesis of 3-(1-(4-carbarnoyl-2-were)-5-(4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid (compound 34C Ar1-X=4-bromophenyl, Ar2 represents a 2-cyclopropyl-1H-imidazol-1-yl, R1=4-carbarnoyl-2-were). The hydrolysis was carried out in accordance with end-stage circuit 5 with obtaining specified in the connection header.

Scheme 35 intentionally missed.

Scheme 36: General scheme for inhibitors of GSNOR patterns 36D

An exemplary method of scheme 36: 3-(1-(4-carbarnoyl-2-were)-5-(4-(2-oxoacridine-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid

Synthesis of ethyl 4,7-dioxo-7-(4-(2-oxoacridine-3-yl)phenyl)heptanoate. To a mixture of ethyl 7-(4-bromophenyl)-4,7-dioxopentanoate ((compound 36A, where Ar1-Br=4-bromophenyl, see also connect the s 5V, scheme 5) (1.50 g, 4.4 mmole) and oxazolidin-2-it (575 mg, 6.6 mmole) in dioxane (5 ml) was added L-Proline (50 mg, of 0.44 mmole), CuI (42 mg, 0.22 mmole) and K2CO3(1.22 g, 8.8 mmole). The resulting mixture was stirred in an atmosphere of N2at 110°C for 48 h, and then evaporated. The residue was diluted with a mixture of EA/water (40 ml/40 ml). The mixture was filtered, and the resulting aqueous layer was extracted with EA (30 ml × 5). The combined organic layers were washed with a saturated solution of sodium chloride, dried NaSO4concentrated and was purified column chromatography on silica gel (pure DHM until mixture DHM:Meon=30:1) to obtain the specified title compound as a white solid (158 mg, yield 10%).

Synthesis of ethyl 3-(1-(4-carbarnoyl-2-were)-5-(4-(2-oxoacridine-3-yl)phenyl)-1H-pyrrol-2-yl)propanoate. To a solution of ethyl 4,7-dioxo-7-(4-(2-oxoacridine-3-yl)phenyl)heptanoate (158 mg, 0.43 mmole) and 4-amino-3-methylbenzamide (130 mg, 0.68 mmole) in EtOH (1 ml) was added Zn(OTf)2(313 mg, 0,86 mmole). The mixture was heated at 120°C under microwave irradiation for 2 h After evaporation under reduced pressure the crude product was purified column chromatography on silica gel (DHM:Meon=20:1) to obtain the specified title compound as a yellow solid (77 mg, yield 39%).

Synthesis of 3-(1-(4-carbarnoyl-2-were)-5-(4-(2-oxoacridine-3-yl)phenyl)-1H-pyrrol-2-yl)about anovas acid. To a solution of ethyl 3-(1-(4-carbarnoyl-2-were)-5-(4-(2-oxoacridine-3-yl)phenyl)-1H-pyrrol-2-yl)propanoate (67 mg, 0.15 mmole) in a mixture of THF/N2O (1 ml, V/V=1/1) was added monohydrate of lithium hydroxide (7 mg, 0.15 mmole). The mixture was stirred at room temperature for 6 hours THF was evaporated in vacuum. The residue was acidified to pH=5 using 5% hydrochloric acid, concentrated and purified prep-TLC to obtain specified in the title compound as a brown solid (24 mg, yield 39%).

Scheme 36A: Alternative conditions for obtaining intermediate connections connection type 36V (scheme 36 above).

Approximate methods of circuit 36A: Synthesis of ethyl 7-(3-fluoro-4-(1H-imidazol-1-yl)phenyl)-4,7-dioxopentanoate (R=H). Ethyl 7-(3,4-differenl)-4,7-dioxopentanoate (351 mg) was treated with imidazole (241 mg) and pyridine (395 mg) in DMSO (3 ml) at 150°C for 7 h under microwave irradiation. The resulting mixture was diluted with water (12 ml) and was extracted with EtOAc (20 ml × 3). After removal of solvents, the mixture was purified accelerated by chromatography on silica gel, elwira EtOAc, to obtain the desired product ethyl 7-(3-fluoro-4-(1H-imidazol-1-yl)phenyl)-4,7-dioxopentanoate (279 mg, 68%) as a light brown solid.

Scheme 37 scheme 38 deliberately missed.

Scheme 39: Synthesis of 3-(1-(4-carbarnoyl-2-were)-5-(4-chlorine is-2-(dimethylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid

Synthesis of compound 39A. To a mixture of compound 16-4 (method 16) (200 mg, 0,419 mmole). NaBH3CN (53 mg, 0,838 mmole), 37%HCHO (1.5 ml, 2,095 mmole) in CH3CN (5 ml) was added Asón (0.5 ml). After stirring at room temperature overnight the solution was concentrated and diluted with water (15 ml), extracted with ethyl acetate (10 ml × 4). The organic phase was separated and dried, purified prep-TLC (PE:EA=1: 1) to obtain compound 39A in the form of a yellow oil (97 mg, 49%).

Synthesis of compound 39B. Following the procedure described in the last two stages of scheme 6 (stages 7 and 8), with purification of the final product prep-HPLC.

Scheme 40: Synthesis of 3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-formamidine)-1H-pyrrol-2-yl)propanoic acid

Synthesis of ethyl 3-(5-(4-chloro-2-formamidine)-1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate (compound 40A): a Mixture of AU2On (301 mg, 2,948 mmole) and HCO2N (226 mg, 4,914 mmole) was stirred at 55°C for 5 minutes the Mixture was added to a solution of compound 16-4 (see method 16 for synthesis) (300 mg, 0,737 mmole) in THF (6 ml), and stirred at 55°C for 10 minutes TLC showed completion of reaction. Volatile impurities were removed under reduced pressure, and the residue was dissolved in EA (50 ml), washed with a feast upon. a solution of NaHCO3(10 ml × 3) and saturated sodium chloride solution (10 ml). The organic layer was dried without the one Na 2SO4, was filtered and was concentrated to obtain the crude product as a yellow solid (320 mg, yield: 99%), which was directly used in the next stage.

Synthesis of 3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-formamidine)-1H-pyrrol-2-yl)propanoic acid (compound 40B): Cm. the methodology described in the final stages of scheme 6 (6F→6H).

The following methods were used to obtain the intermediate compounds used in the above schemes, as shown in the table.

Method 1 - method 11 intentionally missed.

Method 12: Synthesis of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Connection 12-2. A solution of compound 12-1 (12.3 g, is 0.06 mmole), bis(pinacolato)diboron (18,3 g, 0,072 mol), COAs (11,75 g, 0.12 mmole) and Pd(dppf)2Cl2 DHM (2.0 g, of 2.45 mmole) in a mixture of dioxane/H2About (V/V=9/1, 100 ml) was stirred at 80°C during the night. TLC showed that the reaction was completed. The mixture was evaporated to obtain a brown oil. Was added water (60 ml)and the mixture was extracted with ethyl acetate (60 ml × 3). The combined organic layers were dried MgSO4that was filtered, concentrated and purified column chromatography on silica gel (PE:EA=10:1) to obtain compound 12-2 in the form of a yellow solid (9.1 g, 60%).

