Novel dual acting ati and eta receptor antagonists (dara)

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

 

The present invention relates to new compounds and methods for their preparation. These compounds are antagonists of the receptor double action (DARA) receptor (ETA and ET. The invention also relates to combinations of these new connections with previously known means. The invention also relates to the use of these compounds and combinations to obtain drugs for the treatment of arterial hypertension of various kinds, reduce damage to the bodies of various types, treatment or prevention of diabetic nephropathy and treatment mediated by endothelin and angiotensin violations.

Arterial hypertension is an increasingly pervasive condition of having large health and economic consequences both for the individual and for society. Despite the market presence of many classes of antihypertensive drugs, over 40% of patients with hypertension have blood pressure that is not amenable to appropriate controls, despite treatment. Given the multifactorial nature of cardiovascular diseases, including hypertension, simultaneous targeting more than one physiological mechanism seems plausible strategy for achieving the best effects.

With the discovery of the fact that angiotensin (Ang-II) and R is Ceptor AT1 are a target for the treatment of hypertension and congestive heart failure, increased interest in the biological effects of other vasoactive peptides. Cardiovascular homeostasis includes cross-exchange between the renin-angiotensine and endothelioma systems, with each system enhances the response of the other. Thus, Ang-II stimulates the synthesis of mRNA preproendothelin and release of ET-1. ET-1 mediates part of the Ang-II-induced excessive cell proliferation characteristic of damage to end organs. Pre-treatment with the antagonist of the ETA receptor reduces the rise in blood pressure caused by infusion of Ang-II.

The interaction of the renin-angiotensine and endothelioma systems, two major vasoactive systems makes so combined a particularly attractive target. Mixed antagonist of endothelin-angiotensin not only enhances the hypotensive effect of the blockade AT, but also reduces the severity of the damage to end organs, as shown in several rat models of hypertension. So, subeffective dose receptor antagonist AT losartan resulted in normalization of blood pressure when used in combination with an antagonist of the ETA, and this combination also reduced the hypertrophy of the heart muscle and increased survival compared to treatment only with losartan (J. Bohlender et a1, Hypertension 2000:35:992-7).

Reasons for p is epocast using receptor antagonist double action, instead of a fixed combination of several. First, from a regulatory point of view, each connection in a fixed combination must be documented in monotherapy. After this fixed combination should be documented clinically in factorial research and more research. Also with these two drugs in combination should be conducted Toxicological studies. In contrast, receptor antagonist double action can be documented normal for the new connection method.

Secondly, the inclusion of the ETA antagonist in fixed combination is not feasible since the majority of ETA antagonists have a Toxicological effect. To avoid adverse effects inherent in the blockade of ETA, a new receptor antagonist double action must have a higher affinity for IT than ETA. However, the affinity for the ETA should not be zero. Thus, the new receptor antagonist double action has activity as a receptor (ETA, and AT. In addition, in order to avoid blockade of positive actions undertaken through the ETB receptor (vasodilation, natriuresis and clearance of ET-1) and through the AT2 receptor (vasodilation and anti-proliferative effects), new connections should prefer what Ino be selectively target only the receptors ETA and ET.

Previously it was known the use of endothelin antagonists and antagonists of angiotensin II, which are not dual antagonists AT and ETA for the treatment of hypertension. For example, in WO98/49162 on the name of the Texas Biotechnology Corp. disclosed the heteroaromatic sulfonamides as endothelin antagonists. Similarly, in EP 513979 A1 in the name of Merck and Co., Inc. disclosed are antagonists of angiotensin II, including substituted thiophene or furan.

Bristol-Myers Squibbs described several series dual receptor (Jae et al., Pyrrolidine-3-carboxylic acids as Endothelin antagonist. 5. Highly selective, potent and orally active ETA antagonist. J. Med. Chem. 2001, 44: 3978-3984; Tellew et al., Discovery of 4'-[(Imidazol-1-yl)methyl]biphenyl-2-sulphonamids as dual endothelin/angiotensin II receptor antagonists. Bio. & Med. Chem. Lett, 2003, 13: 1093-1096, US2002143024, WOOO/001389 and WO01/044239).

However, the compounds according to the present invention have not been previously disclosed. In addition, it is shown that the selectivity of the compounds according to the present invention has the unexpected selectivity for AT compared to ETA, i.e. the relationship between affinity for ET and ETA.

One object of the present invention is a compound of the formula

where R3 has any of the formula

where R1 is selected from

where

R2, each independently, signifies hydrogen, halogen, C1-C8alkyl, Halogens 1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2-C8quinil, C1-C8alkoxy-C1-C8alkyl, C1-C8alkoxy, aryloxy, C1-C8alkoxy-C1-C8alkoxy, cyano, hydroxyl, hydroxy-C1-C8alkyl, nitro, -(CH2)WNR18R19, where w is equal to 0, 1, 2 or 3 and R18 and R19 independently mean hydrogen, C1-C8alkyl, aryl, aryl-C1-C8alkyl, heteroaryl, heteroaryl-C1-C8alkyl or may together form a five - or six-membered saturated or unsaturated ring structure, optionally containing one or two heteroatoms selected from oxygen, sulfur or nitrogen, and may be optionally substituted C1-C8by alkyl, hydroxyl or oxopropoxy;

R4 means a five - or six-membered mono - or bicyclic ring system having from one to three heteroatoms selected from O, N and S, such as pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolin, oxadiazolyl, imidazolyl, triazolyl, tetrazolyl and peridotites, each of which may be optionally substituted by one or more of the following substituents: hydrogen, halogen, cyano, C1-C8the alkyl, C1-C8alkoxy, trifluoromethyl and-COR32;

R5 and R6 independently researched the mo denote hydrogen, halogen, C1-C8alkyl, -COOR13, -CO-NR18R19, cyano and -- NR18R19, or R5 and R6 may together form a five - or six-membered cycloalkyl, aryl ring or heteroaryl ring structure containing one or two heteroatoms selected from O, N and S, which may be optionally substituted C1-C8the alkyl, C1-C8alkoxy or hydroxy; where R18 and R19 are independently selected from hydrogen, C1-C8of alkyl, aryl-C1-C8of alkyl, heteroaryl-C1-C8of alkyl, (C3-C8cycloalkyl)-C1-C8the alkyl, or may together form a five - or six-membered saturated ring structure, optionally containing one or two heteroatoms selected from O, N and S;

R7 and R8, each independently mean C1-C8alkyl, hydroxy-C1-C8alkyl, C3-C8cycloalkyl, replacement C3-C8cycloalkyl, C1-C8alkoxy-C1-C8alkyl, replacement C1-C8alkoxy-C1-C8alkyl, or R7 and R8 together form cyclobutyl, cyclopentamine, tsiklogeksilnogo, tetrahydrofuranyl or tetrahydropyranyl ring which may be optionally substituted by one or more hydroxyl groups;

R9 independently mean C1-C8alkyl, hydroxy-C1-C8alkyl, replacement halo is EN-C 1-C8alkyl, C3-C8cycloalkyl, (C3-C8cycloalkyl)-C1-C8alkyl, aryl-C1-C8alkyl, C1-C8alkoxy, replacement C1-C8alkoxy, C1-C8alkoxy-C1-C8alkyl, replacement C1-C8alkoxy-C1-C8alkyl, C1-C8alkylsulphonyl, arylcarbamoyl, carboxy, C1-C8alkoxycarbonyl and heteroaryl-C1-C8alkyl;

R9a is independently mean C1-C8alkyl, C1-C8alkoxy-C1-C8alkyl, C1-C8alkylsulphonyl, arylcarbamoyl, heteroarylboronic, carboxy, C1-C8alkoxy and-COOR13;

R10 denotes hydrogen, C1-C8alkyl, (C3-C8cycloalkyl)-C1-C8alkyl or aryl-C1-C8alkyl;

R11 independently mean C1-C8-alkyl, C1-C8alkoxy, aryl-C1-C8alkyl, heteroaryl-C1-C8alkyl (C3-C8cycloalkyl)-C1-C8alkyl;

R12 denotes hydrogen, halogen, C1-C8alkyl, -COOR17, C1-C8alkyl-C1-C8thioalkyl, C1-C8alkoxy or C1-C8alkoxy-C1-C8alkyl, nitro, NHR24;

R13 independently denotes hydrogen, C1-C8alkyl, aryl and heteroaryl;

R14 independently mean hydrogen, C1-C8alkyl, aryl, NHCOR13 and NR18R19, where R18, R19 are independently selected from hydrogen, C1-C8of alkyl, aryl-C1-C8the alkyl or may together optionally form a five - or six-membered saturated ring structure, optionally containing one or two heteroatoms selected from O, N and S;

E means a simple bond, -(CH2)- or-S-;

R17 denotes hydrogen, C1-C4alkyl, optionally substituted by aryl;

R21 means

(a) C1-C8alkyl, halogen-(C1-C8alkyl, aryl-C1-C8alkyl or heteroaryl-C1-C8alkyl,

(b) -(CH2)NR18R19, where R18 and R19 independently mean hydrogen, C1-C8alkyl, aryl, heteroaryl or may together form a five - or six-membered saturated or unsaturated ring structure, optionally containing one or two heteroatoms selected from O, N and S,

(c) aryl or

(d) heteroaryl;

R22 means

(a) -CO2R13, -CO2-C1-C8alkyl, -CO-NR18R19 or

(b) -(CH2)NR18R19, where R18 and R19 independently mean hydrogen, C1-C8alkyl, aryl, heteroaryl or may together form a five - or six-membered saturated or unsaturated ring structure, optionally containing one or two heteroatoms selected from O, N and S;

R23 means

(a) hydrogen, C1-C8alkyl, aryl, C1-C8alkoxy, halogen, heteroaryl, heteroaryl-C 1-C8alkyl, C3-C6cycloalkyl, (C3-C8cycloalkyl)-C1-C8alkyl, -CH2COOR13, -CH2CONHR13 or trifluoromethyl, where any aryl and heteroaryl residues optionally substituted with hydrogen, halogen, C1-C8the alkyl, C1-C8alkoxy, cyano, trifluoromethyl, nitro, amino, -NHSO2-R13, -SO2NHR13, -COOR13, - CONHR13, or

(b) -(CH2)NR18R19, where R18 and R19 independently mean hydrogen, C1-C8alkyl, aryl, heteroaryl or may together form a five - or six-membered saturated or unsaturated ring structure, optionally containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, aryl and heteroaryl, optionally substituted by hydrogen, halogen, C1-C8the alkyl, C1-C8alkoxy, cyano, trifluoromethyl, nitro, amino, -NHSO2-R14, -SO2NHR24, COOH, -COOR17 or CONHR14;

R24 means

C1-C8alkyl, C1-C8alkoxy, aryl, heteroaryl, aryl-C1-C8alkyl, heteroaryl-C1-C8alkyl, (C3-C8cyclonically)-C1-C8alkyl and trifluoromethyl, where any aryl and heteroaryl residues optionally mono - or tizamidine halogen, C1-C8the alkyl, C1-C8alkoxy, cyano, trifluoromethyl, nitro, amino, -NHSO2-R13, -SO2NHR13, COOR13, -CONHR13, -(CH2)NR18R19, g is e, R18 and R19 independently mean hydrogen, C1-C8alkyl or may together form a five - or six-membered saturated or unsaturated ring structure, optionally containing one or two heteroatoms selected from O, N and S;

R25 independently mean C1-C6alkyl, (C3-C6cycloalkyl)-C1-C8alkyl;

R27 is H, aryl, heteroaryl, C1-C8alkyl, C1-C8alkoxy, O-aryl, O-heteroaryl, S-aryl, S-heteroaryl or NR18R19, where R18 and R19 are independently selected from H, C1-C8of alkyl, heteroaryl-C1-C8of alkyl, (C3-C8cycloalkyl)-C1-C8the alkyl or may together form a five - or six-membered saturated ring structure, optionally containing one or two heteroatoms selected from O, N and S, which may be optionally substituted C1-C8the alkyl, where aryl and heteroaryl residues optionally mono - or tizamidine halogen, C1-C8the alkyl, C1-C8alkoxy, trifluoromethyl;

R28 and R28a, each independently, signifies hydrogen, halogen, C1-C8alkyl, hydroxy-C1-C8alkyl, C3-C8cycloalkyl, (C3-C8cycloalkyl)-C1-C8alkyl, aryl, heteroaryl, aryl-C1-C8alkyl, C1-C8alkyl-C1-C8thioalkyl, C1-C8alkoxy, C1-C8alkoxy-C1-C8 alkyl or R28 and R28a together with the carbon atom to which they are attached, form a C3-C8cycloalkyl ring;

R29 means

(a) -(CH2)w-COOR17,

(b) -(CH2)w-(C=O)NR18R19, where R18 and R19 are independently selected from H, C1-C8of alkyl, aryl, heteroaryl, or R18 and R19 may together form a five - or six-membered saturated ring structure containing one or two heteroatoms selected from O, N and S, where aryl or heteroaryl residues can be mono - or tizamidine halogen, C1-C8the alkyl, C1-C8alkoxy and trifluoromethyl, or

(c) -(CH2)W-CH2-OH, where w is equal to 0,1 or 2;

R30 and R30a, each independently, signifies hydrogen, C1-C8alkoxy or together form a carbonyl;

R31 each independently mean hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy-C1-C8alkyl, cyano, hydroxy, hydroxy-C1-C8alkyl, C2-C8quinil and halogen-C1-C8alkyl;

R32 means C1-C6alkyl, C3-C6cycloalkyl, aryl and heteroaryl; and

R33 means C1-C8alkoxycarbonyl;

including its pharmaceutically acceptable salt, hydrate, solvate, atropoisomeric, enantiomers, diastereomers, tautomers, polymorphs and prodrugs.

In another embodiment, the present and the attainment refers to the connection, as defined above, but including only its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a compound as defined above, where R3 has any of the formula

where R1 is selected from

where

R2, each independently, signifies hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy-C1-C8alkyl, C1-C8alkoxy, C1-C8alkoxy-C1-C8alkoxy, hydroxyl, hydroxy-C1-C8alkyl, -(CH2)WNR18R19, where w is 1, and R18 and R19 form a five - or six-membered saturated or unsaturated ring structure, optionally containing one to two heteroatoms selected from oxygen, sulfur or nitrogen, and may be optionally substituted C1-C8the alkyl or oxopropoxy;

R4 means a five - or six-membered mono - or bicyclic ring system having one to three heteroatoms selected from O, N and S, such as pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl and peridotites, each of which may be optionally substituted by one or more of the following substituents: hydrogen, halogen, C1-C8the alkyl, C1-C8alkoxy,

R5 and R6 independently denote water is od C1-C8alkyl, or

R5 and R6 may together form a five - or six-membered cycloalkyl or aryl ring which may be optionally substituted C1-C8by alkyl;

R7 and R8 together form cyclobutyl, cyclopentyl or cyclohexyl;

R9 means C1-C8alkyl;

R9a is independently mean C1-C8alkyl, C1-C8alkoxy-C1-C8alkyl, C1-C8alkylsulphonyl, arylcarbamoyl, heteroarylboronic, carboxy and-COOR13;

R10 denotes hydrogen, C1-C8alkyl or (C3-C8cycloalkyl)-C1-C8alkyl;

R11 independently mean C1-C8-alkyl, C1-C8alkoxy, aryl-C1-C8alkyl, heteroaryl-C1-C8alkyl (C3-C8cycloalkyl)-C1-C8alkyl;

R12 denotes hydrogen, C1-C8alkoxy or-COOR17;

R13 means hydrogen, C1-C8alkyl, aryl or heteroaryl;

E is for easy communication;

R17 denotes hydrogen;

R23 denotes hydrogen, C1-C8alkyl, aryl, C1-C8alkoxy, halogen, heteroaryl, heteroaryl-C1-C8alkyl, C3-C6cycloalkyl or trifluoromethyl, where any aryl and heteroaryl residues optionally substituted with hydrogen, halogen, C1-C8the alkyl, C1-C8alkoxy, trifluoromethyl;

R24 means the AET C 1-C8alkyl, aryl, heteroaryl, aryl-C1-C8alkyl, heteroaryl-C1-C8alkyl, (C3-C8cycloalkyl)-C1-C8alkyl and trifluoromethyl, where any aryl and heteroaryl residues optionally mono - or tizamidine halogen, C1-C8the alkyl, C1-C8alkoxy or trifluoromethyl;

R25 means C1-C6alkyl, and

R27 is H, aryl, heteroaryl, C1-C8alkyl, C1-C8alkoxy, O-aryl, O-heteroaryl, S-aryl or NR18R19, where R18 and R19 form a five - or six-membered saturated ring structure, optionally containing one or two heteroatoms selected from O, N and S, which may be optionally substituted C1-C8by alkyl;

R28 and R28a, each independently, signifies hydrogen, halogen or C1-C8alkyl;

R29 denotes-COOH;

R30 and R30a together form a carbonyl;

R31 denotes halogen and

R33 means C1-C8alkoxycarbonyl.

Specific examples of the compounds shown in the examples 1-104.

Another object of the present invention is a method for obtaining compounds, as defined above, comprising at least one of the following stages:

a) interaction of thiophene with sulfurylchloride with getting thienylallylamine,

b) interaction of thienylallylamine with the primary amine obtained with the eat sulfonamida,

c) N-protection sulfonamida to obtain N-protected sulfonamida,

d) litvinovna halogenated thiophene with getting litoraneo thiophene,

(e) a combination litoraneo of thiophene with halogen-substituted complex alkilany ether aromatic carboxylic acids or aromatic aldehyde with getting aristotelova of ester or aldehyde,

f) recovering aristotelova of ester or aldehyde with getting aristotelova alcohol,

g) converting the hydroxyl group aristotelova alcohol aristotile derivative having a leaving group,

h) interaction aristotile derivative having a leaving group with a nucleophile, and

i) removing the protective group of N-protected sulfonamida.

Another object of the present invention is a combination comprising a compound as defined above, and at least one beta-blockers, calcium antagonists, diuretics, ACE inhibitors, renin inhibitors, antagonists of angiotensin II inhibitors vasopeptidase, receptor antagonists mineralocorticoids, antihypertensive drugs and antidiabetics.

Another object of the present invention is a combination comprising a compound as defined above, and at least one beta-blockers, calcium antagonists, diuretico is, of ACE inhibitors, renin inhibitors, antagonists of angiotensin II inhibitors vasopeptidase, receptor antagonists mineralocorticoids, antihypertensive drugs, antidiabetics, fibrinolytic funds, antithrombotic funds and lepidophyma funds.

Another object is a pharmaceutical composition comprising a compound as defined above, in a mixture with a pharmaceutical adjuvant, diluent or carrier.

In another embodiment, the present invention relates to pharmaceutical compositions containing the combination, as defined above, in a mixture with a pharmaceutical adjuvant, diluent or carrier.

Another object of the present invention is the use of compounds as defined above, to obtain drugs for the treatment of arterial hypertension of various kinds, reduce organ damage of various kinds, treatment, or prevention of cardiomyopathy of different origin, diabetic vasculopathy and its complications, treatment of disorders mediated by endothelin and angiotensin, including, but not limited to, vascular inflammatory conditions, including atherosclerosis, and cancer of the prostate.

Another object of the present invention is the use of the combination, as defined by you is e, to obtain medicines for the treatment of arterial hypertension of various kinds, reduce organ damage of various kinds, treatment, or prevention of cardiomyopathy of different origin, diabetic vasculopathy and its complications, treatment of disorders mediated by endothelin and angiotensin, including, but not limited to, vascular inflammatory conditions, including atherosclerosis, and cancer of the prostate.

Another object of the present invention is the use of receptor antagonist dual action receptor AT and ETA, which has a higher affinity for IT than ETA, to obtain drugs for the treatment of arterial hypertension of various kinds, reduce organ damage of various kinds, treatment, or prevention of cardiomyopathy of different origin, diabetic vasculopathy and its complications, treatment of disorders mediated by endothelin and angiotensin, including, but not limited to, vascular inflammatory conditions, including atherosclerosis, and cancer of the prostate.