Method 13 method 14 intentionally missed.

Method 15: Synthesis of(4-bromo-2-methoxyphenyl)ethanone

Connection 15-1. To a stirred suspension of 3-bromophenol (50 g, of 0.29 mole) in pyridine (200 ml) and dichloromethane (100 ml) was added dropwise acetylchloride (25 ml of 0.35 mol) at 0°C., and the mixture was stirred for 18 h at room temperature. LC-MS showed that the reaction was completed. Pyridine and dichloromethane was evaporated in vacuum. Was added water (600 ml) and acidified with hydrochloric acid to pH 2. The reaction mixture was extracted with ethyl acetate (500 ml × 3), and the organic phase was dried with anhydrous sodium sulfate, was filtered, concentrated and purified column chromatography (PE:EA=60:1) to obtain compound 15-1 in the form of a colourless liquid (46 g, 74%).

Connection 15-2. Stir a suspension of compound 15-1 (46 g, 0,0,21 mole) and anhydrous powdered aluminum chloride (57 g at 0.42 mol) was heated at 160°C for 3 hours the Reaction mixture was cooled to room temperature and poured into ice (200 g) and water (800 ml), and purified hydrochloric acid at pH 7. The reaction mixture was extracted with ethyl acetate (500 ml × 3), and the organic phase is washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, was filtered, concentrated and purified column chromatography (PE:EA=60:1) to obtain compound 15-2 in the form of a light green solid (35.1 g, 76%).

Connection 15-3 To a suspension of compound 15-2 (25 g, 0.12 moles) and potassium carbonate (24 g, 0,18 mol) in anhydrous DMF (20 ml) was added MeI (22,6 ml of 0.23 mol)and the reaction mixture was stirred at room temperature overnight. LCMS showed that the reaction was completed. Then poured into water (300 ml)and the mixture was extracted with ethyl acetate, and the organic phase (200 ml × 3) and washed with saturated solution of sodium chloride, dried with anhydrous sodium sulfate, was filtered, concentrated to obtain compound 15-3 in the form of a colorless solid (26,1 g, 98%).

Method 16: Synthesis of ethyl 3-(5-(2-amino-4-chlorophenyl)-1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate

Connection 16-2. To a solution of compound 16-1 (6.50 g, 27,66 mmole) and NiCl2(7,80 g, 55,3 mmole) in EtOH (50 ml) was slowly added NaBH4(the ceiling of 5.60 g, 138,3 mmole). The resulting mixture was stirred at 0°C for 2 h, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 ml), washed with water (50 ml × 3), dried Na2SO4concentrated and was purified on a column of silica gel (PE:EA=5:1) to obtain compound 16-2 as a dark solid (3,778 g, yield 67%).

Connection 16-3. A solution of compound 16-2 (3,778 g, 18,43 mmole), bis(pinacolato)diboron (8.5 g, 33,17 mol), COAs (3.2 g, 36,86 mmole) and Pd(dppf)2Cl2·DHM (500 mg, of 0.92 mmole) in DMSO (50 ml) was stirred at 85°C. for 2.5 hours TLC show is La, that reaction was completed. Was added water (60 ml)and the mixture was extracted with ethyl acetate (60 ml × 3). The combined organic layers were dried Na2SO4that was filtered, concentrated and purified on a column of silica gel (PE:EA=10:1) to obtain compound 16-3 in the form of a yellow solid (5.0 g, yield 100%).

Connection 16-4. To a solution of compound 16-3 (7.0 g, to 27.7 mmole), Na2CO3(of 11.75 g, 110,8 mmole) and compound 6E (ethyl 3-(5-bromo-1-(4-cyano-2-were)-1H-pyrrol-2-yl)propanoate, see diagram 6) (10 g, with 21.4 mmole) in DMSO (30 ml) was added Pd(PPh3)4(3.0 g, 8,31 mmole). After degassing and saturated with nitrogen, the reaction mixture was stirred at 80°C during the night. TLC showed that the reaction was completed. After cooling to room temperature was added water (50 ml), and extracted with ethyl acetate (50 ml × 4). The combined organic layers were dried Na2SO4that was filtered, concentrated and purified on a column of silica gel (PE:EA=3:1) to obtain compound 16-4 in the form of a yellow solid (3,10 g, yield 27%).

Method 17 intentionally missed.

Method 18: Synthesis of 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

Connection 18-2. Got the same methodology as described in method 12, with dioxane as solvent, and purified column chromatography (PE:EA=5:1) to obtain C the left-hand connection with the release of 35%.

Method 19: Synthesis of 1-(5-bromothiophene-3-yl)ethanone

Connection 19-2. To a solution of 3-acetylthiophene (2,52 g, 20 mmol, 1.0 equiv.) in the SPLA (50 ml) was added NaOAc (2,46 g, 30 mmol, 1.5 equiv.), then dropwise bromine (3.2 g, 20 mmol, 1.0 equiv.) within 30 minutes the Mixture was allowed to mix at room temperature over night. Was added water (150 ml)and the reaction mixture was stirred for 2 hours resulting solid substance was collected by filtration, washed with water (10 ml) and RE (20 ml), and dried to obtain compound 19-2 in the form of a brown solid (1.52 g, yield 37%).

Method 20 method 22 intentionally missed.

Method 23: Synthesis of N-(4-AMINOPHENYL)methanesulfonamide (compound 23-3, R=H) and N-(4-amino-3-were)methanesulfonamide (compound 23-3, R=CH3)

The approximate method example 23: Synthesis of N-(4-AMINOPHENYL)methanesulfonamide (compound 23-3, R=H)

Connection 23-2, R=N. To a solution of pyridine (50 ml) and MsCl (15,86 g, 139,13 mmole) in DHM (150 ml) was added a solution of 4-nitrobenzylamine (16.0 g, 115,94 mmole) in pyridine (100 ml) at 0°C. the Mixture was stirred at room temperature for 4 h Volatile impurities were removed under reduced pressure. The residue was washed with water (200 ml × 3) and dried under reduced pressure to obtain specified in the title compound as a yellow powder (23,20 g, yield 95%).

Connection 23-3 R=N. To a solution of compound 23-2, R=H (23,0 g, 106,48 mmole) in Meon (100 ml) was added 10% Pd/C (3.0 g), saturated N2. Then gradually added to the solution HCO2NH4(67,0 g of 1.06 mol) in Meon (500 ml) in a bath of ice-water for 5 minutes After adding the mixture was heated to 45°C. and was stirred overnight and was filtered. The filtrate was evaporated under reduced pressure to obtain a yellow solid, which was washed EA (500 ml × 3). The combined organic layers were evaporated under reduced pressure, was purified column chromatography on silica gel (PE:EA=1:2) to give N-(4-AMINOPHENYL)methanesulfonamide in the form of a yellow solid (9.80 g, yield 49%).

Method 24: Synthesis of 1-(3-chlorothiophene-2-yl)ethanone

Connection 24-1. To a solution of 3-chlorothiophene (4,80 g, 40,48 mmole) in THF (50 ml) was added BuLi (2,5N in hexane, to 17.9 ml) at -30°C. After addition the mixture was stirred for 30 min at -10°C, and then cooled to -45°C. was Added N-methoxy-N-methylacetamide (55,0 g, 48.8 mmole), and left to warm to room temperature over 40 min, and left for 20 minutes was Added a saturated solution of sodium chloride (80 ml) to to quench the reaction was extracted with EA (60 ml × 3). The combined organic layers were dried anhydrous Na2SO4that was filtered, concentrated to obtain 24-1 (~80% purity) as a yellow mA is La (6,80 g), which is directly used in the next stage.

Method 25: Synthesis of 1-(3-bromo-5-methoxythiophene-2-yl)ethanone

Connection 25-1. To a suspension of the hydrochloride M,0-dimethylhydrogen (100 g, 1026 mmol) in DHM (1000 ml) was added triethylamine (300 ml, 2052 mmole) at 0°C. To the suspension was added dropwise acetylchloride for 2 h at 0°C. After addition the mixture was left to warm to room temperature and was stirred for 2 hours the Mixture was washed with a saturated solution of sodium chloride (1 l), 1 N HCl (500 ml), saturated solution of sodium chloride (200 ml) and dried with magnesium sulfate, was filtered and was concentrated with obtaining a brown oil, which was purified by distillation to obtain compound 25-1 in the form of a transparent liquid (65 g, 61%).

Connection 25-2. To a solution of thiophene (84 g, 1.0 mol) in chloroform (34 ml) was added dropwise bromine at room temperature for 3 hours After the addition the mixture was stirred at room temperature overnight. The mixture was heated at 50°C for 3 hours, the Reaction mixture was washed with 1M NaOH (aq. 100 ml), saturated solution of sodium chloride (100 ml × 2), respectively. The organic phase was dried with anhydrous sodium sulfate, was filtered and was concentrated to obtain a light yellow oil, which was hardened in methanol (100 ml). T is ardoe substance was filtered and dried in vacuum to obtain compound 25-2 (89 g, 56%).

Connection 25-3. 25-2 (9.5 g, 30 mmol) was dissolved in anhydrous THF (100 ml) and was cooled to -78°C. To the specified solution was added dropwise n-BuLi (8 ml, 21 mmol) for 30 min, and stirred for 30 minutes was added dropwise compound 25-1 at -78°C, stirred for 30 min and left to warm to room temperature, then extinguished with a saturated solution of ammonium chloride. The organic phase was separated and washed with a saturated solution of sodium chloride, dried anhydrous Na2SO4, was filtered and was concentrated to obtain a yellow oil, which was purified column chromatography (elution: PE/EA=10/1) to obtain compound 25-3 in the form of a yellow solid (2.3 g, 28%).

Connection 25-4. To a solution of compound 25-3 (2.4 g, 8.5 mmole) in methanol (35 ml) was added triethylorthoformate (15 ml) and TsOH (300 mg, 1.7 mmole). The solution was heated at the boil under reflux for 10 hours, the Methanol was evaporated in vacuo, and the residue was divided between EA (300 ml) and 5% sodium bicarbonate (100 ml). The organic phase was separated, dried with anhydrous sodium sulfate, was filtered and was concentrated to obtain compound 25-4 in the form of a yellow oil which was used directly in the next stage (2.3 g, 82%).

Connection 25-5. To a solution of compound 25-4 (6.0 g, and 18.3 mmole) in DMF (75 ml) was added sodium methoxide (9,9 g, 183 mmole), oxided (1.5 g, to 18.3 mmole) and sodium iodide (2.8 g, and 18.3 mmole). The mixture was heated at 100°C for 4 hours TLC showed that the reaction was completed, the reaction was suppressed with a saturated solution of sodium chloride (250 ml). The solid was filtered, and the filtrate was extracted with ethyl acetate (100 ml × 3). The combined organic layers were dried with anhydrous sodium sulfate, was filtered and was concentrated to obtain a brown oil, which was purified column chromatography (elution: PE/EA=3/1) to obtain the compound 25-5 in the form of a light yellow oil (1.2 g, 23%).

Connection 25-6. To a solution of compound 25-5 (1.2 g, 4,29 mmole) in DHM (8 ml) and water (10 ml) was added triperoxonane acid (10 ml). The reaction mixture was stirred at room temperature for 4 h was Added a saturated solution of sodium bicarbonate (10 ml)and the organic phase was separated, dried with anhydrous sodium sulfate, was filtered and was concentrated to obtain a brown oil, which was purified column chromatography (elwira: PE/EA=10/1) to obtain compound 25-6 as a pale yellow solid (750 g, 74%).

Method 26 intentionally missed.

Method 27: Synthesis of 4-amino-3-methylbenzenesulfonamide

Connection 27-2: AU2O (16 ml of 0.16 mol) was added to a solution of compound 27-1 (20 g, 0,107 mole) in 80 ml of pyridine. The mixture was stirred at room t is mperature within 2 hours. Then was added EtOH (40 ml), and the solid was isolated by filtration and washed with EtOH to obtain compound 27-2 in the form of a brown solid (10.3 g, yield 56%).

Connection 27-3: Compound 27-2 (10 g, 43.6 mmole) was added to the flask containing 1N NaOH (36 ml)and the mixture was stirred at room temperature for 3 hours. The solvent was removed, and the residue washed with EtOH. Connection 27-3 were isolated by filtration as a pale solid (8.8 g, yield 88%).

Connection 27-4: Connection 27-3 (16 g, 63.7 mmole) and DMF (20 ml) was added into the flask, and then was added dropwise SOCl2(18,4 g, 155 mol) at 30-40°C. When the addition was completed the mixture was stirred at room temperature for 2 hours. Then the mixture was added slowly to ice, and appeared solid. The solid was isolated by filtration and dried to obtain compound 27-4 as a pale solid (6.0 g, yield 38%).

Connection up 27-5: a Solution of compound 27-4 (6.0 g, and 24.2 mmole) in 50 ml THF was added dropwise to 50 ml of NH4OH at 0°C. the Mixture was stirred at room temperature for 1 h the Solvent was removed under reduced pressure, and the residue was extracted with EA (30 ml × 4). The organic layer was dried Na2SO4and was filtered, concentrated with getting the connection up 27-5 in the form of a pale solid (5.1 g, yield 93%).

Connection 27-6: a Mixture of compound 7-5 (5,1 g, 22.3 mmole), HCl (2 N, 76.5 ml) and EtOH (100 ml) was boiled under reflux overnight. The mixture is then neutralized Na2CO3(aq.) to pH=8. The mixture was extracted with EA (80 ml × 4), dried Na2SO4and concentrated to obtain compound 27-6 in the form of a pale solid (4.9 g, yield 100%).