Another object of the present invention is a method of treatment of arterial hypertension of various kinds, reduce organ damage of various kinds, treatment, or prevention of cardiomyopathy of different origin is to be placed, diabetic vasculopathy and its complications, treatment of disorders mediated by endothelin and angiotensin, including, but not limited to, vascular inflammatory conditions, including atherosclerosis, and cancer of the prostate by injection to the mammal of a compound as defined above.

Another object of the present invention is a method of treatment of arterial hypertension of various kinds, reduce organ damage of various kinds, treatment, or prevention of cardiomyopathy of different origin, diabetic vasculopathy and its complications, treatment of disorders mediated by endothelin and angiotensin, including, but not limited to, vascular inflammatory conditions, including atherosclerosis, and cancer of the prostate by injection to the mammal a combination as defined above.

Another object of the present invention is a method of treatment of arterial hypertension of various kinds, reduce organ damage of various kinds, treatment, or prevention of cardiomyopathy of different origin, diabetic vasculopathy and its complications, treatment of disorders mediated by endothelin and angiotensin, including, but not limited to, vascular inflammatory conditions, including atherosclerosis, and cancer treatment the intercessor is Oh gland, by introducing the mammal receptor antagonist dual action receptor AT and ETA, which has a higher affinity for IT than ETA.

Definitions

As used herein, the term "C1-C8alkyl" means a straight or branched alkyl group containing from 1 to 8 carbon atoms. Examples of the specified C1-C8of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl, hexyl, heptyl and octyl straight or branched chain. For the group "C1-C8alkyl" are considered sub-groups, such as C1-C7alkyl, C1-C6alkyl, C2-C8alkyl, C2-C7alkyl, C2-C6alkyl, C3-C5alkyl, C4-C6alkyl, C5-C7alkyl, etc.

As used herein, the term "C1-C8alkoxy" means a straight or branched alkoxygroup containing from 1 to 8 carbon atoms. Examples of the specified C1-C8alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and pentox, hexose, heptose, actoxy straight or branched chain. For the group "C1-C8alkoxy" are considered sub-groups, such as C1-C7alkoxy, C1-C6alkoxy,C 2-C8alkoxy, C2-C7alkoxy, C2-C6alkoxy, C3-C5alkoxy, C4-C6alkoxy, C5-C7alkoxy, etc.

As used herein, the term "C2-C8alkenyl" means a straight or branched alkenylphenol group containing from 2 to 8 carbon atoms. Examples of the specified C2-C8alkenyl include vinyl, 1-propenyl, 2-propenyl, n-butenyl, Isobutanol, second-butenyl and pentenyl, hexenyl, heptenyl and octenyl straight or branched chain. For the group "C2-C8alkenyl" are considered sub-groups, such as C2-C7alkenyl, C2-C6alkenyl, C3-C8alkenyl, C3-C7alkenyl, C3-C6alkenyl, C3-C5alkenyl, C4-C6alkenyl, C5-C7alkenyl etc.

As used herein, the term "C2-C8quinil" means a straight or branched alkenylphenol group containing from 2 to 8 carbon atoms. Examples of the specified C2-C8the quinil include ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl and pentenyl, hexenyl, heptenyl and octenyl straight or branched chain. For the group "C2-C8quinil" are considered sub-groups, such as C2-C7quinil, C2-C6quinil, C2 -C8quinil, C3-C7quinil, C3-C6quinil, C3-C5quinil, C4-C6quinil, C5-C7quinil etc.

As used herein, the term "C3-C8cycloalkyl" means a cyclic alkyl group containing 3 to 8 carbon atoms. Examples of the specified C3-C8cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. For the group "C3-C8cycloalkyl" are considered sub-groups, such as C3-C7cycloalkyl, C3-C6cycloalkyl, C3-C5cycloalkyl, C4-C6cycloalkyl, C5-C7cycloalkyl etc.

As used herein, the term "C3-C8cycloalkane" means a cyclic alkyl group containing 3 to 8 carbon atoms, associated with ekzoticheskim an oxygen atom. Examples of the specified C3-C8cycloalkane include cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane. For the group "C3-C8cycloalkane" are considered sub-groups, such as C3-C7cycloalkane, C3-C6cycloalkane, C3-C5cycloalkane, C4-C6cycloalkane, C5-C7cycloalkane etc.

As used in this description is AI, the term "C3-C8cycloalkenyl" means cyclic alkenylphenol group containing from 3 to 8 carbon atoms. Examples of the specified C3-C8cycloalkenyl include 1-cyclopropyl, 2-cyclopropyl, 1-cyclobutenyl, 1-cyclopentenyl, 1-cyclohexenyl, 1-cycloheptenyl and 1-cyclooctene. For the group "C3-C8cycloalkenyl" are considered sub-groups, such as C3-C7cycloalkenyl, C3-C6cycloalkenyl, C3-C5cycloalkenyl, C4-C6cycloalkenyl, C5-C7cycloalkenyl etc.

As used herein, the term "aryl" means a mono - or bicyclic aromatic ring system such as phenyl, naphthyl optionally monosubstituted or disubstituted by a group selected from hydrogen, halogen, C1-C8of alkyl, C1-C8alkoxy, cyano and trifloromethyl.

As used herein, the term "heteroaryl" means a five - or six-membered mono - or bicyclic ring system containing one to three heteroatoms selected from O, N and S. Examples of heteroaryl are furyl, thienyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl and peridotites.

As used in this description is AI, the term "heterocycle" means a five - or six-membered mono - or bicyclic ring saturated or partially saturated systems containing one to three heteroatoms selected from O, N and S. Examples of heteroaryl are tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinil, tetrahydrothieno and imidazolidinyl.

As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine. The term "pagelogin" means the group to which is attached the maximum possible number of halogen atoms.

As used herein, when two or more groups are used in conjunction with each other, this means that each group substituted directly by the previous group. For example, C1-C8alkoxycarbonyl means a carbonyl group substituted C1-C8alkoxygroup. Similarly, heteroaryl-C1-C8alkyl means C1-C8alkyl group, a substituted heteroaryl group.

As used herein, the term "preventing" or "prevention" has its ordinary meaning and thus means to prevent or alleviate the serious consequences of the disease or a side effect due to early detection.

As used herein, the term "mammal" means any person or animal such as monkeys, CA who you are, dogs, cats, horses, cows, etc.

As used in this description, the single enantiomers, racemic mixtures and unequal mixtures of two enantiomers are included in the scope of the invention, where such isomers exist. It should be understood that all possible diastereomers form (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers), tautomers and atropoisomeric included in the scope of the invention.

As used herein, the term "atropoisomeric" refers to the optical isomers which can be separated only because the rotation is relatively simple relations prevented or significantly delayed, as is often found in cases of limited spatial rotation in bearily systems.

As used herein, the term "polymorph" refers to compounds having the same chemical formula, the same type of salt and having the same form hydrate/MES, but having different crystallographic properties.

As used herein, the term "hydrate" refers to the connection to the molecule which is attached a certain number of water molecules.

As used herein, the term "solvate" refers to a connection to the molecule which are attached a number of the solvent molecules.

The present invention also covers about is carstvo compounds according to the invention, i.e. secondary compounds that become the primary compounds in vivo.

In vivo fissile esters represent only one type of prodrugs of the parent molecule. Hydrolyzable (or splitting) in vivo ester compounds according to the present invention, which contains the carboxyl group, for example, pharmaceutically acceptable ester which is hydrolysed in the human or animal body with the formation of the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-C8alkoxymethyl esters, for example methoxymethyl, C1-C8alcoholometry ester, for example pivaloyloxymethyl; complex palidrome esters; C3-C8cycloalkylcarbonyl-C1-C8alkalemia esters, for example 1-cyclohexylcarbodiimide; 1,3-dioxolan-2-animecrave esters, for example 5-methyl-1,3-dioxolan-2-arylmethyl; and (C1-C8alkoxycarbonylmethyl esters, for example 1-methoxycarbonylmethyl; and can be formed at any carboxy group in the compounds according to the present invention.

As used herein, the term "pharmaceutically acceptable salt" includes additive salt and acid additive salts of the bases. Such salts can is be formed by conventional means, for example, by reaction of the free acid or free base of the compounds according to the invention with one or more equivalents of the appropriate acid or base, optionally in a solvent or medium in which the salt is insoluble, with the subsequent removal of the specified solvent or a specified environment using standard techniques (for example, vacuum or drying by sublimation). Salt can also be obtained by exchange of the counterion compounds according to the invention in the form of a salt with a different counterion using a suitable ion exchange resin.

Suitable acids are non-toxic and include, for example, but not limited to, hydrochloric acid, Hydrobromic acid, yodiewonderdog acid, sulfuric acid, nitric acid, acetic acid, citric acid, ascorbic acid, lactic acid, malic acid and tartaric acid. Suitable bases are non-toxic and include, for example, but not limited to, sodium hydroxide, potassium hydroxide, ammonia, methylamine, dimethylamine, trimethylamine and triethylamine.

In the context of the present description, the term "treatment" also includes "prevention"if no specific instructions to the contrary. The term "treatment" within the context of the present invention also covers the introduction of an effective amount of the connection is in accordance with the present invention, in order to mitigate or existing disease state, acute or chronic, or relapsing condition. It also covers preventive therapy for prevention of recurrent States and permanent therapy for chronic disorders.

Compounds according to the present invention can be administered in the form of a conventional pharmaceutical composition by any route including oral, intramuscular, subcutaneous, local, intranasal, intraperitoneal, vnutritorakalnah, intravenous, epidural, vnutriobolochechnoe, intracerebroventricularly and by injection into the joint.

In one embodiment of the present invention, the route of administration can be oral, intravenous or intramuscular.

The dose will depend on the route of administration, severity of illness, age and body weight of the patient and other factors, which usually sees the doctor, defining the individual and the level of doses, the most suitable for a particular patient.

To obtain pharmaceutical compositions of the compounds according to the present invention, inert, pharmaceutically acceptable carriers can be solid or liquid. Solid forms include powders, tablets, dispersible granules, capsules, pills and suppositories.

A solid carrier can be one or a number of the substances, which can also act as solvents, fragrances, soljubilizatory, lubricants, suspendresume agents, binders or disintegrator tablets; it may also be an encapsulating material.

In powders, the carrier is a finely powdered solid substance that is mixed with finely ground connection according to the present invention or an active component. In tablets, the active ingredient is mixed with carrier having the necessary binding properties in suitable proportions and compacted into a desired shape and size.

To obtain the composition of the suppository low-melting wax such as a mixture of glycerides of fatty acids and cocoa butter, melted and dispersed active ingredient, for example, by stirring. The molten homogeneous mixture is then poured into molds of suitable size and is allowed to cool and harden.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc.

The term "composition" also includes the composition of the active ingredient with encapsulating material as carrier providing a capsule in which the active component (with other carriers or without them) is surrounded by carrier, which is thus in combination with it. Similarly included the wafer.

Tablets, powders, pills and capsules can be used as solid dosage forms suitable for oral administration.

Liquid compositions include solutions, suspensions and emulsions. For example, solutions of the active compounds in sterile water or propylene glycol can be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol.

Aqueous solutions for oral administration can be obtained by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers and thickeners, if desirable. Aqueous solutions for oral use can be obtained by dispersing finely ground active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspendresume agents known in the field of pharmaceutical compositions.

Depending on the method of administration of the pharmaceutical composition according to one variant of implementation of the present invention comprise from 0.05 to 99 wt.% (percent by weight), and according to ternatively variant implementation from 0.10 to 50 wt.% compounds according to the present invention, all mass concentration in percent are calculated on the total weight of the composition.

A therapeutically effective amount for the practice of the present invention can be determined using known criteria, including age, weight and response of the individual patient, and can be interpreted within the context of the disease, which is subjected to treatment or prevention of which is effected by a specialist in this field.

The above object is related to pharmaceutical compositions containing the compound according to the present invention likewise relates to a pharmaceutical composition comprising a combination according to the present invention.

In the following description refer to the schematic reaction to disclose the synthesis of compounds according to the present invention.

Scheme I

Circuit description I:

The compounds of formula X, where R1, R2, R4, R5 and R6 have the meanings given above, can be obtained by removing the protective group from compounds of formula IX, where PG denotes a suitable protective group of nitrogen. Examples of the conditions for removal of the protective groups and protective groups of the nitrogen can be found in T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc, New York, 1991, pp. 309-405. Preferred protective groups of nitrogen are ethoxymethylene (IOM), metaxia cimetidina (MEM) and 2-(trimethylsilyl)ethoxymethylene (SEM) group, and not limited to, for example, C1-C6alkoxycarbonyl group (such as methoxycarbonyl, etoxycarbonyl or isobutoxide), benzyloxycarbonyl (in which the benzene ring may be optionally substituted). The protective group PG may be removed from the compounds of formula IX by treatment one or more agents for the removal of the protective group. It should be understood that the agent or agents for the removal of the protective groups will depend on the particular protective group. Suitable agents for the removal of the protective groups and methods for their use are known in this field. For example, alkoxycarbonyl group can be removed in basic conditions, e.g. sodium hydroxide or alcoholate (e.g. sodium methylate) in a suitable solvent, such as methanol; 2-methoxyethoxymethyl group can be removed using acidic conditions such as hydrochloric acid in a suitable solvent, such as ethanol; and Tris1-C4alkiltrimetilammony group can be removed using tetrabutylammonium in tetrahydrofuran, using triperoxonane acid or using a mixture of hydrochloric acid in a suitable solvent, such as ethanol.

The compounds of formula IX can be obtained from compounds of formula VIII, a substitution of a deleted group (G) by the conjugate base of the compound R1-H, where R1 has the meaning defined above, with a base in an inert solvent. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and potassium hydride or alkylate. The preferred base is sodium hydride. An example of the inert solvent include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether or N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. Examples of reaction temperatures are from about 0°C to 120°C, preferably from about 20°C to 110°C.

The compounds of formula VIII (where LG denotes a leaving group type, but not limited to, -OSO2CH3, -OSO2PhCH3, -OSO2Ph, -OSO2CF3can be obtained by the coupling of compounds of formula VII, for example, but not limited to, ClSO2CH3, ClSO2PhCH3, ClSO2Ph or (CF3SO2)2O, in the presence of a base in an inert solvent. An example of the inert solvent include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether or N,N-dimethylformamide.

The compounds of formula VII can be obtained by reduction of compounds of formula VI in an inert solvent using an alkali metal hydride, such as alumalite lithium.

The compounds of formula VI can be obtained from the resulting catalyzed by palladium combination of the compounds of formula V with the compound of the formula IV in the presence of a suitable base in an inert solvent. Examples of catalysts include palladium tetrakis(triphenylphosphine)palladium(0), palladium(II)chloride. The preferred catalyst based on palladium is tetrakis(triphenylphosphine)palladium(0). Examples of the base include tertiary amines, such as, but not limited to, triethylamine, or an aqueous solution of potassium carbonate, sodium or cesium. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, or alcohols with straight-chain 1,2-dimethoxyethane or combinations thereof. The preferred solvent is a mixture of toluene and ethanol. An example of the reaction temperature is a temperature from about 25°C to 125°C, preferably from about 65°C to 110°C.

The compounds of formula V, where R' is lower alkyl, such as methyl, ethyl, isobutyl, and benzyl, and X imply halogen (chlorine, bromine, iodine) can be obtained from compound B by means known to the expert in this field.

Compounds B are commercially available or can be obtained by means known to the expert in this field.

The compounds of formula IV where Y means suitable boron Deputy, can be obtained by otherovarian compounds of formula III where X is hydrogen or halogen (chlorine, bromine, iodine), and the interaction obtained heterogeneity with a suitable borate is produced in the water. Suitable borate compounds are commercially available or can be obtained by means known to the expert in this field.

The compounds of formula III can be obtained by protection of the nitrogen in the compound of formula II. Examples of protective groups of the nitrogen and ways of protection of nitrogen similar groups and ways of protection of amines as described in T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc. New York, 1991.

The compounds of formula II can be obtained by the coupling of compounds of formula I with a compound R4-NH2.

The compounds of formula I are commercially available or can be obtained by means known to the specialist, through the connection A.

Compound A are commercially available or can be obtained by means known to the expert in this field.

Scheme II

Description of scheme II:

The compounds of formula XVI, where R1, R4, R5 and R6 have the meanings given above, can be obtained by removing the protective group from compounds of formula XV, where PG denotes a suitable protective group of nitrogen. The protective group PG can be removed from compounds of formula XV by treatment one or more agents for the removal of the protective group. It should be understood that the agent or agents for the removal of the protective groups will depend on the particular protective group. Suitable AG the options for removal of the protective groups and methods for use are known in this field.

The compounds of formula XV can be obtained from compounds of formula XIV via the substitution of a deleted group (LG) conjugate base with a compound R1-H, where R1 has the values defined above, using a base in an inert solvent. Examples of bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and potassium hydride or alkylate. The preferred base is sodium hydride. An example of the inert solvent include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether or N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. An example of the reaction temperature is a temperature from about 0°C to 120°C, preferably from about 20°C to 110°C.

The compound of formula XIV (where LG denotes a leaving group type, but not limited to, -OSO2CH3, -OSO2PhCH3, -OSO2Ph, -OSO2CF3can be obtained by the coupling of compounds of formula XIII, for example, but not limited to, ClSO2CH3, ClSO2PhCH3, ClSO2Ph or (CF3SO2)2O in the presence of a base in an inert solvent. An example of the inert solvent include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether or N,N-dimethylformamide.

The compound of formula XIII can be obtained by reduction of compounds the Oia formula XII in an inert solvent using a reducing agent, such as alumalite lithium, sodium borohydride and cyanoborohydride sodium.

The compounds of formula XII can be obtained catalyzed by palladium combination of the compounds of formula XI with the compound of the formula IV in the presence of a suitable base in an inert solvent. Examples of catalysts include palladium tetrakis(triphenylphosphine)palladium(0), palladium(II)chloride. The preferred catalyst based on palladium is tetrakis(triphenylphosphine)palladium(0). Examples of the base include tertiary amines, such as, but not limited to, triethylamine, or an aqueous solution of potassium carbonate, sodium or cesium. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, or alcohols with straight-chain 1,2-dimethoxyethane or combinations thereof. The preferred solvent is a mixture of toluene and ethanol. An example of the reaction temperature is a temperature from about 25°C to 125°C, preferably from about 65°C to 110°C.

The compounds of formula XI are commercially available or can be obtained by means known to the expert in this field.

The compounds of formula IV can be obtained as described in scheme I.

Scheme III

Description of scheme III

The compounds of formula X, where R1, R2, R4, R5 and R6 have the meanings defined Lennie above, can be obtained by removing the protective group from compounds of formula IX as described in scheme I.

The compounds of formula IX can be obtained catalyzed by palladium combination of compounds of formula XIX with a compound of formula IV in the presence of a suitable base in an inert solvent. Examples of catalysts include palladium tetrakis(triphenylphosphine)palladium(0), palladium(II)chloride. The preferred catalyst based on palladium is tetrakis(triphenylphosphine)palladium(0). Examples of the base include tertiary amines, such as, but not limited to, triethylamine, or an aqueous solution of potassium carbonate, sodium or cesium. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, benzene, or alcohols with straight-chain 1,2-dimethoxyethane or combinations thereof. The preferred solvent is a mixture of toluene and ethanol. An example of the reaction temperature is a temperature from about 25°C to 125°C, preferably from about 65°C to 110°C.

The compounds of formula IV can be obtained as described in scheme I.

The compounds of formula XIX can be obtained through the substitution of a deleted group (LG) the compounds of formula XVIII conjugate base with a compound R1-H, where R1 has the values defined above, using a base in an inert solvent. Examples of what Sevani include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and potassium hydride or alkylate. The preferred base is sodium hydride. an example of the inert solvent include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether or N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. An example of the reaction temperature is a temperature from about 0°C to 120°C, preferably from about 20°C to 110°C.

The compounds of formula XVIII (where LG denotes a leaving group type, but not limited to, -OSO2CH3, -OSO2PhCH3, -OSO2Ph, -OSO2CF3can be obtained by the coupling of compounds of formula XVII, for example, but not limited to, ClSO2CH3, ClSO2PhCH3, ClSO2Ph or (CF3SO2)2O, in the presence of a base in an inert solvent. An example of the inert solvent include ethers (tetrahydrofuran, 1,4-dioxane, diethyl ether or N,N-dimethylformamide.

The compounds of formula XVII can be obtained by reduction of compounds of formula V in an inert solvent using reducing agents, such as alumalite lithium, sodium borohydride and cyanoborohydride sodium.

The compounds of formula V can be obtained as described in scheme I.

Due to changing patterns of substitution of compounds of formula I Alt is rnatively isomer, that is, the compound of formula B, can also be used as a starting compound in scheme I, II or III, leading to isomeric form compounds of formula X and formula XVI.

The formula In

Heterocyclic ring, as described in this description, which was not explicitly disclosed, can be obtained similarly heterocyclic rings, which was explicitly disclosed.

In the following description, the present invention covers the following non-limiting examples.

When they are used, the expression "contains" and "contain" means "includes" and "including, but not limited to. Thus there could be other ingredients, carriers and additives.

EXAMPLES

Abbreviations

ACE - angiotensin-converting enzyme

Ang-II - angiotensin

AT - 1 receptor angiotensin II

AT2 - receptor 2 angiotensin II

ETA - receptor And endothelin

ETB endothelin receptor B

LAH - sociallyengaged

CT or CT room temperature

t - triplet

s - singlet

d - doublet

square - Quartet

Queen. quintet

m - multiplet

user. - extended

users broadened singlet

DM doublet of multiplets

ushort broadened triplet

DD - doublet of doublets

General experimental met the Dickey

Mass spectra were recorded on a system Thermo Finnigan LC-MS (LCQ classic). Measurement1H NMR were recorded on a Bruker Avance DPX 400 MHz. Chemical shifts are given in ppm with TMS as internal standard.

Example 1

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(2-butyl-4-oxo-1,3-diazaspiro[4,4]non-1-EN-3-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of ethyl ester of 4-bromo-3-methylbenzoic acid

To a cooled solution (0°C) 4-bromo-3-methylbenzoic acid (25 g, 0,116 mol) in ethanol (100 ml) was added with stirring, concentrated sulfuric acid (8 ml). After complete addition, the reaction mixture was heated under reflux for 6 hours. The reaction mixture was cooled and then concentrated in vacuum. To the residue was added (50 ml) cold water followed by simple extraction with diethyl ether (100 ml×2). The organic layer was washed with a saturated solution of sodium bicarbonate, then with water and saturated salt solution. Finally, the ether layer was dried over sodium sulfate and evaporated in vacuum, obtaining 26 g of ethyl ester of 4-bromo-3-methylbenzoic acid.

Stage 02: Synthesis of 4-bromo-3-(methyl bromide)ethylbenzoic

To a solution of ethyl ester of 4-bromo-3-methylbenzoic acid 25 g, is 0.102 mol) in carbon tetrachloride (100 ml) at room temperature was added N-bromosuccinimide (20,13 g, 0,113 mol) and (1.24 g, of 0.005 mol) of benzoyl peroxide. Then the reaction mixture was heated under reflux for 10 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuum. The residue, thus obtained, was purified, triturating with hexane (100 ml). The solid, thus obtained, was filtered and dried under suction, receiving 12 g of 4-bromo-3-(methyl bromide)ethylbenzoic.

Stage 03: Synthesis of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid

To a cooled solution (0°C) 4-bromo-3-(methyl bromide)ethylbenzoic (12 g, 0,037 mol) in ethanol (25 ml) was added ethoxide sodium (5.0 g, 0,074 mol) and (4 ml) of N,N-dimethylformamide. The reaction mixture was stirred for 4 hours at room temperature. Then the reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (100 ml). An ethyl acetate layer was washed with water and saturated salt solution and, finally, the organic layer was dried over sodium sulfate. The organic layer was evaporated in vacuum, obtaining 10.0 g of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid.

Stage 04: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol the l-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 05: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To reactio the Noah mixture for 30 minutes was added n-utility (106 ml, of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 06: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions to triperoxonane acid (22 ml, 0,3108 mol) at 0°C. After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-METI the thiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (10.5 g, 0,053 mol) in (15 ml) of methylene chloride was added to a solution of 3-amino-4,5-dimethylisoxazole (4 g, 0.035 mol) and dimethylaminopyridine (500 mg) in pyridine (20 ml) at 0°C. After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 4.0 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Stage 08: Synthesis of(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

At 0°C with stirring sodium hydride (0.800 to g, 0,166 mol, 60%dispersion in mineral oil) was added to N,N-dimethylformamide (30 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (4 g, 0,0146 mol). After complete addition, the temperature of the reaction mixture was slowly raised and stirred at temperatureincrease environment for 30 minutes, then re-cooled the reaction mixture to 0°C, then the reaction mixture was added dropwise methoxyethoxymethyl (2.7 g, 0,021 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C, the resulting mixture (90 ml) was added ethyl acetate and stirred the reaction mixture for 20 min, and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, gaining 3.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 09: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophosphonate

In a dry nitrogen atmosphere a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid (3.7 g, 0,010 mol) in tetrahydrofuran (30 ml) was cooled to -78°C. To the resulting solution was IU is slowly added n-utility (11 ml, 0,025 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture is slowly brought up to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (3 ml, 0.015 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×2). The combined extract was washed with water and saturated salt solution. An ethyl acetate layer was dried over sodium sulfate and concentrated in vacuum, obtaining 3.4 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Step 10: Synthesis of ethyl ester of 4-{2[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

To a stirred solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5,2 g, 0,0128 mol) and ethyl ester of 4-bromo-3-ethoxymethyleneamino acid (3.7 g, 0,0128 mol) in toluene (50 ml) and ethanol (25 ml) in ATM is the field of nitrogen was added 2M aqueous solution of sodium carbonate (4.0 g in 19 ml of water). The reaction mixture was stirred in nitrogen atmosphere for 15 minutes and then the reaction mixture was added tetranitropentaerithrite(0) (0,745 g, 0.64 mmol). The reaction mixture was heated to 85°C for 6 hours. The reaction mixture was concentrated and to the residue was added ethyl acetate (25 ml), then cooled water were extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution, dried over sodium sulfate and concentrated completely under vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, getting 0,300 g of ethyl ester of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid as an oily mass.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (0,100 g) was added at 0°C to a stirred solution of tetrahydrofuran (10 ml) in a stream of dry nitrogen, followed by addition of ethyl ether (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid (0,300 g) (15 ml) of tetrahydrofuran. The reaction mixture was stirred at 0°C in accordance with the s 1 hour, then the temperature was raised to room temperature and the mixture was stirred for 4 hours. The excess lithium aluminum hydride was destroyed by addition of sodium hydroxide solution (1 g dissolved in 100 ml water) at 0°C followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sodium sulfate and concentrated completely under vacuum, obtaining 0,240 g (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid.

Step 12: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (0.2 ml, 0,0011 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (0,240 g, 0,00045 mol) in 10 ml of dichloromethane. The reaction mixture was cooled to 0°C, then the reaction mixture was slowly added methanesulfonamide (0,043 ml, 0,00055 mol). The reaction mixture was stirred at room temperature for 3 hours and then placed in ice water followed by extraction with methylene chloride (25 ml×2). The combined extracts were washed with diluted hydrochloric acid, then with water and saturated salt solution, the organic layer was dried the hell sodium sulfate and concentrated, getting 0,220 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(2-butyl-4-oxo-1,3-diazaspiro[4,4]non-1-EN-3-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 2-butyl-1,3-diazaspiro[4,4]non-1-EN-4-it (0,080 g, 0.41 mmol) in dimethylformamide (2 ml) at -15°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (0.025 g, 0.54 mmol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (0,220 g, 0.36 mmol) in 2 ml of dimethylformamide and stirred at room temperature for 24 hours. The mixture then was diluted with ethyl acetate (20 ml), then 5 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum. The residue was purified by chromatography on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, the floor is th 0,230 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(2-butyl-4-oxo-1,3-diazaspiro[4,4]non-1-EN-3-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 14: Synthesis of ethyl ether 1-aminocyclopentane acid

To a stirred solution of 1-aminocyclopentane acid (25 g, rate of 0.193 mol) in ethanol (250 ml) at 0°C was added 15 ml of concentrated sulfuric acid. The reaction mixture was heated under reflux for 24 hours, then cooled and evaporated in vacuum. The residue was neutralized by addition of solid sodium bicarbonate, followed by adding 50 ml of cold water. The mixture was extracted with dichloromethane (200 ml×4). The organic layer was washed with water, saturated salt solution, dried over sodium sulfate and evaporated, receiving 27 g of ethyl ester of 1-aminocyclopentane acid.

Stage 15: Synthesis of 2-butyl-1,3-diazaspiro[4,4]non-1-EN-4-it

To a stirred solution of ethyl ester 1-aminocyclopentane acid (7 g, 0,0445 mol) in 30 ml of toluene was added ethyl ether pentanediol acid (7 g, 0,054 mol), then a catalytic amount of acetic acid (1-2 ml) and the reaction mixture was heated under reflux for 48 hours. The reaction mixture was cooled and concentrated in vacuo, the residue was dissolved in ethyl acetate (50 ml) and then washed with water and saturated salt solution, dried over sodium sulfate and evaporated, receiving 5 g 2-a bout the l-1,3-diazaspiro[4,4]non-1-EN-4-it is in the form of a light yellow oil.

Stage 16: (4,5-dimethylisoxazol-3-yl)amide 3-[4-(2-butyl-4-oxo-1,3-diazaspiro[4,4]non-1-EN-3-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(2-butyl-4-oxo-1,3-diazaspiro[4,4]non-1-EN-3-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid (0,230 g, 0.32 mmol) at room temperature was added 95%ethanol (5 ml) and 6 N. aqueous solution of hydrochloric acid (4 ml). The reaction mixture was heated under reflux for 3 hours. The reaction mixture was concentrated in vacuo, and the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution. The reaction solution is then acidified to pH 5 with acetic acid and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The crude product was purified flash chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 50 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(2-butyl-4-oxo-1,3-diazaspiro[4,4]non-1-EN-3-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C31H40N4O5S2

Molecular weight: 612,80

1H NMR (DMSO-d6): or 0.83 (t, J=7.2 Hz, 3H), of 1.06 (t, J=7.2 Hz, 3H), of 1.28 and 1.33 (m, 2H), 1,51-and 1.54 (m, 2H), and 1.56 (s, 3H), 1,66-1,71 (m, 2H), 1,84-to 1.87 (m, 6H), of 2.20 (s, 3H), 2,32-of 2.38 (m, 2H), 2,48 (s, 3H), 3,23-of 3.27 (m, 2H), 4,07-4,11 (m, 2H), 4.72 in-4,74 (m, 2H), 6,74 (s, 1H), 6,97-7,03 (m, 2H), 7,17-7,19 (m, 1H), 10,75 (s, 1H).

Mass spectrum: (m+1) 613.

Example 2

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of 1-phenylbutane-1,3-dione

Ethoxide sodium (13.5 g, 0,198 mol) was added to a stirred solution of dry ethyl acetate (80 ml) to 0.72 mol) at -5°C. To the reaction mixture were added methylvinylketone (20 g, 0.185 mol) at -5°C and then the temperature of the reaction mixture was kept at 0°C for 12 h, the Reaction mixture was then acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and evaporated, getting 21 grams of yellow solid, which represents a 1-phenylbutane-1,3-dione.

Stage 02: Synthesis of 3-amino-1-phenylbut-2-EN-1-it

A mixture of 1-phenylbutane-1,3-dione (20 g, 0,123 mol) and ammonium acetate (38 g, 0.49 mol) in dry methanol (200 ml) was stirred and heated under reflux for 24 reaktsionnuyu the mixture was concentrated in vacuo and to the residue was added chilled water followed by extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and evaporated, receiving 19 g of yellow solid, which represents a 3-amino-1-phenylbut-2-EN-1-it.

Stage 03: Synthesis of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione

Propionate (7 ml, 0,0763 mol) was added to a solution of acid Melodrama (10 g, 0,069 mol) in pyridine (12 ml, was 0.138 mol) and methylene chloride (50 ml) at 0°C for 30 min, the temperature of the reaction mixture was allowed to rise to ambient temperature and was stirred for 1 h, the Reaction mixture was then acidified using 1 N. hydrochloric acid, and was extracted with methylene chloride (50 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum to give 10 g of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of a solid crystalline substance.

Stage 04: Synthesis of 3-benzoyl-6-ethyl-2-methyl-1H-pyridin-4-it

A mixture of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione (17,39 g, 0,087 mol) and 3-amino-1-phenylbut-2-EN-1-it (10 g, 0,062 mol) was stirred and heated at 120°C for 2 h Then the reaction mixture was purified by chromatography on a column of silica gel, elirwayweilia fraction of 10%methanol and ethyl acetate, obtaining 5.8 g of 3-benzoyl-6-ethyl-2-methyl-1H-pyridin-4-it is in the form of a yellow solid.

Stage 05: Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)phenylmethanone

3-Benzoyl-6-ethyl-2-methyl-1H-pyridin-4-one (2.7 g, to 0.011 mol) was added to phosphorus oxychloride (8 ml) at 0°C. Then the reaction mixture was stirred, heated to 50°C and the temperature of the reaction mixture was maintained for 8 hours. Spent processing viparita phosphorus oxychloride in a vacuum, and the residue, thus obtained, was podslushivaet to pH 8 with a saturated solution of sodium bicarbonate, followed by extraction with methylene chloride (50 ml×2). The combined organic extracts were washed with water and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and concentrated, obtaining 2.6 g of (4-chloro-6-ethyl-2-methylpyridin-3-yl)phenylmethanone in the form of a yellow oil.

Stage 06: Synthesis of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine

(4-chloro-6-ethyl-2-methylpyridin-3-yl)phenylmethanone (2.5 g, 0,0096 mol) was dissolved in ethanol (10 ml) and the reaction mixture was added hydrazinehydrate (2.3 ml, 0,048 mol). The reaction mixture was stirred and heated under reflux for 4 hours. Then the reaction mixture was evaporated in vacuum. To the residual mass was added ice water, the solid, the floor is obtained thereby was filtered and dried under suction, obtaining 1.8 g of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine.

Stage 07: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture (245 g, 1.12 mol) for 1 hour was added di-tert-butylboronic. After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in 500 ml of ethyl acetate. An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving 130 g of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 08: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 09: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions to triperoxonane acid (22 ml, 0,3108 mol) at 0°C. After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with Meiling what oridam (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Step 10: Synthesis of 3-bromothiophene-2-sulphonylchloride

3-Bromothiophene (10 g, 0,0617 mol) were placed in methylene chloride (60 ml) and cooled the reaction mixture to -78°C. Then the reaction mixture at -78°C was added dropwise chlorosulfonic acid (25 ml, 0,396 mol). The temperature of the reaction mixture was slowly raised to 0°C and maintained for 1 hour. The reaction mixture was slowly poured into ice-cold water followed by extraction with methylene chloride (100 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over anhydrous sodium sulfate and was evaporated in vacuum, obtaining a solid brown color. The crude compound was purified by chromatography on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, obtaining of 5.4 g of 3-bromothiophene-2-sulphonylchloride.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid

To a solution of 3-amino-4,5-dimethylisoxazole (2 g, 0,0178 mol) (25 ml) in pyridine and dimethylaminopyridine (0,230 g, 0,0019 mol) at 0°C was added 3-br motofen-2-sulphonylchloride (5.0 g, 0,01912). Then the temperature of the reaction mixture was slowly raised to room temperature (28°C) and then the reaction mixture was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue was acidified using 1 N. hydrochloric acid to pH 1, followed by extraction with dichloromethane (50 ml×3). The combined organic extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 3.5 g (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid as a brown solid.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid

In a stream of dry nitrogen, sodium hydride (0,600 g of 0.0125 mol, 60% in mineral oil) was added in portions to a solution of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid (3.5 g, 0,0103 mol) in N,N-dimethylformamide (30 ml) at -15°C. After complete addition, the reaction mixture was stirred at room temperature for 30 minutes and Then the reaction mixture was re-cooled to 0°C. To the reaction mixture for 30 minutes was added dropwise 2-methoxyethoxymethyl (1.55 g, 0,0124 mol), maintaining the temperature of the reaction mixture to 0°C. the Reaction mixture was stirred at 0°C for 30 min and then at room for the Noah temperature for 4 h Then the reaction mixture was diluted with ethyl acetate (100 ml) followed by the addition (30 ml) of ice-cold water. The organic layer was separated, washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 2.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulphonic acid in the form of a yellow oil.

Stage 13: Synthesis of(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid

To a stirred solution of 2.7 g (0,0063 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid and 1.04 g (0,006 mol) 4-forevernow acid in toluene (15 ml) and ethanol (12 ml) under nitrogen atmosphere was added a 2M aqueous solution of sodium carbonate (2 g in 16 ml of water). The reaction mixture was stirred for 15 minutes, then the reaction mixture was added tetranitropentaerithrite(0). The reaction mixture was heated to 85°C for 6 hours, the Reaction mixture was cooled to room temperature and was added ethyl acetate (50 ml) followed by evaporation in vacuum. To the residual mass was added ethyl acetate (100 ml), then cooled and water is MES were extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining 1.1 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid in the form of oil.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid

Sociallyengaged (0,100 g, 0,0029 mol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran followed by the addition (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid (1.1 g, 0,0024 mol) in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, then the temperature was raised to room temperature (28°C) and was stirred for 4 h, the Reaction mixture was treated by adding sodium hydroxide solution (1 g dissolved in 100 ml of water) in the reaction mixture at 0°C followed by extraction with ethyl acetate (50 ml×2). The combined organic layers were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 1.0 g (4,5-dimethylisoxazol-3-yl)-(-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid in the form of oil.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid

To a cooled to 0°C a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid (1.0 g, 0,0022 mol) in 60 ml dichloromethane was added N-ethyldiethanolamine (0.6 ml, 0,0033 mol) followed by slow addition to the reaction mixture solution methanesulfonanilide (0.2 ml, 0,0033 mol) in 10 ml of dichloromethane. The reaction mixture was then heated and stirred at room temperature for 3 hours was Carried out by processing of adding to the reaction mixture was ice-cold water followed by extraction with methylene chloride (25 ml×2). The combined organic extract was washed with diluted hydrochloric acid, then with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, getting 0,700 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid in the form of a viscous liquid.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(6-ethyl-4-methyl-3-fenile the azolo[4,3-c]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

To a stirred solution of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine (0,344 g, 0,00145 mol) in dimethylformamide (5 ml) at 0°C in a stream of dry nitrogen gas was added in portions sodium hydride (60% in mineral oil) (0,100 g, 0,00174 mol). After the addition the temperature of the reaction mixture was raised to room temperature and maintained for 30 minutes, the Reaction mixture was then re-cooled to 0°C was added dropwise a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid (0,700 g, 0,00145 mol) in dimethylformamide (5 ml) and the mixture was stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of water at 0°C, was extracted the ethyl acetate (50 ml×2) and the combined organic extract was washed with water and saturated salt solution. Then the organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 1.0 g (4,5-dimethylisoxazol-3-yl(2-methoxyethoxymethyl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid resin.

Stage 17: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

To 1.0 g (1.48 mmol) of 4,5-dimetil oxazol-3-yl(2-methoxyethoxymethyl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid at room temperature was added 95%ethanol (10 ml) and 5 ml of 6 N. an aqueous solution of hydrochloric acid. The reaction mixture was then heated under reflux for 2 hours the Reaction mixture was cooled and concentrated in vacuum. The residue thus obtained was diluted with water and the pH of the solution was brought to pH 5 with sodium bicarbonate solution. The solution was extracted with ethyl acetate (50 ml×2), the combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, receiving 200 mg of amorphous yellowish foam.

Molecular formula: C31H29N5O3S2

Molecular weight: 583,72.