Method 28: Synthesis of 1-(5-bromo-4-chlorothiophene-2-yl)ethanone (compound 28-2) and 1-(4-chlorothiophene-2-yl)ethanone (connection 28-3)

Connection 28-1. To a solution of 3-chlorothiophene (6,52 g, 55 mmol) in CHCl3(30 ml) and Asón (30 ml) was added NBS (9.80 g, 55 mmol). The mixture was heated at the boil under reflux for 1.5 h, then cooled to room temperature. Was added water (70 ml)and the mixture was extracted with CHCl3(30 ml × 2). The combined organic layers were washed a feast upon. a solution of NaHCO3(40 ml) and a saturated solution of sodium chloride (30 ml), dried anhydrous Na2SO4that was filtered, concentrated to obtain compound 28-1 in the form of a brown oil (10,02 g, quantitative yield)which was used directly in the next stage.

Synthesis of 1-(5-bromo-4-chlorothiophene-2-yl)ethanone (compound 28-2). To a mixture of compound 28-1 (10.0 g, 50.6 mmole) and AlCl3(of 8.09 g, 60,7 mmole) in DHM (120 ml) was added dropwise acetylchloride (4,76 g, 60,7 mmole) for 5 min at 0°C. After the addition the mixture p is remedial over night at room temperature, washed with diluted hydrochloric acid (1,2N, 150 ml) and a saturated solution of sodium chloride (150 ml), dried anhydrous Na2SO4that was filtered, concentrated and purified column chromatography on silica gel (PE/EA = 20/1 to 3/1) to obtain the compound 28-2 in the form of a brown solid (8.0 mg, yield: 66%).

Synthesis of 1-(4-chlorothiophene-2-yl)ethanone (connection 28-3). To a solution of compound 28-2 (3,20 mg, made 13.36 mmole) in EtOH (70 ml) was added 10% Pd/C (2.50 g) and AcONa (1.10 g, made 13.36 mmole). The reaction mixture was stirred in hydrogen atmosphere at room temperature for 3 h, was filtered, and the filtrate was concentrated. The obtained residue was dissolved in EA (100 ml) washed the feast upon. a solution of NaHCO3(40 ml) and a saturated solution of sodium chloride (30 ml), dried anhydrous Na2SO4that was filtered, concentrated and purified column chromatography on silica gel (PE/EA = 30/1 to 5/1) to obtain the compound 28-3 in the form of a yellow oil (1,32 g, yield: 62%).

Method 29 method 32 intentionally missed.

Method 33: Synthesis of N-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)formamide

The synthesis of compounds 33-2: a mixture of HCO2N (644 mg, 14 mmol) and a-C2On (1,16 g, 11.4 mmole) was heated at 55°C for 2 h, and then cooled to room temperature. Were added THF (1 ml) and the connection is giving 33-1 (880 mg, of 4.38 mmole) in THF (1 ml)and the resulting mixture was continuously stirred at room temperature for 3 hours After evaporation the residue was extracted with EA (5 ml × 3). The organic phase is then washed the feast upon. aqueous solution of sodium bicarbonate (10 ml) and sodium chloride (10 ml), dried with anhydrous sodium sulfate, was filtered and was concentrated to obtain compound 33-2 in liquid form (845 mg, yield: 85%), which was used directly in the next stage.

The synthesis of compounds 33-3: to a mixture of compound 33-2 (845 mg, of 4.38 mmole), KOAc (726 mg, 7.4 mmole), B(pin)2(1,41 g, 5.6 mmole) and dioxane was added Pd(dppf)2Cl2(20 mg, 0.02 mmole). After degassing and saturation with nitrogen and the mixture was heated under reflux at 90°C during the night. TLC showed that the reaction was completed. Was added water (10 ml)and the mixture was extracted with ethyl acetate (10 ml × 3). The combined organic layers were dried Na2SO4that was filtered, concentrated and purified column chromatography on silica gel (PE:EA=4:1) to obtain compound 33-3 as a colourless solid (220 mg, yield: 29%).

Method 34 intentionally missed.

Method 35: Synthesis of 4-aminobenzenesulfonamide

Following the method/scheme described in method 27, for the synthesis of 4-amino-3-methylbenzenesulfonamide.

Method 36-40 intentionally missed.

Method 41: Synthesis of 1-(5-brough the-2-methoxyphenyl)ethanone

Connection 41-2. To a solution of compound 41-1 (2.0 g, 13,32 mmole) in acetone (25 ml) was added NBS (2.37 g, 13,32 mmole) and 1M aq. HCl (0,13 ml of 0.13 mmole). The reaction mixture was stirred at room temperature for 3 h, and then concentrated to dryness under reduced pressure. The residue was dissolved in D (40 ml), the precipitate was filtered and dried in vacuum to obtain compound 41-2 in the form of a white solid (2,90 g, yield: 95%).

Example 2: Tests with GSNOR

Various compounds were tested in vitro for their ability to inhibit the activity of GSNOR. Exemplary compounds and their corresponding activity against GSNOR described above in the paragraph before the table 1. Expression and purification GSNOR described in article Biochemistry, 2000, 39, SS-10729.

Fermentation GSNOR: Prior crops were planted from sliced rod GSNOR in glycerol in 2XYT medium containing 100 ug/ml ampicillin after incubation over night at 37°C. the Cells were then added to fresh 2XYT (4 l)containing ampicillin and grown until OD (A600of 0.6-0.9 at 37°C before introduction. The GSNOR expression was induced with 0.1% arabinose at incubation over night at 20°C.

Cleaning GSNOR: Paste the cells of E. coli were subjected to lysis by nitrogen cavitation, and free lysate was purified by Ni affinity chromatography on ACT FPLC (Amersham Pharmacia). The column was suirable 20 mm Tris pH 8.0/250 mm Nal with a gradient of 0-500 mm imidazole. Erwerbende faction GSNOR containing fused Smt-GSNOR, insisted during the night with Ulp-1 at 4°C to remove affinity to the target, then re-run on a Ni column under the same conditions. GSNOR was recovered in the flow fraction, and for crystallography then purified using the Q-sepharose and continuous heparin chromatography in 20 mm Tris pH 8.0, 1 mm DTT, 10 μm ZnSO4.

Analysis with GSNOR: Methods: Solutions of GSNO and enzyme/NADH received fresh every day. The solution was filtered and left to warm to room temperature. The GSNO solution: 100 mm NaPO4(pH 7.4), to 0.480 mm GSNO. 396 μl of a solution of GSNO was added to the cuvette, then 8 μl of test compound in DMSO (or DMSO for full control of the reaction), and mixed with the pipette tip. Test compounds were received at a final concentration of 10 mm in 100% DMSO. 2-fold serial dilution was made in 100% DMSO. 8 µl of each dilution was added into the analysis so that the final concentration of DMSO in the assay was 1%. The concentration of the test compounds was in the range from 100 to 0.003 microns. A solution of the enzyme/NADH: 100 mm NaPO4(pH 7.4), 0,600 mm NADH, 1.0 microgram/ml GSNO reductase. 396 μl of enzyme solution/NADH was added to the cuvette to initiate the reaction. The cuvette was placed in the UV/optical spectrophotometer Cary 3E, and the change in absorption at 340 nm/min at 25°C was recorded for 3 minutes. Analyses were carried out is reedy for each concentration of the compound. IC50 values for each compound was calculated using the standard analysis of the curve in the Enzyme Kinetics Module of SigmaPlot.