1H NMR (DMSO-d6): of 1.29 (t, J=7.2 Hz, 3H), of 1.44 (s, 3H), of 2.08 (s, 3H), 2,47 (s, 3H), 2,80-of 2.86 (m, 2H), 5,72 (s, 2H), 7,11-7,13 (m, 1H), 7,28-7,31 (m, 2H), 7,40-the 7.43 (m, 2H), 7,51-7,56 (m, 4H), 7,65-to 7.68 (m, 2H), of 7.90-7,92 (m, 1H), 10,80 (users, 1H).

Mass spectrum: (m-1) 582

Example 3

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenylsulfonyl-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of 3-aminomethylenemalonate

A mixture of methylpropionamide (50 g, 0,3842 mol) and ammonium acetate (148 g, 1,921 mol) in dry methanol (500 ml)was stirred and heated under reflux for 2 days. The reaction mixture was cooled and concentrated in vacuum. The residue, thus obtained, was podslushivaet to pH 8 and extracted with ethyl acetate. An ethyl acetate layer was washed with water, saturated salt solution, the organic layer was dried over sodium sulfate and concentrated, gaining 50 g 3-aminomethylenemalonate in the form of a light yellow liquid.

Stage 02: Synthesis of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid

To a mixture of 3-aminomethylenemalonate (50 g, 0,387 mol) and methylpropionamide (50 g, 0.384 mol) in o-xylene (200 ml) was added 40A molecular sieves (50 g). Then the reaction mixture was stirred and heated under reflux with the unit Dean-stark for 5 days. The reaction mixture was cooled to room temperature and the molecular sieves were filtered off. The filtrate was concentrated and the crude compound was purified by chromatography on a column of silica gel using a mixture of 50% dichloromethane:methanol as eluent, obtaining 20 g of the desired product as a white solid

Stage 03: Synthesis of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid

In a stream of dry nitrogen gas totalization (39 g, 0,197 mol) was added to a stirred suspension of 2,6-diethyl-4-oxo-1,4-dihydro what iridin-3-methylcarbazole (25 g, 0,119 mol) in acetonitrile (250 ml). After the fall of the initial ectothermy the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and suspended solid product was separated by filtration, obtaining 20 g of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid.

Stage 04: Synthesis of methyl ester of 4-amino-2,6-diethylnicotinamide acid

Methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid (40 g, 0,110 mol) at 0°C was added to concentrated sulfuric acid (57 ml, 1.10 mol) and then the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and poured into ice. the pH of the resulting solution was brought to pH 8 with solid sodium carbonate and was extracted with dichloromethane (200 ml×2). The combined organic layers were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, gaining 19 g of 4-amino-2,6-diethylpyrazine-3-methylcarbazole in the form of a white solid

Stage 05: Synthesis of ethyl ether 5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro[1, 6]naphthiridine-3-carboxylic acid

Diethylmalonate (15 ml, 0,093 mol) and 4-amino-2,6-diethylpyrazine-3-methylcarbazole (19,0 g, 0.09 mol) of relax is whether the solution ethoxide sodium (7 g, 0.10 mol) in ethanol (60 ml) and the reaction mixture was heated at 150°C and a pressure of 100 psi for 20 hours in an autoclave. The reaction mixture was allowed to cool, the volatiles were removed by evaporation and the resulting semi-solid substance was rubbed with a simple ester, getting a solid white color, which was separated by filtration and dissolved in water. The resulting solution was then acidified using 1 N. hydrochloric acid, getting a solid white color, which was filtered and dried under suction, receiving 11 g of 5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro-1,6-naphthiridine-3-ethylcarboxylate in the form of a white solid.

Stage 06: Synthesis of 5,7-diethyl-4-hydroxy-1H-[1,6]naphthiridine-2-it

5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro-1,6-naphthiridine-3-ethylcarboxylate (11 g) was dissolved in a mixture of water (11 ml), 1,4-dioxane (22 ml) and concentrated hydrochloric acid (11 ml)and the reaction mixture was heated under reflux for 3 hours. The reaction mixture was then cooled and the suspended solid was filtered, washed with ethanol and simple with ether, and dried under suction, obtaining 4.3 g of 5,7-diethyl-4-hydroxy-1,6-naphthiridine-2(1H)-it is in the form of a white solid.

Stage 07: Synthesis of 4-chloro-5,7-diethyl-1,6-naphthiridine-2(1H)-it

4.3 g is 0.019 mol is) 5,7-diethyl-4-hydroxy-1,6-naphthiridine-2(1H)-it was dissolved in 22 ml of phosphorus oxychloride and the reaction mixture was heated under reflux for 24 hours. The reaction mixture was concentrated, the residue was dissolved in concentrated hydrochloric acid (16 ml) and 22 ml of water and heated under reflux for 4 hours. The reaction mixture was diluted with water and podslushivaet solid sodium bicarbonate. The obtained solid substance was separated by filtration, washed with water and dried under suction, obtaining 3.0 g of 4-chloro-5,7-diethyl-1,6-naphthiridine-2(1H)-it is in the form of a solid orange color.

Stage 08: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture for 1 hour was added di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml)and after standing 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving 130 g of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 09: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Step 10: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions n and 0°C to triperoxonane acid (22 ml 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 11: Synthesis of 3-bromothiophene-2-sulphonylchloride

3-Bromothiophene (10 g, 0,0617 mol) was dissolved in methylene chloride (60 ml) and the reaction mixture was cooled to -78°C. Then at -78°C was added dropwise chlorosulfonic acid (25 ml, 0,396 mol). The temperature of the reaction mixture was slowly raised to 0°C and maintained for 1 hour. The reaction mixture was slowly poured into cold water followed by extraction with methylene chloride (100 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining a solid brown color. The crude compound was purified on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining of 5.4 g of 3-bromothiophene-2-sulphonylchloride.

Step 12: Synthesis of (4,5-dim is telesocial-3-yl)amide 3-bromothiophene-2-sulfonic acid

To a solution of 3-amino-4,5-dimethylisoxazole (2 g, 0,0178 mol) in 25 ml of pyridine and dimethylaminopyridine (0,230 g, 0,0019 mol) at 0°C was added 3-bromothiophene-2-sulphonylchloride (5.0 g, 0,01912). Then the temperature of the reaction mixture was slowly raised to room temperature (28°C) and then the reaction mixture was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue was acidified using 1 N. hydrochloric acid to pH 1, followed by extraction with dichloromethane (50 ml×3). The combined organic extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 3.5 g (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid as a brown solid.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid

In a stream of dry nitrogen, sodium hydride (0,600 g of 0.0125 mol, 60% in mineral oil) was added in portions to a solution of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid (3.5 g, 0,0103 mol) in N,N-dimethylformamide (30 ml). After complete addition, the reaction mixture was stirred at room temperature for 30 minutes and Then the reaction mixture was re-cooled to 0°C. To the reaction mixture is 30 minutes was added dropwise 2-methoxyethoxymethyl (1.55 g, 0,0124 mol), maintaining the temperature of the reaction mixture to 0°C. the Reaction mixture was stirred at 0°C for 30 min and then at room temperature for 4 h Then the reaction mixture was diluted with ethyl acetate (100 ml) followed by the addition (30 ml) of ice-cold water. The organic layer was separated, washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 2.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulphonic acid in the form of a yellow oil.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid

To a stirred solution of 2.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide (0,0063 mol) 3-bromothiophene-2-sulfonic acid and 1.04 g (0,006 mol) 4-forevernow acid in toluene (15 ml) and ethanol (12 ml) under nitrogen atmosphere was added a 2M aqueous solution of sodium carbonate (2 g in 16 ml of water). The reaction mixture was stirred for 15 minutes and then added tetranitropentaerithrite(0). The reaction mixture then was heated at 85°C for 6 hours the Reaction mixture was cooled to room temp the atmospheric temperature and then added ethyl acetate (50 ml). The reaction mixture was concentrated in vacuo and the residual mass was added ethyl acetate (100 ml), then cooled with water, followed by extraction with ethyl acetate (100 ml×2). The combined extract was washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 1.1 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid in the form of oil.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid

Sociallyengaged (0,100 g, 0,0029 mol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran (15 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid (1.1 g, 0,0024 mol) in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, the temperature was then raised to room temperature (28°C) and was stirred for 4 h, the Reaction mixture was treated by adding to the reaction mixture at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (50 ml×2). The joint organization of the institutions layers were washed with water and saturated salt solution, the organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 1.0 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid in the form of oil.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid

To a cooled to 0°C a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid (1.0 g, 0,0022 mol) in 60 ml dichloromethane was added N-ethyldiethanolamine (0.6 ml, 0,0033 mol) followed by slow addition to the reaction mixture solution methanesulfonanilide (0.2 ml, 0,0033 mol) in 10 ml of dichloromethane. The reaction mixture was then heated and stirred at room temperature for 3 hours was Carried out by processing of adding to the reaction mixture was ice-cold water followed by extraction with methylene chloride (25 ml×2). The combined organic extract was washed with diluted hydrochloric acid, then with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, getting 0,700 g (4,5-dimethylisoxazol-3-yl)-(2-m is toxicokinetic)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid in the form of a viscous liquid.

Stage 17: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-chloro-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

4-chloro-5,7-diethyl-1,6-naphthiridine-2-(1H)-he (1 g, 4,22 mmol) was added at 0°C under nitrogen atmosphere to a suspension of sodium hydride (0,242 g 5,04 mmol, 50%) in 10 ml of N,N-dimethylformamide and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was re-cooled to 0°C was added dropwise a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid (2.4 g and 4.65 mmol) in 10 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with 40 ml ethyl acetate, then 10 ml of cold water, the organic phase was separated and the aqueous layer was again extracted with 20 ml ethyl acetate. The combined organic layer was washed with water and saturated salt solution, dried over sodium sulfate and concentrated. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 300 mg (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-chloro-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid.

Stage 18: Synthesis of (4,5-dim is telesocial-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenylsulfonyl-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

Sodium hydride (25 mg, 0.83 mmol 50%) was added to a solution of thiophenol (0.04 ml, 0.44 mmol) in 2 ml DMF and the mixture was stirred until the termination of the boil. Then added portions of the solid mass (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-chloro-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (300 mg, 0.44 mmol, spot-2). The reaction mixture was stirred and heated at 50°C for 2 hours, then poured into water and was stirred for 30 minutes and Then the mixture was acidified with diluted hydrochloric acid to pH 1 and extracted with ethyl acetate. An ethyl acetate layer was washed with water and saturated salt solution. Then the organic layer was dried over sodium sulfate and concentrated, receiving 300 mg (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenylsulfonyl-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid in the form of a viscous mass.

Stage 19: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenylsulfonyl-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

(4,5-Dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenylsulfonyl-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (0.3 g, 0.40 mmol) was placed in ethanol (5 ml), was added 6 N. of chlorestol the portly acid (5 ml) and the reaction mixture was heated under reflux for 2 h at 100°C. The reaction mixture was concentrated in vacuo, the residue thus obtained was diluted with water, then the pH of the solution was brought to pH 5 with saturated sodium bicarbonate solution and was extracted with ethyl acetate (25 ml×2). An ethyl acetate layer was washed with water and saturated salt solution, dried over sodium sulfate and concentrated. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 70 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenylsulfonyl-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid in the form of a white solid.

Molecular formula: C34H32N4O4S3

Molecular weight: 656,84.

1H NMR (DMSO-d6): to 1.19 (t, J=7.2 Hz, 3H), of 1.42 (t, J=7.2 Hz, 3H), of 1.46 (s, 3H), 2,11 (s, 3H), was 2.76-2,78 (m, 2H), 3,47-to 3.52 (m, 2H), 5,48 (s, 2H), 5,80 (s, 1H), 7,11 (d, J=4,8 Hz, 1H), 7,21 (d, J=8,4 Hz, 2H), 7,37 (d, J=8 Hz, 2H), of 7.65 to 7.75 (m, 6H), 7,94 (d, Hz, J=5,2, 1H), 10,83 (s, 1H).

Mass spectrum: (m+1) 657.

Example 4

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(3-benzoyl-6-ethyl-2-methylpyridin-4-intoximeter)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of 1-phenylbutane-1,3-dione

Ethoxide sodium (13.5 g, 0,198 mol) at -5°C was added to a stirred solution of dry ethyl acetate (80 ml, 0,72 m is l). To the reaction mixture at -5°C was added methylvinylketone (20 g, 0.185 mol) and then the temperature of the reaction mixture maintained at 0°C for 12 h, the Reaction mixture was then acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and evaporated, getting 21 grams of yellow solid, which represents a 1-phenylbutane-1,3-dione.

Stage 02: Synthesis of 3-amino-1-phenylbut-2-EN-1-it

A mixture of 1-phenylbutane-1,3-dione (20 g, 0,123 mol) and ammonium acetate (38 g, 0.49 mol) in dry methanol (200 ml) was stirred and heated under reflux for 24 hours the Reaction mixture was concentrated in vacuo and to the residue was added chilled water followed by extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and evaporated, receiving 19 g of yellow solid, which represents a 3-amino-1-phenylbut-2-EN-1-it.

Stage 03: Synthesis of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione

Propionate (7 ml, 0,0763 mol) at 0°C for 30 minutes was added to a solution of acid Melodrama (10 g, 0,069 mol) in pyridine (12 ml, was 0.138 mol) and methylene is loride (50 ml), the temperature of the reaction mixture was allowed to rise to ambient temperature and then was stirred for 1 h, the Reaction mixture was then acidified using 1N. hydrochloric acid, and was extracted with methylene chloride (50 ml×2). The combined extracts were washed with water and saturated salt solution, the organic layer was dried over sodium sulfate and concentrated in vacuum to give 10 g of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of a solid crystalline substance.

Stage 04: Synthesis of 3-benzoyl-6-ethyl-2-methyl-1H-pyridin-4-it

A mixture of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione (17,39 g, 0,087 mol) and 3-amino-1-phenylbut-2-EN-1-it (10 g, 0,062 mol) was stirred and heated at 120°C for 2 h, the Reaction mixture was cooled to room temperature and the crude compound was purified on a column of silica gel using a mixture of 10% methanol:ethyl acetate as eluent, obtaining 5.8 g of 3-benzoyl-6-ethyl-2-methyl-1H-pyridine-4-it is in the form of a yellow solid.

Stage 05: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboron the t (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 06: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture is eremetical for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 07: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) at 0°C was added in portions to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 08: Synthesis of 3-bromothiophene-2-sulphonylchloride

3-Bromothiophene (10 g, 0,0617 mol) were placed in methylene chloride (60 ml) and the resulting solution was cooled to -78°C. Then the reaction mixture at -78 the C was added dropwise chlorosulfonic acid (25 ml, 0,396 mol). The temperature of the reaction mixture was slowly raised to 0°C and maintained for 1 hour. The mixture was then slowly poured into ice-cold water followed by extraction with methylene chloride (100 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over anhydrous sodium sulfate and was evaporated in vacuum, obtaining a solid brown color. The crude compound was purified on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining of 5.4 g of 3-bromothiophene-2-sulphonylchloride.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid

To a solution of 3-amino-4,5-dimethylisoxazole (2 g, 0,0178 mol) in 25 ml of pyridine and dimethylaminopyridine (0,230 g, 0,0019 mol) at 0°C was added 3-bromothiophene-2-sulphonylchloride (5.0 g, 0,01912). Then the temperature of the reaction mixture was slowly raised to room temperature (28°C) and then the reaction mixture was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue was acidified using 1 N. hydrochloric acid to pH 1, followed by extraction with dichloromethane (50 ml×3). The combined organic extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 3.5 g (4,dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid as a brown solid.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid

In a stream of dry nitrogen, sodium hydride (0,600 g of 0.0125 mol, 60% in mineral oil) at -15°C was added in portions to a solution of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid (3.5 g, 0,0103 mol) in N,N-dimethylformamide (30 ml). After complete addition, the reaction mixture was stirred at room temperature for 30 minutes and Then the reaction mixture was re-cooled to 0°C. To the reaction mixture for 30 minutes was added dropwise 2-methoxyethoxymethyl (1.55 g, 0,0124 mol), maintaining the temperature of the reaction mixture to 0°C. the Reaction mixture was stirred at 0°C for 30 min and then at room temperature for 4 h Then the reaction mixture was diluted with ethyl acetate (100 ml) followed by the addition (30 ml) of ice-cold water. The organic layer was separated, washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 2.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulphonic acid in the form of a yellow oil.

Stage 11: Synthesis of (4,5-dimetrios the ol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid

To mix the solution (2.7 g, 0,0063 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid and 4-forevernow acid (1.04 g, 0,006 mol) in toluene (15 ml) and ethanol (12 ml) under nitrogen atmosphere was added a 2M aqueous solution of sodium carbonate (2 g in 16 ml of water). The reaction mixture then was stirred for 15 minutes, then the reaction mixture was added tetranitropentaerithrite(0) (0.40 g, 0,00034 mol). The mixture was heated at 85°C for 6 h and then cooled to room temperature, then added ethyl acetate (50 ml). The reaction mixture was concentrated in vacuo and the residual mass was added ethyl acetate (100 ml), then cooled with water, followed by extraction with ethyl acetate (100 ml×2). The combined extract was washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 1.1 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid in the form of oil.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid

Sociallyengaged (0,100 g, 0,0029 mol) doba is ranged in a stream of nitrogen at 0°C and under stirring to a tetrahydrofuran (25 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid (1.1 g, 0,0024 mol) in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, the temperature was raised to room temperature (28°C) and the mixture was stirred for 4 h, the Reaction mixture was treated by adding at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (50 ml×2). The combined organic layers were washed with water and saturated salt solution, then the organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 1.0 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid in the form of oil.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid

Cooled to 0°C a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid (1.0 g, 0,0022 mol) in 60 ml dichloromethane was added N-ethyldiethanolamine (0.6 ml, 0,0033 mol) followed by slow addition to the reaction mixture solution methanesulfonanilide (0.2 ml, 0,0033 mol) in 10 ml of dichloromethane. The reaction mixture was then heated and stirred at room temperature for 3 hours was Carried out by processing of adding to the reaction mixture of ice water with subsequent ex what Roccia with methylene chloride (25 ml×2). The combined organic extract was washed with diluted hydrochloric acid, then with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, getting 0,700 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid in the form of a viscous liquid.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(3-benzoyl-6-ethyl-2-methylpyridin-4-intoximeter)phenyl]thiophene-2-sulfonic acid

To a stirred solution of 3-benzoyl-6-ethyl-2-methyl-1H-pyridin-4-it (0,294 g, 0,0012 mol) in N,N-dimethylformamide (5 ml) at 0°C in a stream of dry nitrogen gas was added in portions sodium hydride (60% in mineral oil) (0,070 g, 0,0014 mol). After the addition the temperature of the reaction mixture was raised to room temperature and maintained for 30 minutes the Mixture was re-cooled to 0°C, was added dropwise a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid (0.6 g, 0,0011 mol) in 5 ml of dimethylformamide and the mixture was stirred at room temperature for 24 h the Mixture was then Oh what was Adali and was diluted with ethyl acetate (40 ml) followed by addition of water (10 ml) at 0°C, then was extracted with ethyl acetate (50 ml×2), the combined organic extract was washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum, obtaining 0.5 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(3-benzoyl-6-ethyl-2-methylpyridin-4-intoximeter)phenyl]thiophene-2-sulfonic acid resin.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-benzoyl-6-ethyl-2-methylpyridin-4-intoximeter)phenyl]thiophene-2-sulfonic acid

To 0.5 g (0.73 mmol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(3-benzoyl-6-ethyl-2-methylpyridin-4-intoximeter)phenyl]thiophene-2-sulfonic acid at room temperature was added 95%ethanol (5 ml) and 5 ml of 6 N. aqueous solution of hydrochloric acid. The reaction mixture was heated under reflux for 3 h and then concentrated in vacuum. The residue thus obtained was diluted with water and the pH of the solution was brought to pH 5 with sodium bicarbonate solution. Then the mixture was extracted with ethyl acetate (50 ml×2). The combined organic extracts were washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The crude compound was purified using flash chromatography on a column of silica gel using a mixture of g is Xan/ethyl acetate as eluent, receiving 70 mg of an amorphous yellow foam, representing (4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-benzoyl-6-ethyl-2-methylpyridin-4-intoximeter)phenyl]thiophene-2-sulfonic acid.