Conditions final analysis: 100 mm NaP04, pH 7.4, 0,240 mm GSNO, 0,300 mm NADH, 0.5 μg/ml GSNO reductase and 1% DMSO. The final volume of 800 μl/cell.

Example 3: Analysis of GSNOR inhibition in animal models in vivo

To demonstrate the effect on the inhibition of GSNOR used a mouse model of asthma, which is similar to the model previously described for the effect of GSNO reductase and bioavailability of SNO (article Que, etc., Science, 2005). Que and others have Shown that after the introduction of ova-albumin (OVA) mice wild-type display bronchial reactivity with elevated levels of GSNOR, and have light, which decompose SNO. In contrast to wild-type mice, Que and others have shown that mice with a genetic decomposition of GSNOR increase pulmonary SNO and protect against induced OVA hyperresponsiveness of the Airways.

To determine whether similar observations can occur if GSNOR inhibited pharmacologically by GSNOR inhibitor, used the model of mouse OVA (i.e., the model of mouse wild-type Que and others). In this analysis of OVA-sensitive mice were administered 1 mg/kg, 10 mg/kg or 30 mg/kg compound 1 intravenously 24 hours prior to placement in plethysmograph whole body (Buxco Research Systems, Wilmington, NC), and provide fresh air.

The studied animals were then introduced Aeros the eh increased dosages bronchodilatory agent methacholine, pharmacological agent, commonly used to determine the degree of bronchial hyperresponsiveness in experimental subjects. In this analysis the mice were injected elevated concentrations of methacholine, each dose was maintained for 3 minutes, and then measured. Dose methacholine was 0 mg/ml, 5 mg/ml, 20 mg/ml and 50 mg/ml, the Degree of bronchial hyperresponsiveness was measured as 'enhanced pause' (Penh), a single index hyperresponsiveness of the Airways (article Dohi, etc., Lab Invest., 1999, 79(12), SS-1571).

Introduction connections 1 produced low bronchodilatory response from these test animals compared to animals treated only with the media. These results are combined with high levels of bioactivity SNO available for bronchodilatory metacholine changes.

Example 4: Efficiency GSNORi in the experiment with asthma

Experimental model of asthma:

Model mice induced by ovalbumin (OVA) asthma used for screening inhibitors of GSNOR in effectiveness against caused by methacholine (MCh) hyperresponsiveness of bronchoconstrictive/respiratory tract. This widely used and well characterized model, which is represented in the phenotype of acute allergic asthma with analogies asthma people. The effectiveness of GSNOR inhibitors were evaluated using prophylactic the methods, in which the GSNOR inhibitors were introduced prior to the introduction of MCh. Bronchoconstriction in response to the introduction of high doses of MCh was assessed using whole body plethysmography combined (Penh; Buxco). The number of eosinophilic infiltrate in bronchial washing fluid (BALF) was also determined as the value of pulmonary inflammation. The effects of GSNOR inhibitors compared with native and Combivent (inhalation; IH) as a positive control.

Materials and methods

Sensitivity to the allergen and methodology introduction

OVA (500 μg/ml) in PBS were mixed with equal volumes of 10% (wt/V) of potassium aluminium sulphate in distilled water, and incubated for 60 min at room temperature, then the pH was brought to 6.5 with 10 N NaOH. After centrifugation at 750×g for 5 min rest OVA/alum re-suspended to the original volume in distilled water. The mice were injected intraperitoneal (IP) injection of 100 μg OVA (0.2 ml 500 ág/ml in normal saline solution) in combination with alum on day 0. Mice were anestesiologi IP injection of 0.2 ml of a mixture of ketamine and xylazine (0,44 and 6.3 mg/ml, respectively) in normal salt solution, and was placed on the Bulletin Board in the supine position. 250 μg (100 μl of 2.5 mg/ml) OVA (on day 8) and 125 μg (50 μl of 2.5 mg/ml) OVA (days 15, 18 and 21) were placed on the rear side of each animal.

Testing pulmonary function (Penh)

The reactivity of the respiratory the ways in vivo by metacholine was measured 24 h after the last injection of OVA in mice in the mind, moving freely, spontaneously breathing, using whole body plethysmography combined in the camera Buxco (Wilmington, NC). The mice were injected aerosol saline solution or high doses of methacholine (5, 20 and 50 mg/ml)obtained in ultrasonic nebulizer for 2 minutes Degree of bronchoconstriction expressed as the increase in pause (Penhcalculated dimensionless quantity, which corresponds to a measurement of the resistance of the respiratory tract, impedance and intrapleural pressure in the same mice. Values of Penhwere taken and averaged for 4 min after each injection of the aerosol. Penhwas calculated as follows: Penh=[(Te/Tr-1)×(PEF/PIF)], where Terepresents the time of exhalation, Tris the relaxation time, PEF is a peak expiratory flow, and PIF is a peak flow inspiratory × coefficient of 0.67. Time for full pressure to change from maximum to user-defined percentage of the maximum represents the relaxation time. Measurement of Trstarts with the maximum pressure and ends at 40%.

Infiltration of eosinophils in BALF

After measuring hyperresponsiveness of the Airways of mice were bled by heart puncture, and then BALF were collected from both lungs or the right lung after disconnecting the left lung from the broker who Hove. The total number of cells in BALF was determined from aliquots of 0.05 ml, and the remaining fluid was centrifuged at 200×g for 10 min at 4°C. the remainder of the cells re-suspended in a salt solution containing 10% BSA, strokes, obtained on glass plates. Eosinophils were stained for 5 min 0,05% aqueous eosin and 5% acetone in distilled water, washed with distilled water and re-stained 0,07% methylene blue.

Inhibitors of GSNOR and controls

Inhibitors of GSNOR was restored in phosphate buffered salt solution (PBS), pH 7.4, at concentrations in the range from 0,00005 to 3 mg/ml GSNOR Inhibitors were injected into mice (10 ml/kg) as a single dose intravenous (IV) or orally. Introduction the dosage was carried out from 30 minutes to 24 hours before the administration of MCh. The effects of GSNOR inhibitors were compared with the PBS media entered in the same way.

Combivent was used as positive control in all trials. Combivent (Boehringer Ingelheim) was administered into the lung through inhalation device containing the product, but customized for the introduction of the mouse, using the tip of a pipette. Combivent was administered for 48 h, 24 h and 1 h before the introduction of MCh. Each inhalation (or dose) Combivent provided a dose of 18 mcg ipratropium bromide (IpBr) and 103 mg of sulfate albuterol, or about 0.9 mg/kg IpBr and 5 mg/kg albuterol.

Statistical analyses

The values of area under the curve d is I P enhthe introduction of a basic substance, brine and high doses of MCh was calculated using GraphPad Prism 5,0 (San Diego, CA)and expressed as a percentage of the corresponding (IV or oral input) control of the media. Statistical differences between the treated groups and the corresponding control group of media in each study was calculated using one-step ANOVA, Dunnetts (JMP to 8.0, SAS Institute, Cary, NC). P value<0.05 for treated groups and the corresponding control group of media was considered a significant difference.

Results

The results for compounds 1

Compound 1, administered intravenously (IV), was effective against experimental asthma that are defined to mitigate caused by methacholine (MCh) bronchoconstriction and pulmonary inflammation. Significant efficiency compound 1 was observed for a single IV dose of 0.01 mg/kg for 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%), was 42.1±2,8% (p<0,0001). Eosinophilic infiltration in bronchial washing fluid (BALF) was decreased by 98% (p<0,0001). Significant efficiency compound 1 was also observed after 1 h (AUC=76,4±6,6; p=0,0082) and up to 48 h (AUC=64,4±55; p=<0,0001) to MCh in a single IV dose of 0.1 mg/kg the Value ED50, the dose of compound 1, showing a 50% reduction response is Penh, was to 0.011±0.003 mg/kg

The results for compounds 2

Compound 2, administered intravenously (IV), was effective against experimental asthma that are defined to mitigate caused by methacholine (MCh) bronchoconstriction. Significant efficiency compound 2 was observed for a single IV doses of 0.01, 0.1 and 1 mg/kg per 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%)65.3±6,5% (p=0.0002); 50,5±6,3% (p<0,0001) and 41.7±5,2% (p<0,0001) for 0.01, 0.1, and 1 mg/kg, respectively, for compound 2. The results for compound 3

Connection 3 intravenous (IV), was effective against experimental asthma that are defined to mitigate caused by methacholine (MCh) bronchoconstriction and pulmonary inflammation. Significant efficiency compound 3 was observed for a single IV dose of 1 mg/kg per 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%)was 71,0±8,6% (p=0,0051). Eosinophilic infiltration in bronchial washing fluid (BALF) was decreased by 46% (p=0.0002).

The results for compounds 6

The connection 6, intravenous (IV) or orally was effective against experimental asthma that are defined to mitigate caused by methacholine (MCh) bronchoconstriction and lung in which palenia. Significant efficacy of compound 6 was observed for a single IV dose of 1 mg/kg per 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%)65.3±5,9% (p=0.0001). Eosinophilic infiltration in bronchial washing fluid (BALF) was decreased by 92% (p<0,0001). Significant efficacy of compound 6 was also observed for a single oral dose of 30 mg/kg per 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%)24.6±3,0% (p<0,0001). Eosinophilic infiltration in bronchial washing fluid (BALF) was decreased by 100% (p=0,0004).

The results for compound 7

Connection 7 intravenous (IV), was effective against experimental asthma that are defined to mitigate caused by methacholine (MCh) bronchoconstriction. Significant efficacy of compound 7 was observed for a single IV dose of 0.1 and 1 mg/kg per 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%), $ 56.1±2,2% (p<0,0001) and 50.4±3,7% (p<0,0001) for 0.1 and 1 mg/kg compound 7, respectively.

The results for compounds 26

The connection 26, intravenous (IV) or orally was effective against experimental asthma, as defined by smahc the tion caused by methacholine (MCh) bronchoconstriction and pulmonary inflammation. Significant efficiency compound 26 was observed for a single IV dose of 0.1, 1 and 10 mg/kg per 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%)was 64,2±7,6% (p=0,0007); 60,2±7,9% (p=0.0002) and 40.7±2,4% (p<0,0001) for 0.1 mg/kg, 1 mg/kg and 10 mg/kg, respectively, for connection 26. Eosinophilic infiltration in bronchial washing fluid (BALF) was decreased by 79% (p=0,0064); 100% (p=0,0007); and 100% (p=0,0007) for 0.1 mg/kg, 1 mg/kg and 10 mg/kg, respectively, for connection 26. Significant efficiency compound 26 was also observed after 30 min (AUC=35,2±9,3; p<0,0001) to MCh in a single IV dose of 10 mg/kg of Eosinophilic infiltration in bronchial washing fluid (BALF) was decreased by 94% (p<0,0001). Significant efficiency compound 26 was also observed after a single oral dose of 30 mg/kg per 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%), accounted for 26.7±1,4% (p<0,0001). Eosinophilic infiltration in bronchial washing fluid (BALF) was decreased by 100% (p=0,0019).

The results for compounds 33

The connection 33, administered intravenously, was effective against experimental asthma that are defined to mitigate caused by methacholine (MCh) bronchoconstriction and pulmonary inflammation. Significant efficiency 33 n who was also observed for a single IV dose of 1 mg/kg per 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%), amounted to 72.9±8,7% (p=0,0089). Eosinophilic infiltration in bronchial washing fluid (BALF) was decreased by 61% (p<0,0001).

The results for compound 67

Connection 67, intravenous (IV), was effective against experimental asthma that are defined to mitigate caused by methacholine (MCh) bronchoconstriction and pulmonary inflammation. Significant efficiency compound 67 was observed for a single IV dose of 1 mg/kg per 24 h prior to MCh. The area under the curve (AUC) for response Penh, described as a percentage of the control media (AUC=100%)78.7±8,1% (p=0,0323). Eosinophilic infiltration in bronchial washing fluid (BALF) was decreased by 63% (p<0,0001).

Specialist in the art it is clear that various modifications and changes may be made in the methods and compositions of the present invention without departing from the scope or scope of the present invention.

1. The compound of formula I or its pharmaceutically acceptable salt:

where Ar is selected from the group consisting of phenyl and thiophene-sludge;
R1selected from the group consisting of unsubstituted of imidazolyl, imidazolyl substituted C1-C6the alkyl, chlorine, bromine, fluorine, hydroxy-group and metoxygroup;
2selected from the group consisting of hydrogen, methyl, chlorine, fluorine, hydroxy-group, metoxygroup, ethoxypropan, propoxylate, carbamoyl, dimethylaminopropyl, amino, formamido and trifloromethyl; and
X is selected from the group consisting of CO and SO2.

2. The compound according to claim 1, where R1selected from the group consisting of unsubstituted of imidazolyl and imidazolyl substituted C1-C6the alkyl.

3. The compound according to claim 2, where C1-C6alkyl represents methyl or ethyl.

4. The compound according to claim 2, where ArR1R2selected from the group consisting of:
;;;
;
where R3selected from H, methyl and ethyl.

5. The compound according to claim 2, selected from the group consisting of the following compounds:
3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(5-(1H-imidazol-1-yl)thiophene-2-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-(2-ethyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(-(4-(1H-imidazol-1-yl)thiophene-2-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophene-2-yl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(3-fluoro-4-(1H-imidazol-1-yl)phenyl)-1 H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(3-fluoro-4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-(2-methyl-1H-imidazol-1-yl)thiophene-2-yl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(4-(1H-imidazol-1-yl)-2-methoxyphenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophene-3-yl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(5-(2-ethyl-1H-imidazol-1-yl)thiophene-2-yl)-1H-pyrrol-2-yl)propanoic acid
3-(5-(5-(2-methyl-1H-imidazol-1-yl)thiophene-2-yl)-1-(2-methyl-4-sulfamoylbenzoyl)-1H-pyrrol-2-yl)propanoic acid.