Molecular formula: C31H29N3O5S2

Molecular weight: 587,71.

1H NMR (DMSO-d6): of 1.26 (t, J=7.2 Hz, 3H), of 1.48 (s, 3H), 2,12 (s, 3H), 2,22 (s, 3H), 2,74-of 2.81 (m, 2H), 5,19 (s, 2H), 6,98-7,01 (m, 1H), 7,11-7,13 (m, 3H), 7,27-7,29 (m, 2H), 7,55-EUR 7.57 (m, 2H), 7,69-to 7.77 (m, 3H), 7,94 (m, 1H), 10,85 (s, 1H).

Mass spectrum: (m+1) 588.

Example 5

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organization is practical layer was dried over sodium sulfate and evaporated in vacuum, receiving the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 02: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 03: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) at 0°C was added in portions to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 04: Synthesis of 3-bromothiophene-2-sulphonylchloride

3-Bromothiophene (10 g, 0,0617 mol) was dissolved in methylene chloride (60 ml) and the solution was cooled to -78°C. Then the reaction mixture at -78°C was added dropwise chlorosulfonic acid (25 ml, 0,396 mol). The temperature of the reaction mixture was slowly raised to 0°C and maintained for 1 hour. The reaction mixture was slowly poured into ice-cold water followed by extraction with methylene chloride (100 ml×3). The combined organic extract was washed with water and saturated salt solution and then dried over anhydrous sodium sulfate, was evaporated is in vacuum, getting a solid brown color. The crude compound was purified on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining of 5.4 g of 3-bromothiophene-2-sulphonylchloride.

Stage 05: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid

To a solution of 3-amino-4,5-dimethylisoxazole (2 g, 0,0178 mol) in 25 ml of pyridine and dimethylaminopyridine (0,230 g, 0,0019 mol) at 0°C was added 3-bromothiophene-2-sulphonylchloride (5.0 g, 0,01912). Then the temperature of the reaction mixture was slowly raised to room temperature (28°C) and then the reaction mixture was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue was acidified using 1 N. hydrochloric acid to pH 1, followed by extraction with dichloromethane (50 ml×3). The combined organic extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 3.5 g (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid as a brown solid.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid

In a stream of dry nitrogen, sodium hydride (0,600 g of 0.0125 mol, 60% in mineral oil) at -15°C was added p is rceme to a solution of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid (3.5 g, 0,0103 mol) in N,N-dimethylformamide (30 ml). After complete addition, the reaction mixture was stirred at room temperature for 30 minutes and Then the reaction mixture was re-cooled to 0°C. To the reaction mixture for 30 minutes was added dropwise 2-methoxyethoxymethyl (1.55 g, 0,0124 mol), maintaining the temperature of the reaction mixture to 0°C. the Reaction mixture was stirred at 0°C for 30 min and then at room temperature for 4 h Then the reaction mixture was diluted with ethyl acetate (100 ml) followed by the addition (30 ml) of ice-cold water. The organic layer was separated, washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 2.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulphonic acid in the form of a yellow oil.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid

To a stirred solution of 2.1 g (0,0063 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid and 4-forevernow acid, 1.04 g (0,006 mol) in toluene (15 ml) and ethanol (12 ml) in almost the re nitrogen was added 2M aqueous sodium carbonate solution (2 g in 16 ml of water). The reaction mixture was stirred for 15 minutes and then added tetranitropentaerithrite(0) (0.40 g, 0,00034 mol). The reaction mixture was heated at 85°C for 6 h, then cooled to room temperature and was added ethyl acetate (50 ml). The reaction mixture was then concentrated in vacuum. To the residual material was added ethyl acetate (100 ml), then cooled with water, followed by extraction with ethyl acetate (100 ml×2). The combined extract was washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using 1:2 hexane/ethyl acetate as eluent, obtaining 1.1 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid in the form of oil.

Stage 08: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid

Sociallyengaged (0,100 g, 0,0029 mol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran followed by the addition (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid (1.1 g, 0,0024 mol) in tetrahydrofuran (15 ml). The reaction mixture was stirred at 0°C for 1 h, then the temperature was raised to room for the Noah temperature (28°C) and was stirred for 4 h The reaction mixture was treated by adding sodium hydroxide solution (1 g dissolved in 100 ml water) at 0°C followed by extraction with ethyl acetate (50 ml×2). The combined organic layers were washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum, obtaining 1.0 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid in the form of oil.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid

To a cooled to 0°C a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid (1.0 g, 0,0022 mol) in 60 ml dichloromethane was added N-ethyldiethanolamine (0.6 ml, 0,0033 mol) followed by slow addition to the reaction mixture solution methanesulfonanilide (0.2 ml, 0,0033 mol) in 10 ml of dichloromethane. The reaction mixture was then heated and stirred at room temperature for 3 hours was Carried out by processing of adding to the reaction mixture was ice-cold water followed by extraction with methylene chloride (25 ml×2). The combined organic extract was washed with diluted hydrochloric acid, then with water and saturated salt solution. The organic layer was dried over what Ulfat sodium and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, getting 0,700 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid in the form of a viscous liquid.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

To a stirred solution of 5,7-diethyl-1H-[1,6]naphthiridine-2-she (0.4 g, 0,0020 mol) in N,N-dimethylformamide (5 ml) at 0°C in a stream of dry nitrogen gas was added in portions sodium hydride (60% in mineral oil) (0,115 g 0,0025 mol). After the addition the temperature of the reaction mixture was raised to room temperature and maintained for 30 minutes, the Reaction mixture was re-cooled to 0°C was added dropwise a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid (1.0 g, 0,0020 mol) in N,N-dimethylformamide (5 ml) and the mixture was stirred at room temperature for 24 h the Reaction mixture then was diluted with ethyl acetate (40 ml), then water (10 ml) at 0°C and then were extracted with ethyl acetate (50 ml×2). The combined extract was washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuo is e, receiving the crude compound. The crude compound was purified on a column of silica gel, using hexane:ethyl acetate as eluent, getting 460 mg (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naftalin-1-yl)phenyl]thiophene-2-sulfonic acid resin.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

To 0,460 g (0.75 mmol) of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-yl)phenyl]thiophene-2-sulfonic acid at room temperature was added 95%ethanol (5 ml) and 5 ml of 6 N. aqueous solution of hydrochloric acid. The reaction mixture was heated under reflux for 3 h and then concentrated in vacuum. The residue thus obtained was diluted with water, the pH of the solution was brought to pH 5 with sodium bicarbonate solution and the mixture was extracted with ethyl acetate (50 ml×2). The combined organic extracts were washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The crude compound was purified using flash chromatography on a column of silica gel using a mixture of l:l hexane/ethyl acetate as eluent, receiving 200 mg of a yellowish foam, before the bringing of a (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid.

Molecular formula: C28H28N4O4S2

Molecular weight: 548,67.

1H NMR (DMSO-d6): of 1.17 (t, J=7.2 Hz, 3H), 1,25 (t, J=7.2 Hz, 3H), 1,45 (s, 3H), 2,10 (s, 3H), 2,70 was 2.76 (m, 2H), 3.04 from-3,11 (m, 2H), of 5.53 (s, 2H), 6,72 (d, J=IO Hz, 1H), 7,12 (d, J=5,2 Hz, 1H), 7,16 (s, 1H), 7.23 percent (d, Hz J=8 2H), 7,39 (d, Hz, J=8, 2H), 7,94 (d, J=4,8 Hz, 1H), 8,24 (d, Hz, J=10, 1H), 10,83 (s, 1H). Mass spectrum: (m-1) 547.

Example 6

(4,5-Dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione

Propionate (35 ml, 0,381 mol) was added over 30 minutes to a solution of acid Melodrama (50 g, 0,345 mol) in pyridine (60 ml, 0,690 mol) and methylene chloride (200 ml) at 0°C, the temperature of the reaction mixture was allowed to rise to ambient temperature and was stirred for 1 h the Mixture was then acidified using 1 N. hydrochloric acid, and was extracted with methylene chloride (200 ml×2). The combined extracts were washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum, receiving 50 g of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of a solid crystalline substance.

Stage 02: Synthesis of 3-acetyl-6-ethyl-2-methyl-1H-pyridin-4-it

A mixture of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione (37,8 g, 0,189 mol) and 4-aminophen-3-EN-2-she (12.5 g, 0,126 mol) was heated under reflux at 120°C for 2 h, the Reaction mixture was cooled and the crude compound was purified on a column of silica gel using a mixture of 10% methanol:ethyl acetate as eluent, receiving 6 g of 3-acetyl-6-ethyl-2-methyl-1H-pyridin-4-it is in the form of a yellow solid.

Stage 03: Synthesis of 1-(4-chloro-6-ethyl-2-methylpyridin-3-yl)ethanone

3-Acetyl-6-ethyl-2-methyl-1H-pyridin-4-one (5 g, or 0.027 mol) at 0°C was added to 10 ml of phosphorus oxychloride. The reaction mixture was heated and stirred at 50°C and kept at this temperature for 8 hours. The reaction mixture was evaporated in vacuum and the residue, thus obtained, was podslushivaet to pH 8 with a saturated solution of sodium bicarbonate, followed by extraction with methylene chloride (50 ml×2). The combined organic extracts were washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated, obtaining 3.2 g of 1-(4-chloro-6-ethyl-2-methylpyridin-3-yl)ethanone in the form of a yellow oil liquid.

Stage 04: Synthesis of 6-ethyl-3,4-dimethyl-1H-pyrazolo[4,3-C]pyridine

1-(4-chloro-6-ethyl-2-methylpyridin-3-yl)alanon (1.7 g, 0,0086 mol) was dissolved in whom canola (20 ml) and to the solution was added hydrazinehydrate (2,15 ml, of 0.038 mol). The reaction mixture was slowly heated to reflux and kept at the boil under reflux for 4 hours. The reaction mixture was evaporated in vacuum and the residue was placed on ice. The solid, thus obtained, was filtered and dried under suction, receiving 1 g of 6-ethyl-3,4-dimethyl-1H-pyrazolo[4,3-c]pyridine.

Stage 05: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered, PR is mawali cold toluene (50 ml) and dried under suction, receiving (130 g) of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 06: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere (5-methylisoxazol-3-yl)carbamino acid tert-butyl ester (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 07: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) at 0°C was added in portions to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction is mesh was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 08: Synthesis of 5-methylthiophene-2-sulphonylchloride

2-methylthiophene (50 g, 0.51 mol) in chloroform at a temperature from -5°C to 0°C was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform (100 ml). The reaction mixture was stirred at 0°C for 3 h and the crude material reaction was slowly placed in ice-cold water followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution, dried over anhydrous sodium sulfate and was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (10.5 g, 0,053 mol) in 15 ml of methylene chloride at 0°C was added to a solution of 3-amino-4,5-dimethylisoxazole (4 g, 0.035 mol) and dimethylaminopyridine (500 mg) in pyridine (20 ml). PEFC is complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 4.0 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and with stirring, sodium hydride (3.4 g, 0.07 mol, 60%dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C and then added dropwise to the reaction mixture of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixtures is ü was cooled to 0°C, added (90 ml) of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture of 25 ml of ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 11: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophosphonate

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. was Slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After time to relax is of the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Step 12: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

To a stirred solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (15 g, 0,037 mol) and ethyl ester of 4-bromo-3-ethoxymethyleneamino acid (11 g, of 0.038 mol) in toluene (120 ml) and ethanol (60 ml) under nitrogen atmosphere was added an aqueous solution of 2M sodium carbonate (4.0 g in 19 ml of water). The reaction mixture was stirred in nitrogen atmosphere for 15 minutes and then added tetranitropentaerithrite(0) (2.15 g, 0,0018 mol). The mixture was heated to 85°C for 6 hours. The reaction mixture was concentrated, to the residue was added ethyl acetate (25 ml), then cooled water and extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated concrete is salt, was dried over sodium sulfate and concentrated completely under vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 8 g of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid as an oily mass.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1.4 g 0,037 mol) at 0°C in a stream of nitrogen was added to a mixed solution of tetrahydrofuran followed by the addition of ethyl ether (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethylene)acetic acid (8 g, 0.014 mol) in 35 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 hour, then the temperature was raised to room temperature and the mixture was stirred for 4 hours. The excess lithium aluminum hydride was destroyed by adding at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sodium sulfate and concentrated completely under vacuum, obtaining 4.7g (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)and the IDA 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid.

Stage 14: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (2,13 ml, 0.012 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (3.2 g, 0,0060 mol) in 10 ml of dichloromethane. The reaction mixture was cooled to 0°C, then the reaction mixture was slowly added methanesulfonamide (0.6 ml, 0,0073 mol). The mixture was stirred at room temperature for 3 hours and then placed in ice water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with diluted hydrochloric acid, then with water and saturated salt solution, the organic layer was dried over sodium sulfate and concentrated, obtaining of 3.3 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine (0,380 g, 0,0021 mol) in N,N-d is methylformamide (5 ml) at -15°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (0.125 g, 0,0026 mol). After complete addition, the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was then re-cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (1.25 g, 0.002 mmol) in 5 ml of N,N-dimethylformamide, and then stirred at room temperature for 24 h the Reaction mixture was then was diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was separated, then washed with water and saturated salt solution, and finally dried over sodium sulfate and evaporated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 1.0 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-Sultonova acid as a viscous oily mass.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylene the olo[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (1.0 g, of 1.46 mmol) at room temperature was added 95%ethanol (7 ml) and 6 N. aqueous solution of hydrochloric acid (7 ml). The reaction mixture was heated under reflux for 3 h and then concentrated in vacuum. The residue thus obtained was diluted with water and the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution. The resulting solution was then acidified to pH 5 with acetic acid and extracted with ethyl acetate (25 ml×2). The combined organic layers were washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 200 mg (4,5-dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C30H35N5O4S2

Molecular weight: 593,76.

1H NMR (DMSO-d6): of 1.02 (t, J=6.8 Hz, 3H), of 1.26 (t, J=6.8 Hz, 3H), 1,49 (s, 3H), and 2.14 (s, 3H), of 2.46 (s, 3H), 2.63 in (s, 3H), was 2.76 (m, 5H), 3,24 of 3.28 (m, 2H), of 4.05 (s, 2H), of 5.55 (s, 2H), of 6.68 (s, 1H), 6,92 (d, 1=1,6 Hz, 1H), 6,99 (d, J=7,6 Hz, 1H), 7,28 (s, 1H), 7,38 (s, 1H), 10,85 (s, 1H).

Mass spectrum: (m+1) 594.

Example 7

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]is aftereden-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving 130 g of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 02: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino to the slots (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 h Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 03: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) at 0°C was added in portions to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, organically the layer was dried over sodium sulfate and evaporated in vacuum, getting 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 04: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. the Temperature of the reaction mixture was kept at 0°C for 3 hours the Crude reaction mass was slowly introduced into ice-cold water followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution, dried over anhydrous sodium sulfate and was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Stage 05: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (10.5 g, 0,053 mol) in (15 ml) of methylene chloride was added at 0°C to a solution of 3-amino-4,5-dimethylisoxazole (4 g, 0.035 mol) and dimethylaminopyridine (500 mg) in pyridine (20 ml). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed the extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 4.0 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

At 0°C with stirring sodium hydride (0.800 to g, 0,166 mol, 60%dispersion in mineral oil) was added to N,N-dimethylformamide (30 ml) followed by addition of 5-methylthiophene-2-sulphonic acid (4,5-dimethylisoxazol-3-yl)amide (4 g, 0,0146 mol). After complete addition, the temperature of the reaction mixture was slowly raised and stirred at ambient temperature for 30 minutes, then the reaction mixture was re-cooled to 0°C and then adding to the reaction mixture dropwise of methoxyethoxymethyl (2.7 g, 0,021 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C, was added (90 ml) of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again the extras who were garofali with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, gaining 3.7 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 07: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution x is Orica ammonium, followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 08: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)-5-methylthiophene-2-sulfonic acid

To a stirred solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (3.4 g, 0,008 mol) and 4-bromobenzaldehyde (1.5 g, 0,0081 mol) in toluene (20 ml) and ethanol (10 ml) under nitrogen atmosphere was added a 2M aqueous solution of sodium carbonate (2,36 g in 11 ml of water). The reaction mixture was stirred in nitrogen atmosphere for 15 minutes, then added tetranitropentaerithrite(0) (0,430 g, 0,00037 mol) and the reaction mixture was heated at 85°C for 6 hours the Mixture was cooled and was added ethyl acetate (25 ml) followed by stirring at room temperature for 10 minutes the Reaction mixture was concentrated and the residue, thus obtained, was dissolved in ethyl acetate (100 ml), further washing with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column with silicagel is m, using a mixture of hexane:ethyl acetate as eluent, obtaining 1.8 g of 3-(4-formylphenyl)-5-methylthiophene-2-(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide in the form of an oily mass.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (0,300 g, 0,0088 mol) was added to tetrahydrofuran at 0°C in dry nitrogen atmosphere followed by the addition (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid (1.8 g, to 0.0039 mol) in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, then the temperature was raised to room temperature and was stirred for 4 hours, the Excess lithium aluminum hydride was destroyed by addition of sodium hydroxide solution (1 g dissolved in 100 ml water) at 0°C followed by extraction with ethyl acetate (50 ml×2). The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 1.5 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulphonic acid in the form of an oily liquid.

Step 10: Synthesis of 3-(4-methysulfonylmethane)-5-methylthiophene-2-(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide

To a solution of (4,5-dimethyl shall isoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (1.5 g, 0,0032 mol) in 20 ml of dichloromethane was added N-ethyldiethanolamine (1.2 ml, 0,0034 mol). The reaction mixture was cooled to 0°C and then the reaction mixture was slowly added methanesulfonamide (0.3 ml, 0,0038 mol). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 3 hours Then the mixture was poured into ice water, followed by extraction with methylene chloride (25 ml×2). The combined extracts were washed with diluted hydrochloric acid, then with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, getting 0.800 to g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)-5-methylthiophene-2-sulphonic acid in the form of a viscous liquid.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 5,7-diethyl-1H-[1,6]naphthiridine-2-it (0,467 g, 2.3 mmol) in N,N-dimethylformamide (3 ml) at -15°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (0,170 g, 3.5 mmol). After adding those is the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 30 minutes Then the reaction mixture was re-cooled to 0°C was added dropwise a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)-5-methylthiophene-2-sulfonic acid (1.2 g, 2.2 mmol) in 10 ml of N,N-dimethylformamide, the reaction mixture was stirred at room temperature for 24 h Then the reaction mixture was diluted with ethyl acetate (40 ml) and water (20 ml). The organic layer was separated, washed with water and saturated salt solution and finally dried over sodium sulfate and evaporated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 1:4 hexane/ethyl acetate as eluent, getting 0,500 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulphonic acid in the form of an oily liquid.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

To a solution of 95%ethanol (6 ml) and 6 N. aqueous solution of hydrochloric acid (6 ml) at room temperature was added (0,500 g, from 0.76 mmol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid. The reaction mixture was then heated with education is the principal refrigerator for 3 h and concentrated in vacuum. The residue thus obtained was diluted with water, the pH of the solution was brought to pH 5 with sodium bicarbonate solution and was extracted with ethyl acetate (30 ml×2). The combined organic extract was washed with water and saturated salt solution, dried over sodium sulfate and concentrated, receiving 400 mg of the crude product, which was purified on a column of silica gel using a mixture of 1:4 hexane/ethyl acetate as eluent, receiving 340 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulphonic acid in the form of a white solid.

Molecular formula: C29H30N4O4S2

Molecular weight: 562,70.