6. The compound according to claim 1, where ArR1selected from the group consisting of 4-chlorphenyl, 3-chlorphenyl, 4-bromophenyl, 3-bromophenyl, 4-ftoheia, 3-ftoheia, 4-hydroxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-chlorothiophene-2-yl, 5-chlorothiophene-2-yl, 3-bromothiophene-2-yl, 4-bromothiophene-2-yl, 5-bromothiophene-2-yl and 5-bromothiophene-3-yl.

7. The compound according to claim 1, selected from the group consisting of the following compounds: 3-(1-(4-carbarnoyl-2-were)-5-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(5-bromothiophene-2-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(4-bromophenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(3-chloro-4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(3-chloro-4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-methoxy-3-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(3-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(4-amino-3-chlorophenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(3,4-differenl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(2,4-differenl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chlorophenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(4-bromothiophene-2-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-fluoro-3-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-carbarnoyl-3-forfinal)-1H-pyrrol-2-yl)who Romanova acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-methoxy-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-forfinal)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-forfinal)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-fluoro-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(2-chloro-4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(2-ethoxy-4-forfinal)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-methoxy-2-(trifluoromethyl)phenyl)-1 H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-fluoro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-3-forfinal)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-ethoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(5-bromo-2-methoxyphenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(4-bromo-2-methoxyphenyl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(5-bromothiophene-3-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-METI is phenyl)-5-(4-hydroxy-3-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(2-carbarnoyl-4-chlorophenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(2,4-acid)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-propoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-hydroxy-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-(dimethylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(5-chlorothiophene-2-yl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chloro-2-formamidine)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(3-chlorothiophene-2-yl)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-formamido-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(3-bromo-5-methoxythiophene-2-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid;
3-(1-(4-carbarnoyl-2-were)-5-(4-chlorothiophene-2-yl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(5-bromo-4-chlorothiophene-2-yl)-1-(4-carbarnoyl-2-were)-1H-pyrrol-2-yl)propanoic acid
3-(5-(4-bromothiophene-2-yl)-1-(2-methyl-4-sulfamoylbenzoyl)-1H-pyrrol-2-yl)propanoic acid.

8. The pharmaceutical composition inhibiting the activity of S - nitrosoglutathione, with the holding compound according to claim 1 in a therapeutically effective amount together with a pharmaceutically acceptable carrier or excipient.

9. A method of treating asthma, which includes the introduction of the compounds of formula I according to claim 1 in a therapeutically effective amount of the needy in this patient.

10. The method of obtaining the pharmaceutical composition of claim 8, comprising combining the compound of formula I defined in claim 1 with a pharmaceutically acceptable carrier or excipient.

11. The compound of formula II or its pharmaceutically acceptable salt:

where Ar is selected from the group consisting of phenyl and thiophene-sludge;
R4selected from the group consisting of unsubstituted of imidazolyl and imidazolyl, substituted C1-C6by alkyl;
R5selected from the group consisting of hydrogen, fluorine, hydroxy-group and metoxygroup;
R6selected from the group consisting of hydrogen, chlorine, bromine and fluorine;
R7selected from the group consisting of hydrogen and methyl; and
R8selected from the group consisting of CONH2, SO2NH2and NHSO2CH3.

12. Connection to item 11, where C1-C6alkyl represents methyl or ethyl.

13. Connection to item 11, where ArR4R5selected from the group consisting of:
;;
;
where R9selected from H, methyl and ethyl.

14. The compound according to claim 1, selected from the group consisting of the following compounds:
3-(5-(5-(2-methyl-1H-imidazol-1-yl)thiophene-2-yl)-1-(4-sulfamoylbenzoyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(5-(2-methyl-1H-imidazol-1-yl)thiophene-2-yl)-1-(2-methyl-4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(4-(2-methyl-1H-imidazol-1-yl)thiophene-2-yl)-1-(2-methyl-4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(5-(2-methyl-1H-imidazol-1-yl)thiophene-2-yl)-1-(2-methyl-4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(4-(2-methyl-1H-imidazol-1-yl)thiophene-2-yl)-1-(4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid;
3-(5-(2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid
3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(4-(methylsulfonylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid.

15. The pharmaceutical composition inhibiting the activity of S-isoglutamine containing compound according to claim 11 in a therapeutically effective amount together with a pharmaceutically acceptable carrier or excipient.

16. A method of treating asthma, which includes the introduction of the compounds of formula II according to claim 11 in tera is efticiency effective amount of the needy in this patient.

17. A method of obtaining a pharmaceutical composition according to item 15, comprising combining the compound of formula II, as defined in claim 11 with a pharmaceutically acceptable carrier or excipient.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound, which is N3-1H-indol-5-yl-5-pyridin-4-ylpyrazine-2,3-diamine, or a pharmaceutically acceptable salt thereof, which can act as inhibitors of protein kinase, especially FLT3 tyrosine kinase. The invention also relates to a pharmaceutical composition which contains said compound in combination with another molecularly directed (target) agent, which is a traditional cytotoxic agent or a compound used after chemotherapy, supporting therapy targeted on stem cells and in case of MLL rearrangement acute lymphoblastic leukaemia in children.

EFFECT: obtaining a novel compound which can be used in medicine for preventing or treating haematological malignant growths such as AML, MLL, T-ALL, B-ALL and CMML, myeloproliferative diseases, autoimmune diseases and skin diseases, such as psoriasis and atopic dermatitis.

16 cl, 2 tbl, 26 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a dye which contains a binding group in its molecular structure, wherein said binding group provides covalent bonding of said dye to a surface, and said binding group is represented by formula 1 , in which the binding site of said binding group inside said molecular structure of said dye is located at the terminal carbon atom marked with an asterisk in said formula. G is selected from -COOH, -SO3H, -PO3H2, -BO2H2 -SH, -OH, -NH2, A is selected from a group consisting of H, -CN, -NO2, -COOR, -COSR, -COR, -CSR, -NCS, -CF3, -CONR2, -OCF3, C6H5.mFm, in which m=1-5, R is H or any linear or branched alkyl chain of general formula -CnH2n+1 n=0-12, preferably 0-4, or any substituted or unsubstituted phenyl or biphenyl, where said dye is represented by formula (2) or formula (4), where said chromophore is a squarylium dye derivative or a croconium dye derivative, which is capable of absorbing light with a wavelength in the visible and/or infrared range, preferably in the range from 300 to 1200 nm or part thereof, wherein each derivative of said squarylium dye and said croconium dye has aromatic ring systems Ar1 and Ar2, that are bonded to the squarylium dye or croconium dye derivatives. The invention also relates to methods of producing chromophore which is part of a dye and is a dye itself, as well as devices using said dye and applications thereof as a sensitising agent and a sensor.

EFFECT: disclosed dyes are also capable of absorbing light in the long-wave spectral range.

32 cl, 23 ex, 20 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: chemistry.

SUBSTANCE: described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

EFFECT: compounds can be used as anti-cancer agents, particularly as agents for treating solid tumours.

8 cl, 217 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a biologically active substance possessing the antiaggregant properties. The technical effect: what is produced is a drug preparation of a new compound of (2E)-3-[1-(2-hydroxy-3-piperidin-1-ylpropyl)-1 H-indol-3-yl]-1-(2-thienyl)prop-2-en-1-one hydrochloride of formula I possessing antiaggregant action:

.

EFFECT: substance may be used in medicine for producing a drug preparation for preventing the conditions associated with a high thrombogenic potential of blood.

1 cl, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, enantiomers and pharmaceutically acceptable salts thereof having the properties of AKT/protein kinase inhibitors. In formula 1 G represents phenyl, naphthalene, 5-member heteroaryl with 1 sulphur atom in a ring or 9-member bicyclic heteroaryl specified in indolyl wherein phenyl, naphthalene, 5-member heteroaryl is optionally substituted by one of three Ra groups; R1 and R1a are independently specified in H, Me, Et, -CH2OH, CF3, CHF2 or CH2F; R2 represents H, -OH, -OMe or F; R2a representsH, Me or F; R3 represents H, Me, Et; R4 represents H, 6-member heterocyclyl containing an oxygen atom as a heteroatom, cyclopropyl methyl or C1-C4 alkyl is optionally substituted F,-OH or -O(C1-C3 alkyl); R5 and R5a are independently specified in H and C1-C4 alkyl, or R5 and R5a together with an atom whereto attached form a carbonyl group or 5-6-member cycloalkyl; each Ra independently represents halogen, C1-C6-alkyl, C3-C6-cycloalkyl,-O-(C1-C6-alkyl), CF3, CN, phenyl, pyrazole, CH2F, CHF2, -OCH2F, -OCHF2, -OH, -SO2(C1-C6-alkyl), C(O)NH2; and j represents 1 or 2; and provided j represents 2, j-ring carbon atom, opposite NR4, may be substituted by heteroatom O.

EFFECT: compounds may be used for treating hyperproliferative diseases, such as cancer.

35 cl, 9 dwg, 4 tbl, 141 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I, enantiomers and pharmaceutically acceptable salts thereof which have selective inhibitory action on AKT protein kinase, in particular protein kinase B. In formula I: A represents R1 and R1a are independently specified in H, Me, Et. vinyl, CF3, CHF2 or CH2F:R2 represents H, OH, OMe or F; R2a represents H, Me or F; R3 represents H. Me. Et or CF3; G represents phenyl optionally substituted by one to four groups Rc, or 5-6-member heteroaryl containing one heteroatom specified in sulphur optionally substituted by halogen; R5 and R6 independently represent H, OCH3, C3-C6-cycloalkyl independently substituted by F, OH, C1-C3alkyl or O(C1-C3alkyl), 4-6-member heterocyclyl containing one heteroatom specified in nitrogen optionally substituted by F, OH, C1-C3alkyl, cyclopropylmethyl or -C(=O)(C1-C3alkyl), or C1-C6-alkyl optionally substituted by one or more groups independently specified in OH, oxo O(C1-C6-alkyl), CN, F, NH2. NH(C1-C6-alkyl), O(C1-C6-alkyl)2. cyclopropyl. phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanil or tetrahydropyranyl. The other radical values are specified in the patent claim.

EFFECT: compounds may be used treating the conditions selected from inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynaecological and dermatological diseases and disorders, preferentially in treating cancer.

15 cl, 2 tbl, 8 dwg, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new phenylimidazole derivatives of general formula , wherein R1 represents a hydrogen atom, a phenyl lower-alkyl group or a pyridyl lower-alkyl group with a benzene ring and a pyridine ring are optionally substituted by 1 or 2 substitutes specified in a group consisting of halogen atoms, cyano group and halogen-substituted lower-alkyl groups; one or R2 and R3 represents a hydrogen atom, and another one represents a lower alkoxy group; R4 represents a lower-alkyl group, a difurylglyoxal group, a thienyl group or a phenyl group optionally substituted by 1 or 2 substitutes specified in a group consisting of lower-alkyl groups, lower-alkoxy groups, halogen atoms, a carboxyl group, lower alkoxycarbonyl groups, and halogen-substituted lower-alkyl groups; R5 and R6 are identical or different, and represent a hydrogen atom or a lower alkyl group; R7 and R8 are identical or different, and represent a hydrogen atom or a lower alkoxy group; provided R1 represents an unsubstituted phenyl lower-alkyl group, R2 represents a lower alkoxy group, R3 represents a hydrogen atom, R4 represents an unsubstituted phenyl group or a phenyl group containing 1 or 2 halogen-substituted lower-alkyl groups, and R5 represents a hydrogen atom, then R6 is other than a hydrogen atom. Also, the invention refers to an LPL activator, an agent for preventing or treating hyperlipidaemia, an agent for treating arteriosclerosis, and an agent for treating obesity on the basis of the compound of formula (1).

EFFECT: there are prepared new phenylimidazole derivatives effective for LPL activation.

23 cl, 10 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - 5-hydroxy-6-methyl-1-(thietanyl-3)pyrimidine-2,4(1H,3H)-dione of formula , which inhibits generation of active forms of oxygen and has antioxidant activity.

EFFECT: improved properties of compounds.

2 cl, 1 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an improved method for preparing 2-arylamino-4-hetarylpyrimidines of formula (I) which possess inhibitory action on serine-threonine kinase Haspin on the enzymatic level, and may be used as drug substances for oncological diseases. In formula (I), wherein Het = , , , , , , , , , , ,

R=H; 2-Me; 3-Me; 4-Me; 2,3-di-Me; 2-MeO; 3-MeO; 4-MeO; 4-EtO; 4-PhO; 2-Cl; 3-Cl; 4-Cl; 4-F; 2-Me, 3-Cl. The method consists in a reaction of related hetarylmethylketone and N,N-dimethylformamide dimethylacetale on boiling of reagents in isopropyl alchohol for 6 hours to produce 3-dimethylamino-1-hetaryl-2-propen-1-ones with adding in situ related aryl guanidine and further boiling for 2 hours. The process is conducted at molar ratio (mole) of hetarylmethylketone: N,N-dimethylformamide dimethylacetale : aryl guanidine = 1:1.5:1.

EFFECT: method simplifies the process due to cutting a process time and reducing consumption of the initial ingredients.

6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel compound - 6-methyl-1-(thietanyl-3)uracil of formula 1 , which stimulates the protective activity of phagocytes.

EFFECT: obtaining compounds which stimulate the protective activity of phagocytes.

2 cl, 1 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and medicine and specifically to a novel compound - 6-(thietanyl-3)aminopyrimidine-2,4(1H,3H)-dione of formula (1), which inhibits lipid peroxidation.

EFFECT: obtaining a compound which inhibits lipid peroxidation.

2 cl, 1 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I): . Therein the values A, R1, R2, R6, r, Rc are presented in cl.1 of the patent claim, as well as to pharmaceutically acceptable salts or tautomers of the above compound being poly(ADP-ribose)polymerase (PARP) inhibitors.

EFFECT: preparing the pharmaceutically acceptable salts or tautomers of the above compound being poly(ADP-ribose)polymerase (PARP) inhibitors.

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