1H NMR (DMSO-d6): of 1.18 (t, J=7.2 Hz, 3H), of 1.26 (t, J=7.2 Hz, 3H), of 1.46 (s, 3H), 2,11 (s, 3H), 2,47 (s, 3H), was 2.76 is 2.80 (m, 2H), 3,12-3,17 (m, 2H), 5,54 (s, 2H), 6,79-for 6.81 (m, 1H), 6,86 (s, 1H), 7,20-7,26 (m, 3H), of 7.36 (d, J=8,4 Hz, 2H), 8,28-8,31 (m, 1H), a 10.74 (s, 1H).

Mass spectrum: (m-1) 561.

Example 8

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenoxy-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of 3-aminomethylenemalonate

A mixture of methylpropionamide (50 g, 0,3842 mol) and ammonium acetate (148 g, 1,921 mol) in dry methanol (500 ml) was stirred and heated under reflux during 2 days. The reaction mixture was cooled and concentrated in vacuum. The residue, thus obtained, was podslushivaet to pH 8 and extracted with ethyl acetate. An ethyl acetate layer was washed with water, saturated salt solution, the organic layer was dried over sodium sulfate and concentrated, gaining 50 g 3-aminomethylenemalonate in the form of a light yellow liquid.

Stage 02: Synthesis of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid

To a mixture of 3-aminomethylenemalonate (50 g, 0,387 mol) and methylpropionamide (50 g, 0.384 mol) in o-xylene (200 ml) was added (50 g) 40A molecular sieves. The reaction mixture was stirred and heated under reflux using a Dean apparatus stark within 5 days. The mixture was cooled to room temperature and the molecular sieves were filtered off from the reaction mixture. The filtrate was concentrated and the crude compound was purified on a column of silica gel using a mixture of 50% dichloromethane:methanol as eluent, obtaining 20 g of the desired product as a white solid.

Stage 03: Synthesis of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid

In a stream of dry nitrogen gas totalization (39 g, 0,197 mol) was added to a stirred suspension of 2,6-diethyl-4-oxo-1,4-dihydropyridines-3-METI is the carboxylate (25 g, 0,119 mol) in acetonitrile (250 ml). After the fall of the initial ectothermy the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and suspended solid product was separated by filtration, obtaining 20 g of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid.

Stage 04: Synthesis of methyl ester of 4-amino-2,6-diethylnicotinamide acid

Methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid (40 g, 0,110 mol) was added at 0°C to concentrated sulfuric acid (57 ml, 1.10 mol) and then the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and poured into ice. the pH of the resulting solution was brought to pH 8 by addition of solid sodium carbonate and the solution then was extracted with dichloromethane (200 ml×2). The combined organic layers were washed with water and saturated salt solution, dried over sodium sulfate and concentrated, gaining 19 g of 4-amino-2,6-diethylpyrazine-3-methylcarbazole in the form of a white solid.

Stage 05: Synthesis of ethyl ether 5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro[1,6]naphthiridine-3-carboxylic acid

Diethylmalonate (15 ml, 0,093 mol) and 4-amino-2,6-diethylpyrazine-3-methylcarbazole (19,0 g, 0.09 mol) is obavljale to the solution ethoxide sodium (7 g, 0.10 mol) in ethanol (60 ml) and the reaction mixture was heated at 150°C and a pressure of 100 psi for 20 hours in an autoclave. The mixture was allowed to cool, the volatiles were removed by evaporation and the resulting semi-solid substance was rubbed with a simple ester, getting a solid white color, which was separated by filtration. The solid was dissolved in water and the solution is then acidified with 1.5 N. hydrochloric acid, getting a solid white color, which was filtered and dried under suction, receiving 11 g of 5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro-1,6-naphthiridine-3-ethylcarboxylate in the form of a white solid.

Stage 06: Synthesis of 5,7-diethyl-4-hydroxy-1H-[1,6]naphthiridine-2-it

5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro-1,6-naphthiridine-3-ethylcarboxylate (11 g) was dissolved in a mixture of water (11 ml), 1,4-dioxane (22 ml) and concentrated hydrochloric acid (11 ml) and the reaction mixture was heated under reflux for 3 hours. The reaction mixture was then cooled and the suspended solid was filtered, washed with ethanol and simple with ether, and dried under suction, obtaining 4.3 g of 5,7-diethyl-4-hydroxy-1,6-naphthiridine-2(1H)-she is not quite white solid.

Stage 07: Synthesis of 4-chloro-5,7-diethyl-1,6-naphthiridine-2(1H)-it

4.3 g (0,mol) 5,7-diethyl-4-hydroxy-1,6-naphthiridine-2(1H)-it was dissolved in 22 ml of phosphorus oxychloride, and the reaction mixture was heated under reflux for 24 hours. The reaction mixture was concentrated, the residue was dissolved in concentrated hydrochloric acid (16 ml) and 22 ml of water and heated under reflux for 4 hours. The mixture was diluted with water and podslushivaet solid sodium bicarbonate, the resulting solid substance was separated by filtration, washed with water and dried under suction, obtaining 3.0 g of 4-chloro-5,7-diethyl-1,6-naphthiridine-2 (1H)-it is in the form of a solid orange color.

Stage 08: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butalbitalboth (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product of the races is varali in hot toluene (200 ml), and after keeping for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 09: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Step 10: Synthesis of 4,5-dimethylisoxazol-3-ylamine

<> Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) at 0°C was added in portions to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 11: Synthesis of 3-bromothiophene-2-sulphonylchloride

3-Bromothiophene (10 g, 0,0617 mol) was dissolved in methylene chloride (60 ml) and the reaction mixture was cooled to -78°C. Then was added dropwise at -78°C chlorosulfonic acid (25 ml, 0,396 mol). The temperature of the reaction mixture was slowly raised to 0°C and maintained for 1 hour. The reaction mixture was slowly poured into ice-cold water followed by extraction with methylene chloride (100 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining a solid brown color. The crude compound was purified chromate what graphy on a column of silica gel, using a mixture of hexane:ethyl acetate as eluent, obtaining of 5.4 g of 3-bromothiophene-2-sulphonylchloride.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid

To a solution of 3-amino-4,5-dimethylisoxazole (2 g, 0,0178 mol) in 25 ml of pyridine and dimethylaminopyridine (0,230 g, 0,0019 mol) at 0°C was added 3-bromothiophene-2-sulphonylchloride (5.0 g, 0,01912). Then the temperature of the reaction mixture was slowly raised to room temperature (28°C) and then the reaction mixture was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue was acidified using 1 N. hydrochloric acid to pH 1, followed by extraction with dichloromethane (50 ml×3). The combined organic extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 3.5 g (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid as a brown solid.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid

In a stream of dry nitrogen, sodium hydride (0,600 g of 0.0125 mol, 60% in mineral oil) at -15°C was added in portions to a solution of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid (3.5 g, 0,0103 mol) in N,-dimethylformamide (30 ml). After complete addition, the reaction mixture was stirred at room temperature for 30 minutes and Then the reaction mixture was re-cooled to 0°C. To the reaction mixture were added for 30 minutes, dropwise 2-methoxyethoxymethyl (1.55 g, 0,0124 mol), maintaining the temperature of the reaction mixture to 0°C. the Reaction mixture was stirred at 0°C for 30 min and then at room temperature for 4 h Then the reaction mixture was diluted with ethyl acetate (100 ml) followed by the addition (30 ml) of ice-cold water. The organic layer was separated, washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 2.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulphonic acid in the form of a yellow oil.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid

To a stirred solution of 2.7 g (0,0063 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid and 4-forevernow acid, 1.04 g (0,006 mol) in toluene (15 ml) and ethanol (12 ml) under nitrogen atmosphere was added 2M aqueous rasterbate sodium (2 g in 16 ml of water). The reaction mixture was stirred for 15 minutes, then added tetranitropentaerithrite(0) (0.40 g, 0,00034 mol). The reaction mixture was heated at 85°C for 6 h, then cooled to room temperature and was added ethyl acetate (50 ml). The mixture was concentrated in vacuo and the residual mass was added ethyl acetate (100 ml), then cooled with water, followed by extraction with ethyl acetate (100 ml×2). The combined extract was washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 1.1 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid in the form of oil.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid

Sociallyengaged (0,100 g, 0,0029 mol) at 0°C was added in a stream of nitrogen to a stirred solution of tetrahydrofuran (15 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid (1.1 g, 0,0024 mol) in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, the temperature was raised to room temperature (28°C) and AC is stirred for 4 hours The reaction mixture was treated by adding at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (50 ml×2). The combined organic layers were washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum, obtaining 1.0 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid in the form of oil.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid

To a cooled to 0°C a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid (1.0 g, 0,0022 mol) in 60 ml dichloromethane was added N-ethyldiethanolamine (0.6 ml, 0,0033 mol) followed by slow addition to the reaction mixture solution methanesulfonanilide (0.2 ml, 0,0033 mol) in 10 ml of dichloromethane. The reaction mixture was then heated and stirred at room temperature for 3 hours was Carried out by processing of adding to the reaction mixture was ice-cold water followed by extraction with methylene chloride (25 ml×2). The combined organic extract was washed with diluted hydrochloric acid, then with water and saturated salt solution. The organic layer was dried with natalitetom sodium and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, getting 0,700 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid in the form of a viscous liquid.

Stage 17: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-chloro-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

4-chloro-5,7-diethyl-1,6-naphthiridine-2-(1H)-he (0.16 g, 0.6 mmol) at 0°C under nitrogen atmosphere was added to a suspension of sodium hydride (0,053 g, 1.0 mmol, 50%) (5 ml), N,N-dimethylformamide and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was re-cooled to 0°C was added dropwise a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid (0,367 g, 0.7 mmol) in 5 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 20 hours and then diluted with 40 ml ethyl acetate, then 10 ml of cold water. The organic phase was separated and the aqueous layer was again extracted with 20 ml ethyl acetate. The combined organic layer was washed with water and saturated salt solution, dried over sodium sulfate and concentrated, obtaining 0,350 g of the crude (4,5-demetrisom the azole-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-chloro-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid in the form of a brown oil.

Stage 18: (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenoxy-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

To a solution of phenol (56 mg, 0.59 mmol) in 3 ml of N,N-dimethylformamide at 0°C was added in portions sodium hydride (31 mg, 0.64 mmol, 50%) and the reaction mixture was stirred until the termination of the boil. Then was added dropwise a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-chloro-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (350 mg, 0.50 mmol) in 3 ml of N,N-dimethylformamide. After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred at room temperature for 14 hours, the Reaction mixture was diluted with ethyl acetate, stirred for 10 minutes, then acidified with diluted hydrochloric acid to pH 5 and extracted with ethyl acetate. The organic layer was separated and washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum, receiving 300 mg of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenoxy-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid in the form of a viscous mass.

Stage 19: (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenoxy-2H-1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

0,30 g (0.41 mmol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenylsulfonyl-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid was dissolved in (5 ml) of ethanol was then added 5 ml of 6 N. hydrochloric acid and the mixture was heated under reflux for 3 hours, the Reaction mixture was then concentrated in vacuo, the residue thus obtained was diluted with water pH of the resulting solution was brought to pH 5 with saturated sodium bicarbonate solution and the mixture was then extracted with ethyl acetate (25 ml×2). An ethyl acetate layer was washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, receiving 20 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenoxy-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid in the form of a white solid.

Molecular formula: C34H32N4O5S2

Molecular weight: 640,77.

1H NMR (DMSO-d6): to 1.19 (t, J=7.2 Hz, 3H), of 1.30 (t, J=7.2 Hz, 3H), of 1.47 (s, 3H), 2,12 (s, 3H), 2,70 was 2.76 (m, 2H), 3,12-3,17 (m, 2H), 5,50 (s, 2H), 7,14-of 7.97 (m, 13H), 10,83 (s, 1H).

Mass spectrum: (m+1) 641.

Example 9

(4-Dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 1-phenylbutane-1,3-dione

Ethoxide sodium (13.5 g, 0,198 mol) was added at -5°C to a stirred solution of dry ethyl acetate (80 ml) to 0.72 mol). To the reaction mixture were added at -5°C methylvinylketone (20 g, 0.185 mol) and then the temperature of the reaction mixture maintained at 0°C for 12 h, the Reaction mixture was then acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and evaporated, getting 21 grams of yellow solid, which represents a 1-phenylbutane-1,3-dione.

Stage 02: Synthesis of 3-amino-1-phenylbut-2-EN-1-it

A mixture of 1-phenylbutane-1,3-dione (20 g, 0,123 mol) and ammonium acetate (38 g, 0.49 mol) in dry methanol (200 ml) was stirred and heated under reflux for 24 hours the Reaction mixture was concentrated in vacuo and to the residue was added chilled water followed by extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Then the organic layer was dried over sodium sulfate and evaporated, receiving 19 g of yellow solid, which represents a 3-amino-1-phenylbut-2-EN-1-it.

Stage 03: Synthesis of 5-(1-hydroxypropylamino)-2,2-di is ethyl-1,3-dioxane-4,6-dione

Propionate (7 ml, 0,0763 mol) was added over 30 minutes to a solution of acid Melodrama (10 g, 0,069 mol) in pyridine (12 ml, was 0.138 mol) and methylene chloride (50 ml) at 0°C, the temperature of the reaction mixture was allowed to rise to ambient temperature and was stirred for 1 h, the Reaction mixture was then acidified using 1 N. hydrochloric acid, and was extracted with methylene chloride (50 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum to give 10 g of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of a solid crystalline substance.

Stage 04: Synthesis of 3-benzoyl-6-ethyl-2-methyl-1H-pyridin-4-it

A mixture of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione (17,39 g, 0,087 mol) and 3-amino-1-phenylbut-2-EN-1-it (10 g, 0,062 mol) was stirred and heated at 120°C for 2 h, the Reaction mixture was purified by chromatography on a column of silica gel, elwira desired fraction of 10%methanol and ethyl acetate, obtaining 5.8 g of 3-benzoyl-6-ethyl-2-methyl-1H-pyridin-4-it is in the form of a yellow solid.

Stage 05: Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)phenylmethanone

3-Benzoyl-6-ethyl-2-methyl-1H-pyridin-4-one (2.7 g, to 0.011 mol) was added p and 0°C to phosphorus oxychloride (8 ml). The reaction mixture was stirred, heated to 50°C and then the temperature was maintained for 8 hours. Was processed, viparita phosphorus oxychloride in a vacuum, and the residue, thus obtained, was podslushivaet to pH 8 with a saturated solution of sodium bicarbonate, followed by extraction with methylene chloride (50 ml×2). The combined organic extracts were washed with water and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and concentrated, obtaining 2.6 g of (4-chloro-6-ethyl-2-methylpyridin-3-yl)phenylmethanone in the form of a yellow oil.

Stage 06: Synthesis of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine

(4-chloro-6-ethyl-2-methylpyridin-3-yl)phenylmethanone (2.5 g 0,0096 mol) was dissolved in ethanol (10 ml) and the reaction mixture was added hydrazinehydrate (2.3 ml, 0,048 mol). The mixture was stirred and heated under reflux for 4 hours. Then the reaction mixture was evaporated in vacuum. To the residue was added ice water and the solid, thus obtained, was filtered and dried under suction, obtaining 1.8 g of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine.

Stage 07: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 say what) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml) and after standing for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 08: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane)under Arriva the temperature of the reaction mixture at -78°C. The reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 09: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions at 0°C to triperoxonane acid (22 ml 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Step 10: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform on balali to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. the reaction Temperature was maintained at 0°C for 3 hours the Crude reaction mass was slowly loaded into the icy water, followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution, dried over anhydrous sodium sulfate and was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in 25 ml of methylene chloride was added at 0°C to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of brown Tverdov the substance.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and with stirring, sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml), followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and the mixture was stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C and then added dropwise to the reaction mixture of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C, was added 90 ml of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on columns is e with silica gel, using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 13: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum produces the 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 14: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

To a stirred solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (15 g, 0,037 mol) and ethyl ester of 4-bromo-3-ethoxymethyleneamino acid (11 g, of 0.038 mol) in toluene (120 ml) and ethanol (60 ml) under nitrogen atmosphere was added a 2M aqueous solution of sodium carbonate (4.0 g in 19 ml of water). The reaction mixture was stirred in nitrogen atmosphere for 15 minutes and then added tetranitropentaerithrite(0) (2.15 g, 0,0018 mol). The reaction mixture was heated at 85°C for 6 hours, then concentrated and to the residue was added ethyl acetate (25 ml), then cooled water, followed by extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution, dried over sodium sulfate and concentrated completely under vacuum. The crude compound was purified by chromatography on a column of silica gel using a mixture of 4:1 hexane/ethyl acetate as eluent, obtaining 8 g of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid as an oily mass.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-metakit kemetyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1.4 g 0,037 mol) was added at 0°C to a stirred solution of tetrahydrofuran (25 ml) in a stream of nitrogen followed by the addition of ethyl ether (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethylene)acetic acid (8 g, 0.014 mol) in 35 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 hour, then the temperature was raised to room temperature and the mixture was stirred for 4 hours. The excess lithium aluminum hydride was destroyed by adding at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sodium sulfate and concentrated completely under vacuum, obtaining 4.7g (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid.

Stage 16: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (2,13 ml, 0.012 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (3.2 g, 0,0060 mol) in 10 ml of dichloromethane. The reaction mixture ohla is given to 0°C, then the reaction mixture was slowly added methanesulfonamide (0.6 ml, 0,0073 mol). The mixture was stirred at room temperature for 3 hours and then placed in ice water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with diluted hydrochloric acid, then with water and saturated salt solution, the organic layer was dried over sodium sulfate and concentrated, obtaining of 3.3 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid.

Stage 17: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine (0,454 g, 0,0019 mol) in N,N-dimethylformamide (6 ml) at -15°C in a stream of dry nitrogen was added in portions sodium hydride (60% in mineral oil) (0,110 g, 0,0023 mol). After complete addition, the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was re-cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethylene the silt ether methanesulfonic acid (1.1 g, 0,0018 mmol) in 6 ml N,N-dimethylformamide. After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and then was stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml) and then adding (10 ml) of cold water. The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 1:4 hexane/ethyl acetate as eluent, obtaining of 0.90 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 18: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

95%ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (10 ml) was added at room temperature with stirring to about 0.90 g (1.20 mmol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid. The reaction mixture is heated is Ali under reflux for 3 h and then concentrated in vacuum. The residue thus obtained was diluted with water and the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution. The reaction solution is then acidified to pH 5 with acetic acid and then was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution and finally dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 1:2 hexane/ethyl acetate as eluent, receiving 100 mg of 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide.

Molecular formula: C35H37N5O4S2

Molecular weight: 655,83.

1H NMR (DMSO-d6): a 1.01 (t, J=6.8 Hz, 3H), of 1.29 (t, J=7,6 Hz, 3H), of 1.47 (s, 3H), 2,11 (s, 3H), 2,47 (s, 3H), 2.63 in (s, 3H), 2,79-of 2.86 (m, 2H), 3,23-3,29 (m, 2H), 4,06 (s, 2H), 5,71 (s, 2H), 6,70 (s, 1H), 6,94-6,97 (m, 1H), 7,11-7,13 (m, 1H), 7,37 (s, 1H), 7,50-7,56 (m, 4H), to 7.64-to 7.67 (m, 2H), 10,71 (s, 1H).

Mass spectrum: (m+1) 656.

Example 10

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(2-methylinosine-4-intoximeter)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1.01 mol) was dissolved in pyridine (200 ml, 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving 130 g of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 02: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-butyl who iti (106 ml, of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 03: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) at 0°C was added in portions to triperoxonane acid (22 ml 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 04: Synthesis of 3-bromothiophene-2-sulphonylchloride

p>

3-Bromothiophene (10 g, 0,0617 mol) was dissolved in methylene chloride (60 ml) and the reaction mixture was cooled to -78°C. Then the reaction mixture at -78°C was added dropwise chlorosulfonic acid (25 ml, 0,396 mol). Then the temperature was slowly raised to 0°C and kept at this temperature for 1 hour. The reaction mixture was slowly poured into cold water followed by extraction with methylene chloride (100 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining a solid brown color. The crude compound was purified on a column of silica gel using a mixture of 4:1 hexane/ethyl acetate as eluent, obtaining of 5.4 g of 3-bromothiophene-2-sulphonylchloride.

Stage 05: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid

To a solution of 3-amino-4,5-dimethylisoxazole (2 g, 0,0178 mol) in (25 ml) in pyridine and dimethylaminopyridine (0,230 g, 0,0019 mol) at 0°C was added 3-bromothiophene-2-sulphonylchloride (5.0 g, 0,01912). Then the temperature of the reaction mixture was slowly raised to room temperature (28°C) and then the reaction mixture was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue was acidified using 1 N. chlorostoma orodno acid, to pH 1, followed by extraction with dichloromethane (50 ml×3). The combined organic extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 3.5 g (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid as a brown solid.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-ethoxymethyl)amide 3-bromothiophene-2-sulfonic acid

To a solution of (4,5-dimethylisoxazol-3-yl)amide 3-bromothiophene-2-sulfonic acid (18.6 g, by 0.055 mol) in N,N-dimethylformamide (60 ml) at -15°C was added in portions sodium hydride (60% in mineral oil) (3,17 g of 0.066 mol). After stirring at room temperature for 30 min, the reaction mixture was cooled to 0°C using a bath of ice and salt. To the reaction mixture dropwise over 30 minutes was added chlorotoxin (of 7.82 g, 0,082 mol), maintaining the temperature of the reaction mixture to 0°C. the Reaction mixture was stirred in a bath of ice and salt for 30 min and then at room temperature for 4 h, the Reaction mixture then was diluted with ethyl acetate (100 ml), then 30 ml of ice cold water, the organic layer was separated, washed with water and saturated salt solution and finally dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica compound is elem, using a mixture of 4:1 hexane/ethyl acetate as eluent, obtaining of 8.2 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulphonic acid in the form of a yellow oil.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-(4-formylphenyl)thiophene-2-sulfonic acid

To mix the solution of 7.8 g, 0,0195 mol) of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-bromothiophene-2-sulfonic acid and 4-forevernow acid (2,96 g, 0,0198 mol) in toluene (60 ml) and ethanol (30 ml) under nitrogen atmosphere was added a 2M aqueous solution of sodium carbonate (6,27 g in 30 ml water) and stirring of the mixture was continued for 15 minutes. Then to the reaction mixture were added tetranitropentaerithrite(0) (1,14 g 0,99 mmol), then heated at 85°C for 6 hours. The reaction mixture was cooled to room temperature and was added 50 ml of ethyl acetate. The reaction mixture was concentrated in vacuo and to the residue thus obtained was added ethyl acetate (100 ml), then cooled water. The layers were separated and the aqueous layer was then extracted with ethyl acetate (100 ml). The combined extract was washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 4:1 hexane/ethyl acetate as eluent, olucha 10.2 g (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-(4-formylphenyl)thiophene-2-sulfonic acid as an oily mass.

Stage 08: Synthesis of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-(4-hydroxymethylene)thiophene-2-sulfonic acid

In a stream of dry nitrogen alumoweld lithium (1.4 g, being 0.036 mol) was added at 0°C to a stirred solution of tetrahydrofuran (20 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-(4-formylphenyl)thiophene-2-sulfonic acid (10.0 g, 0,024 mol) in 50 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, then the temperature was raised to room temperature and stirring was continued for 4 h the Reaction mixture was then cooled to 0°C and the solution was added 50 ml of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (50 ml×2). The organic layer was separated and washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum, obtaining 6.0 g (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-(4-hydroxymethylene)thiophene-2-sulfonic acid in the form of an oily liquid.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid

N-ethyldiethanolamine (3,7 ml, 0.02 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-(4-hydroxymethylene)thiophene-2-sulfonic KIS is the notes (6.0 g, 0,0142 mol) in 60 ml dichloromethane. The reaction mixture was cooled to 0°C and then slowly added to the solution of methanesulfonamide (1,32 ml, 0,0161 mol) in 10 ml of dichloromethane. After the addition the temperature of the reaction mixture maintained at room temperature for 3 hours. Then add ice-cold water followed by extraction with methylene chloride (25 ml×2). The combined organic extract was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, obtaining 6.0 g (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid in the form of a viscous liquid.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-[4-(2-methylinosine-4-intoximeter)phenyl]thiophene-2-sulfonic acid

To a stirred solution of 2-methyl-1H-quinoline-4-it (0.16 g, 1.0 mmol) in N,N-dimethylformamide (5 ml) at 0°C in a stream of dry nitrogen gas was added in portions sodium hydride (60% in mineral oil) (72,0 mg, 1.5 mmol). After complete addition, the temperature of the reaction mixture was raised to room temperature and kept for 30 m is N. The reaction mixture was re-cooled to 0°C was added dropwise a solution of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-(4-methysulfonylmethane)thiophene-2-sulfonic acid (0.5 g, 1.0 mmol) in 5 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 24 h and then was cooled to 0°C, then added ethyl acetate (40 ml), then 10 ml of water. The organic layers were separated, the aqueous layer was extracted with ethyl acetate (50 ml×2) and the combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining the crude compound. The crude compound was purified on a column of silica gel using a mixture of 1:1 hexane/ethyl acetate as eluent, obtaining 510 mg (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-[4-(2-methylinosine-4-intoximeter)phenyl]thiophene-2-sulfonic acid in the form of a viscous liquid.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(2-methylinosine-4-intoximeter)phenyl]thiophene-2-sulfonic acid

To 0.51 g (0.90 mmol) of (4,5-dimethylisoxazol-3-yl)ethoxymethylene 3-[4-(2-methylinosine-4-intoximeter)phenyl]thiophene-2-sulfonic acid at room temperature was added ethanol (6 ml) and 6 ml of 6 N. aqueous solution of hydrochloric acid. The reaction mixture was heated with education is the principal refrigerator for 3 h, then was concentrated in vacuo and the resulting residue was diluted with water. the pH of the resulting solution was brought to pH 5 with sodium bicarbonate solution and was extracted with ethyl acetate (50 ml×2). The combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 1:1 hexane/ethyl acetate as eluent, receiving 90 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(2-methylinosine-4-intoximeter)phenyl]thiophene-2-sulfonic acid in the form of a yellowish solid.

Molecular formula: C26H23N3O4S2

Molecular weight: 505,61.

1H NMR (DMSO-d6): and 1.54 (s, 3H), 2,12 (s, 3H), 2.63 in (s, 3H), 5,41 (s, 2H), 7,12-to 7.18 (m, 2H), of 7.48-7,53 (m, 1H), 7,55-7,58 (m, 2H), to 7.59-to 7.61 (m, 2H), 7.68 per-7,73 (m, 1H), 7,85-7,88 (m, 2H), 8,13-8,16 (m, 1H), of 10.93 (s, 1H).

Mass spectrum: (m-1) 504.

Example 11

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then cooled the received mixture to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 02: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane)under Arriva the temperature of the reaction mixture at -78°C. The reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 03: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions at 0°C to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 04: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform (10 ml) was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. the Reaction mixture was stirred at 0°C for 3 hours the Crude reaction mass was slowly loaded into the icy water, followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Stage 05: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in 25 ml of methylene chloride at 0°C was added to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid in the de brown solid.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and with stirring, sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and the mixture was stirred at ambient temperature for 30 minutes, then the reaction mixture was re-cooled to 0°C and then added dropwise to the reaction mixture of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C, was added 90 ml of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on columns is e with silica gel, using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 07: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum produces the 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 08: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

To a stirred solution of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid (4 g, 0,0139 mol) in dimethoxyethane (50 ml) in a stream of dry nitrogen was added bis(triphenylphosphine)palladium(II)chloride (1 g, 0,00142 mol), then 2M aqueous solution of sodium carbonate (4.3 g in 20 ml water). The reaction mixture was stirred at room temperature for 10 minutes and then was heated to 60°C. To the resulting solution was added dropwise over 45 min a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes After 60 minutes the same procedure was repeated with the subsequent addition of 45 min 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane), and, finally, the reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 hours, the Reaction mixture was cooled to room temperature and was added ethyl acetate (100 ml) followed by addition of water. The organic layers were separated and the aqueous layer was further extragere the Lee ethyl acetate (50 ml×2). The combined organic extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 4:1 hexane/ethyl acetate as eluent, receiving 7 g of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid as a pale yellow oily mass.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1.4 g 0,037 mol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran (20 ml) followed by addition of ethyl ether (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethylene)acetic acid (8 g, 0.014 mol) in 35 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 hour, then the temperature was raised to room temperature and the mixture was stirred for 4 hours, the Excess lithium aluminum hydride was destroyed by adding at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sulfate hydroxide is I and concentrated in vacuum, receiving 4.5 g (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid.

Step 10: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (3,35 ml, 0,0193 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (6.7 g, 0,0127 mol) in 50 ml of dichloromethane. The reaction mixture was cooled to 0°C, then the reaction mixture was slowly added methanesulfonamide (1.8 g, 0,0157 mol). The mixture was stirred at room temperature for 3 hours and then placed in ice water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with diluted hydrochloric acid, then with water and saturated salt solution, the organic layer was dried over sodium sulfate and concentrated, obtaining 7.2 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid as a brown oil.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-ethoxymethyl]-5-IU is althofen-2-sulfonic acid

To a stirred solution of 5,7-diethyl-1H-[1,6]naphthiridine-2-she (0.7 g, 0,00346 mol) in N,N-dimethylformamide (6 ml) at -15°C in a stream of dry nitrogen was added in portions sodium hydride (60% in mineral oil) (0,166 g, 0,00346 mol). After complete addition, the reaction mixture was heated to ambient temperature and maintained for 30 minutes and Then the reaction mixture was re-cooled to 0°C and added dropwise at 0°C solution methanesulfonic acid 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ester (1.9 g, 0,00315 mmol) in 6 ml N,N-dimethylformamide. The temperature of the reaction mixture was slowly raised to room temperature and was stirred for 24 h the Reaction mixture then was diluted with ethyl acetate (40 ml), followed by adding 10 ml of cold water. The organic layer was separated and washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 1:1 hexane/ethyl acetate as eluent, obtaining 1.2 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 1: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

To 1.2 g (1,69 mmol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid at room temperature under stirring was added ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated at 90°C for 3 h and then concentrated in vacuum. The residue thus obtained was diluted with water and the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution. The resulting solution was then extracted with ethyl acetate (35 ml×2) and the combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent receiving 700 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C32H36N4O5S2

Molecular weight: 620,78.

1H NMR (DMSO-d6): and 0.98 (t, J=6.8 Hz, 3H), 1,19 (t, J=6.8 Hz, 3H), 1,24 (t, J=7,6 Hz, 3H), of 1.47 (s, 3H), 2,11 (s, 3H), 2,47 (s, 3H), 2,69 is 2.75 (m, 2H), 3.04 from-3,10 (m, 2H), 3,19-of 3.25 (m, 2H), of 4.05 (s, 2H), 5,52 (s, 2H), 6,70 to 6.75 (m,2H), 6,89-6,92 (m, 1H), 7.03 is-7,06 (m, 1H), 7,16 (s, 1H), 7,32 (s, 1H), 8,23 compared to 8.26 (m, 1H), 10,65 (s, 1H).

Mass spectrum: (m-1) 619.

Example 12

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(3-acetyl-2,6-dimethylpyridin-4-intoximeter)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) t is et-butyl ester (5-methylisoxazol-3-yl)carbamino acid.

Stage 02: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 03: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) at 0°C was added in portions to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture OHL who was waiting to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 04: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. the Reaction mixture was stirred at 0°C for 3 h and the crude reaction mass was slowly introduced into ice-cold water followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Stage 05: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in (25 ml) of methylene chloride at 0°C was added to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised to whom atoi temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Stage 06: Synthesis of (4,5 dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and with stirring, sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) at 0°C was added N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and the mixture was stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C and then adding to the reaction mixture dropwise of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction to the offer was cooled to 0°C, added (90 ml) of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 07: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml 0062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. After the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 08: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

To a stirred solution of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid (4 g, 0,0139 mol) in dimethoxyethane (50 ml) in a stream of dry nitrogen was added bis(triphenylphosphine)palladium(II)chloride (1 g, 0,00142 mol), then 2M aqueous solution of sodium carbonate (4.3 g in 20 ml water). The reaction mixture was stirred at room temperature for 1 min and then was heated at 60°C. To the resulting mixture for 45 minutes was added a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane) and the reaction mixture is then heated the Ali under reflux for 60 minutes After 60 minutes the same procedure was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane). Finally, the reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 hours, the Reaction mixture was cooled to room temperature and was added ethyl acetate (100 ml) followed by addition of water. Then the organic layers were separated and the aqueous layer was further extracted with ethyl acetate (50 ml×2). The combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 4:1 hexane/ethyl acetate as eluent, receiving 7 g of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid as a pale yellow oily mass.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1.4 g 0,037 mol) at 0°C in a stream of nitrogen was added to a mixed solution of tetrahydrofuran (20 ml) and then the addition of ethyl ether (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethylene)acetic acid. (8 g, 0.014 mol) in 35 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 hour, then the temperature was raised to room temperature and the mixture was stirred for 4 hours. The excess lithium aluminum hydride was destroyed by adding at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 4.5 g (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid.

Step 10: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (3,35 ml, 0,0193 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (6.7 g, 0,0127 mol) in 50 ml of dichloromethane. The reaction mixture was cooled to 0°C, then slowly added methanesulfonamide (1.8 g, 0,0157 mol). The reaction mixture was stirred at room temperature for 3 hours and then placed in ice water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with diluted hydrochloric acid, then water is the first and saturated salt solution, the organic layer was dried over sodium sulfate and concentrated, obtaining 7.2 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid as a brown oil.

Stage 11: Synthesis of 3-acetyl-2,6-dimethyl-1H-pyridine-4-it

A mixture of 12 g (0.12 mol) of 4-amino-3-penten-2-she and 25 g (0,176 mol) of 2,2,6-trimethyl-1,3-dioxen-4-it was stirred and heated to 120°C for 3 h in an oil bath. The reaction mixture was cooled to room temperature, selected solid was filtered under vacuum, washed with simple ether and dried under suction, receiving 5 g of white crystalline solids, representing 3-acetyl-2,6-dimethyl-1H-pyridin-4-one.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(3-acetyl-2,6-dimethylpyridin-4-intoximeter)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 3-acetyl-2,6-dimethyl-1H-pyridine-4-it (0,451 g, 0,0027 mol) in N,N-dimethylformamide (6 ml) at -15°C in a stream of dry nitrogen was added dropwise sodium hydride (60% in mineral oil) (0,132 g, 0,00275 mol). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and maintained for 30 minutes R the promo mixture was re-cooled to 0°C was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (1.5 g, 0,00248 mol) in 9 ml of N,N-dimethylformamide. After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred at room temperature for 24 h the Reaction mixture then was diluted with ethyl acetate (40 ml), then (10 ml) of cold water. The organic layer was separated and then washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 1:1 hexane/ethyl acetate as eluent, receiving 800 mg (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(3-acetyl-2,6-dimethylpyridin-4-intoximeter)-2-ethoxymethyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-acetyl-2,6-dimethylpyridin-4-intoximeter)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(3-acetyl-2,6-dimethylpyridin-4-intoximeter)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid (0,80 g, 1,19 mmol) at room temperature was added ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated at 90°C for 3 h, then concentrated in vacuo and the residue, the floor is built in such a way was diluted with water. the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution. The resulting solution was extracted with ethyl acetate (25 ml×2), and the combined organic extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 200 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-acetyl-2,6-dimethylpyridin-4-intoximeter)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C29H33N3O6S2

Molecular weight: 583,72.

1H NMR (DMSO-d6)with 1.07 (t, J=7.2 Hz, 3H), and 1.56 (s, 3H), 2,19 (s, 3H), of 2.28 (s, 3H), 2,42 (s, 3H), 2,48 (s, 6H), 3,28-of 3.32 (m, 2H), 4,11 (s, 2H), 5,27 (s, 2H), 6,76 (s, 1H), 7,02-7,07 (m, 2H), 7,27-7,30 (m, 1H), 7,50 (, 1H), 10,70 (s, 1H).

Mass spectrum: (m-1) 582.

Example 13

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-paraolimpiyskogo[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 1-p-toolbutton-1,3-dione

To 50 ml of N,N-dimethylformamide, cooled to 0°C, was added sodium hydride (60% in mineral oil) (7,49 g, 0.31 mol) followed by the addition of RA is down 4-methylacetophenone (38 g, 0,284 mol) in dry ethyl acetate (56 ml of 0.56 mol). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred at room temperature for 12 hours, the Reaction mixture was then acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined organic extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 41 g of yellow solid, which represents the 1-p-toolbutton-1,3-dione.

Stage 02: Synthesis of 3-amino-1-p-tollbooth-2-EN-1-it

A mixture of 1-p-toolbutton-1,3-dione (41 g, 0.23 mol) and ammonium acetate (71,8 g of 0.93 mol) in dry methanol (200 ml) was stirred at room temperature for 24 h the Reaction mixture was then concentrated completely under vacuum and to the residue was added chilled water and podslushivaet to pH 8 using a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 25 g of 3-amino-1-p-tollbooth-2-EN-1-it.

Stage 03: Synthesis of 4-bromo-3-(methyl bromide)ethylbenzoic

To a solution of the ethyl ester of 4-bromo-3-methylbenzoic acid (28 g, 0.11 mol) in 100 ml of carbon tetrachloride was added 22,65 g (0.12 mol) of N-bromosuccinimide and benzoyl peroxide (1.4 g 0,005 mol, 75% in water) and the mixture was heated under reflux for 10 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue, thus obtained, was purified, triturating with hexane (100 ml)to give a solid product which was filtered and dried under suction, receiving of 17.5 g of 4-bromo-3-(methyl bromide)ethylbenzoic.

Stage 04: Synthesis of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid

To a chilled solution of 4-bromo-3-(methyl bromide)ethylbenzoic (17.5 g, 0,054 mol) in ethanol (30 ml) was added ethoxide sodium (7 g, 0,074 mol) and 12 ml of N,N-dimethylformamide. The reaction mixture was stirred for 4 hours at room temperature and then concentrated in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (100 ml). An ethyl acetate layer was washed with water and saturated salt solution and finally dried over sodium sulfate and evaporated in vacuum, obtaining 12.5 g of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid.

Stage 05: Synthesis of 6-dimethyl-3-(4-methylbenzoyl)-1H-pyridine-4-it

A mixture of 2,2,6-trimethyl[1,3]dioxin-4-it (24,36 g to 0.17 mol) and 3-amino-1-p-tollbooth-2-EN-1-it (15 g, 0,086 mol) was heated fix refrigerator at 120°C for 6 hours The reaction mixture was directly purified by chromatography on a column of silica gel using a mixture of 10% methanol:ethyl acetate as eluent, obtaining 3.2 g of 6-dimethyl-3-(4-methylbenzoyl)-1H-pyridine-4-it.

Stage 06: Synthesis of (4-chloro-2,6-dimethylpyridin-3-yl)partridgemania

To 20 ml of chilled (0°C) of phosphorus oxychloride was added 3.2 g, of 0.013 mol) 6-dimethyl-3-(4-methylbenzoyl)-1H-pyridine-4-it. The reaction mixture was stirred and heated at 100°C for 8 hours. Then the reaction mixture was evaporated in vacuo, and the residue, thus obtained, was podslushivaet to pH 8 with a saturated solution of sodium carbonate followed by extraction with methylene chloride (50 ml×2). The combined organic extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum, obtaining 3.2 g of (4-chloro-2,6-dimethylpyridin-3-yl)-p-tailltean.

Stage 07: Synthesis of 4,6-dimethyl-3-p-tolyl-1H-pyrazolo[4,3-c]pyridine

To (4-chloro-2,6-dimethylpyridin-3-yl)Bartolommeo (3.2 g, 0.01 mol) in ethanol (10 ml) was added hydrazinehydrate (5.8 ml, 0.185 mol) followed by addition of two drops of acetic acid. After complete addition, the temperature of the reaction mixture was slowly raised to boiling point and videris is whether within 6 hours. The reaction mixture was cooled to room temperature and then was evaporated in vacuum. The crude mass was placed on ice, the solid, thus obtained, was filtered and dried under suction, receiving 1.6 g of 4,6-dimethyl-3-p-tolyl-1H-pyrazolo[4,3-c]pyridine.

Stage 08: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) tert-putilovo the ester (5-methylisoxazol-3-yl)carbamino acid.

Stage 09: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Step 10: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) at 0°C was added in portions to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture OHL who was waiting to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 11: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. the Reaction mixture is then kept at 0°C for 3 hours the Crude reaction mass was slowly loaded into the icy water, followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in (25 ml) of methylene chloride was added at 0°C to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised the to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and with stirring, sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and the mixture was stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C and then added dropwise to the reaction mixture of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction to the offer was cooled to 0°C, added 90 ml of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 14: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, 0.02 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 15: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

To a stirred solution of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid (4 g, 0,0139 mol) in dimethoxyethane (50 ml) in a stream of dry nitrogen was added bis(triphenylphosphine)palladium(II)chloride (1 g, 0,00142 mol) followed by addition of 2M aqueous sodium carbonate (4.3 g in 20 ml water). The reaction mixture was stirred at room temperature for 10 minutes and then was heated at 60°C. To the obtained solution for 45 minutes, was added dropwise 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophosphonate (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane), and reacts is injecting the mixture was heated under reflux for 60 minutes After 60 minutes the same procedure was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane). The reaction mixture was then heated under reflux for 4 h and stirred at room temperature for 12 hours the Mixture was cooled to room temperature and was added ethyl acetate (100 ml) followed by addition of water. Then the organic layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml×2). The combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 4:1 hexane/ethyl acetate as eluent, receiving 7 g of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid as a pale yellow oily mass.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1.4 g 0,037 mol) at 0°C in a stream of nitrogen was added to a mixed solution of tetrahydrofuran (80 ml) followed by the addition of this is viewed in ether (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid (8 g, 0.014 mol) in 35 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 hour, then the temperature was raised to room temperature and the mixture was stirred for 4 hours. The excess lithium aluminum hydride was destroyed by adding at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 4.7g (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid.

Stage 17: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl)-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (2,13 ml, 0.012 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (3.2 g, 0,0060 mol) in 30 ml of dichloromethane. The reaction mixture was cooled to 0°C, then the reaction mixture was slowly added methanesulfonamide (0.6 ml, 0,0073 mol). The reaction mixture was stirred at room temperature for 3 hours and then placed in ice water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with diluted hydrochloric Ki is lotay, then water and saturated salt solution, the organic layer was dried over sodium sulfate and concentrated, obtaining of 3.3 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid as a brown oil.

Stage 18: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4,6-dimethyl-3-p-tollerate[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 4,6-dimethyl-3-p-tolyl-1H-pyrazolo[4,3-c]pyridine (0,78 g, 3.3 mmol) in N,N-dimethylformamide (15 ml) at -15°C in a stream of dry nitrogen was added in portions sodium hydride (60% in mineral oil) (0.24 g, 5 mmol). After complete addition, the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was re-cooled to 0°C was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (2 g, 3.3 mmol) in 10 ml of N,N-dimethylformamide and the mixture is then stirred at room temperature for 24 h the Mixture was then cooled to 0°C and was diluted with ethyl acetate (40 ml), then (10 ml) of cold water. The organic layer was separated, the aqueous layer was extracted with ethylacetate is (50 ml×2) and the combined organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 2.2 g of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl 3-[4-(4,6-dimethyl-3-p-tollerate[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 19: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-p-tollerate[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

To 2.2 g (2,95 mmol) of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl 3-[4-(4,6-dimethyl-3-p-tollerate[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid was added at room temperature 95%ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was stirred, heated for 3 h and then the reaction mixture was concentrated in vacuum. The residue thus obtained was diluted with water, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×3). The combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column with silicagel is m, using a mixture of hexane:ethyl acetate as eluent, receiving 300 mg of 3-[4-(4,6-dimethyl-3-p-tollerate[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-(4,5-dimethylisoxazol-3-yl)amide.

Molecular formula: C35H37N5O4S2

Molecular weight: 655,84.

1H NMR (DMSO-d6): a 1.01 (t, J=7.2 Hz, 3H), of 1.47 (s, 3H), 2,11 (s, 3H), 2.40 a (s, 3H), 2,47 (s, 3H), 2,48 (s, 3H), of 2.53 (s, 3H), 3,24-of 3.27 (m, 2H), of 4.05 (s, 2H), of 5.68 (s, 2H), 6,70 (s, 1H), 6,93-to 6.95 (m, 1H), 7,08-7,10 (m, 1H), 7,32-7,34 (m, 3H), 7,51-rate of 7.54 (m, 3H), of 10.75 (s, 1H).

Mass spectrum: (m+1) 656,2.

Example 14

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of l-thiophene-2-ivatan-1,3-dione

Sodium hydride (60% in mineral oil) (4,18 g to 0.17 mol) was added at 0°C in a current of dry nitrogen to 40 ml of N,N-dimethylformamide. To the mixture was added a solution of 2-acetylthiophene (20 g, 0.16 mol) in dry ethyl acetate (31 ml, 0.32 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours, the Reaction mixture was then acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined organic extracts were washed with water and saturated salt solution. The organic layer is dried over sodium sulfate and evaporated, getting 27 g l-thiophene-2-ivatan-1,3-dione.

Stage 02: Synthesis of 3-amino-1-thiophene-2-albut-2-EN-1-it

A mixture of 1-thiophene-2-ivatan-1,3-dione (26.5 g, 0.16 mol) and ammonium acetate (48.6 g, to 0.63 mol) in dry methanol (260 ml) was stirred at room temperature for 24 h the Reaction mixture was concentrated completely under vacuum and to the residue was added chilled water. The reaction mixture was podslushivaet to pH 8 with saturated sodium bicarbonate solution followed by extraction with ethyl acetate (100 ml×2). The combined organic extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated, getting to 16.8 g of 3-amino-1-thiophene-2-albut-2-EN-1-it.

Stage 03: Synthesis of 4-bromo-3-(methyl bromide)ethylbenzoic

To a solution of ethyl ester of 4-bromo-3-methylbenzoic acid (28 g, 0.11 mol) in 100 ml of carbon tetrachloride was added 22,65 g (0.12 mol) of N-bromosuccinimide and benzoyl peroxide (1.4 g 0,005 mol, 75% in water) and the mixture was heated under reflux for 10 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue, thus obtained, was purified, triturating with hexane (100 ml)to give a solid product which was filtered and dried under suction, getting 17,5 is 4-bromo-3-(methyl bromide)ethylbenzoic.

Stage 04: Synthesis of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid

To a cooled (0°C) solution of 4-bromo-3-(methyl bromide)ethylbenzoic (17.5 g, 0,054 mol) in ethanol (30 ml) was added ethoxide sodium (7 g, 0,074 mol) and 12 ml of N,N-dimethylformamide. The reaction mixture was stirred for 4 hours at room temperature and then concentrated in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (100 ml). An ethyl acetate layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 12.5 g of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid.

Stage 05: Synthesis of 2,6-dimethyl-3-(thiophene-2-carbonyl)-1H-pyridine-4-it

A mixture of 2,2,6-trimethyl[1,3]dioxin-4-it (28.6 g, 0.20 mol) and 3-amino-1-thiophene-2-albut-2-EN-1-it (16,8 g, 0.10 mol) was heated under reflux at 120°C for 6 hours, the Residue was directly purified by chromatography on a column of silica gel using a mixture of 10% methanol:ethyl acetate as eluent, obtaining 4.6 g of 2,6-dimethyl-3-(thiophene-2-carbonyl)-1H-pyridine-4-she.

Stage 06: Synthesis of (4-chloro-2,6-dimethylpyridin-3-yl)thiophene-2-ylmethanone

2,6-dimethyl-3-(thiophene-2-carbonyl)-1H-pyridin-4-one (4.6 g, 0.01 mol) at 0°C was added to 30 ml oxychloride f is spore. The mixture was stirred and heated at 100°C for 8 hours. Then the reaction mixture was evaporated in vacuum and the residue, thus obtained, was podslushivaet to pH 8 with a saturated solution of sodium carbonate followed by extraction with methylene chloride (50 ml×2). The combined organic extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum, obtaining 4.35 g (4-chloro-2,6-dimethylpyridin-3-yl)thiophene-2-ylmethanone.

Stage 07: Synthesis of 4,6-dimethyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine

(4-Chloro-2,6-dimethylpyridin-3-yl)thiophene-2-ylmethanol (4.35 g, 0.02 mol) was placed in ethanol (20 ml). To the mixture was added hydrazinehydrate (6 ml, 0.185 mol), then two drops of acetic acid. The temperature was slowly raised, and the mixture was heated under reflux and maintained for 6 hours. The reaction mixture was evaporated in vacuum. The crude mass was placed on ice, the solid, thus obtained, was filtered and dried under suction, getting 4,48 g of 4,6-dimethyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine.

Stage 08: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and ZAT is m the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving 130 g of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 09: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), TF is Riva the temperature of the reaction mixture at -78°C. The reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Step 10: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions at 0°C to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 11: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform (10 ml) was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. the Reaction mixture was stirred at 0°C for 3 hours the Crude reaction mass was slowly loaded into the icy water, followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in 25 ml of methylene chloride was added at 0°C to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid in the de brown solid.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and with stirring, sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and the mixture was stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C and then adding to the reaction mixture dropwise of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C, was added (90 ml) of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on columns is e with silica gel, using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 14: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (70 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum produces the 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 15: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

To a stirred solution of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid (4 g, 0,0139 mol) in dimethoxyethane (50 ml) in a stream of dry nitrogen was added bis(triphenylphosphine)palladium(II)chloride (l g, 0,00142 mol) followed by addition of 2M aqueous sodium carbonate (4.3 g in 20 ml water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. was Added dropwise over 45 minutes a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes After 60 minutes the same procedure was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane). The reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 h the Mixture was then cooled to room temperature and was added ethyl acetate (100 ml) followed by addition of water. The organic layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml is 2). The combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 7 g of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid as a pale yellow oily mass.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1.4 g 0,037 mol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran (70 ml) followed by addition of 8 g (0.014 mol) of ethyl ester of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid in 35 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 hour, then the temperature was raised to room temperature and the mixture was stirred for 4 hours. The excess lithium aluminum hydride was destroyed by adding at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over Sul is the sodium atom was concentrated in vacuum, getting 4.7g (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid.

Stage 17: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (2,13 ml, 0.012 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (3.2 g, 0,0060 mol) in 30 ml of dichloromethane. The reaction mixture was cooled to 0°C, then slowly added methanesulfonamide (0.6 ml, 0,0073 mol). The reaction mixture was stirred at room temperature for 3 hours and then placed in ice water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with diluted hydrochloric acid, then with water and saturated salt solution, the organic layer was dried over sodium sulfate and concentrated, obtaining of 3.3 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid as a brown oil.

Stage 18: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-C]pyridine-1-ylmethyl)-2-ethoxymethylene the]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 4,6-dimethyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine (0,76 g, 3.3 mmol) in N,N-dimethylformamide (15 ml) at -15°C in a stream of dry nitrogen was added in portions sodium hydride (60% in mineral oil) (0.24 g, 5 mmol). After complete addition, the reaction mixture was heated to ambient temperature and was stirred for 30 minutes and Then the reaction mixture was re-cooled to 0°C was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (2 g, 3.3 mmol) in 10 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 24 hours. The mixture then was diluted with ethyl acetate (40 ml), followed by adding 10 ml of cold water. The organic layer was separated, washed with water and saturated salt solution and finally dried over sodium sulfate and evaporated in vacuum, obtaining 2.1 g of the crude 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide as a viscous oily mass.

Stage 19: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-C]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid

To 2.1 g (2.8 mmol) of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid at room temperature was added ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was stirred and heated for 3 h Then the reaction mixture was concentrated in vacuo, the residue thus obtained was diluted with water, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (30 ml×3). The combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 320 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C32H33N5O4S3

Molecular weight: 647,84.

1H NMR (DMSO-d6): a 1.01 (t, J=7.2 Hz, 3H), of 1.47 (s, 3H), 2,12 (s, 3H), 2,47 (s, 3H), of 2.53 (s, 3H), of 2.66 (s, 3H), 3,22-of 3.27 (m, 2H), of 4.05 (s, 2H), 5,69 (s, 2H), 6,70-of 6.71 (m, 1H), 6,93-to 6.95 (m, 1H), 7,06-to 7.09 (m, 1H), 7.23 percent-7,25 (m, 1H), 7,34 (s, 1H), 7,52-7,53 (m, 2H), 7,71-,73 (m, 1H), of 10.76 (s, 1H).

Mass spectrum: (m+1) 648,1.

Example 15

(4,5-Dimethylisoxazol-3-yl)amide 3-{4-[3-(3,5-dimethylpyrazol-1-ylmethyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-ethoxymethyl}-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 1-(3,5-dimethylpyrazol-1-yl)pentane-2,4-dione

Sodium hydride (60% in mineral oil) (8.6 g, 0,179 mol) at 0°C was added in a stream of dry nitrogen to N,N-dimethylformamide (100 ml). To the mixture was added a solution of ethyl ester (3,5-dimethylpyrazol-1-yl)acetic acid (30 g, 0,164 mol) in dry acetone (11,4 ml, 0,196 mol). The reaction mixture was stirred at room temperature for 12 hours, then acidified 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated, obtaining 26 g of 1-(3,5-dimethylpyrazol-1-yl)pentane-2,4-dione

Stage 02: Synthesis of 4-amino-1-(3,5-dimethylpyrazol-1-yl)Penta-3-EN-2-it

A mixture of 1-(3,5-dimethylpyrazol-1-yl)pentane-2,4-dione (26 g, 0,134 mol) and ammonium acetate (52 g, 0,675 mol) in dry methanol (200 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated completely under vacuum and to the residue is obavljale chilled water. The reaction mixture was podslushivaet to pH 8 using a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate (100 ml×2). The combined organic extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated, obtaining 20 g of 4-amino-1-(3,5-dimethylpyrazol-1-yl)Penta-3-EN-2-it.

Stage 03: Synthesis of 4-bromo-3-(methyl bromide)ethylbenzoic

To a solution of ethyl ester of 4-bromo-3-methylbenzoic acid (28 g, 0.11 mol) in 100 ml of carbon tetrachloride was added 22,65 g (0.12 mol) of N-bromosuccinimide and benzoyl peroxide (1.4 g 0,005 mol, 75% in water) and the mixture was heated under reflux for 10 hours. The mixture was then cooled to room temperature, filtered and the filtrate was concentrated. The residue, thus obtained, was purified, triturating with hexane (100 ml)to give a solid product which was filtered and dried under suction, receiving of 17.5 g of 4-bromo-3-(methyl bromide)ethylbenzoic.

Stage 04: Synthesis of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid

To a cooled (0°C) solution of 4-bromo-3-(methyl bromide)ethylbenzoic (17.5 g, 0,054 mol) in ethanol (30 ml) was added ethoxide sodium (7 g, 0,074 mol) and (12 ml) and N,N-dimethylformamide. The reaction mixture was stirred for 4 hours at room temperature and the ATEM concentrated in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (100 ml). An ethyl acetate layer was washed with water and saturated salt solution and finally dried over sodium sulfate and evaporated in vacuum, obtaining 12.5 g of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid.

Stage 05: Synthesis of 3-[2-(3,5-dimethylpyrazol-1-yl)acetyl]-2,6-dimethyl-1H-pyridine-4-it

A mixture of 2,2,6-trimethyl[1,3]dioxin-4-it (30 g, 0.21 mol) and 4-amino-1-(3,5-dimethylpyrazol-1-yl)Penta-3-EN-2-it (20 g, 0.10 mol) was heated under reflux at 120°C for 6 hours, the Reaction mixture was cooled to room temperature and directly purified on a column of silica gel using a mixture of 10% methanol:ethyl acetate as eluent, receiving 6 g of 3-[2-(3,5-dimethylpyrazol-1-yl)acetyl]-2,6-dimethyl-1H-pyridine-4-it.

Stage 06: Synthesis of 1-(4-chloro-2,6-dimethylpyridin-3-yl)-2-(3,5-dimethylpyrazol-1-yl)ethanone

3-[2-(3,5-dimethylpyrazol-1-yl)acetyl]-2,6-dimethyl-1H-pyridin-4-one (6 g, is 0.023 mol) was added at 0°C to 30 ml of phosphorus oxychloride. The reaction mixture was stirred at 30°C for 8 hours. The reaction mixture was evaporated in vacuum and the residue was podslushivaet to pH 8 with a saturated solution of sodium carbonate followed by extraction with methylene chloride (50 ml×2). The combined organic extracts were washed with water and a saturated solution of the Oli. Finally, the organic layer was dried over anhydrous sodium sulfate and concentrated, obtaining 1.8 g of 1-(4-chloro-2,6-dimethylpyridin-3-yl)-2-(3,5-dimethylpyrazol-1-yl)ethanone.

Stage 07: Synthesis of 3-(3,5-dimethylpyrazol-1-ylmethyl)-4,6-dimethyl-1H-pyrazolo[4,3-c]pyridine

1-(4-chloro-2,6-dimethylpyridin-3-yl)-2-(3,5-dimethylpyrazol-1-yl)alanon (1.8 g, 0,0065 mol) was dissolved in ethanol (10 ml). To the mixture was added hydrazinehydrate (3.12 ml, 0,0624 mol) followed by addition of two drops of acetic acid. The temperature was slowly raised, was heated under reflux, and then maintained at boiling for 6 hours. The reaction mixture was cooled to room temperature and then was evaporated in vacuum. The crude mass was placed on ice, and the obtained solid was filtered and dried under suction, receiving 0.5 g of 3-(3,5-dimethylpyrazol-1-ylmethyl)-4,6-dimethyl-1H-pyrazolo[4,3-c]pyridine.

Stage 08: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. The ZAT the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 09: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixtures is ü extinguished a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Step 10: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions at 0°C to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 11: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. the Reaction mixture is then kept at 0°C for 3 hours the Crude reaction mass was slowly loaded into the icy water with subsequent extracti the th chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate and was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in 25 ml of methylene chloride was added at 0°C to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and p is remesiana sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C, followed by adding dropwise to the reaction mixture of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C was added (90 ml) of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 14: Synthesis of 3-harrows-N-(4,5-di is ethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 15: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino key is lots

To a stirred solution of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid (4 g, 0,0139 mol) in dimethoxyethane (50 ml) in a stream of dry nitrogen was added bis(triphenylphosphine)palladium(II)chloride (1 g, 0,00142 mol) followed by addition of 2M aqueous sodium carbonate (4.3 g in 20 ml water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. To the resulting mixture for 45 minutes was added a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes After 60 minutes the same procedure was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5.5 g, 0,0136 mol in 25 ml of dimethoxyethane). The reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 h, then cooled to room temperature and was added ethyl acetate (100 ml) followed by addition of water. Then the organic layers were separated, the aqueous layer was extracted with ethyl acetate (50 ml×2). The combined organic extracts were washed with water and saturated salt solution, and finally the organic layer was dried over sodium sulfate is concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 7 g of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid as a pale yellow oily mass.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1.4 g 0,037 mol) was added at 0°C in a stream of nitrogen with stirring to a tetrahydrofuran (20 ml) followed by addition of ethyl ether (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethylene)acetic acid (8 g, 0.014 mol) in 35 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 hour, then the temperature was raised to room temperature and the mixture was stirred for 4 hours. The excess lithium aluminum hydride was destroyed by adding at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 4.7g (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfones is th acid.

Stage 17: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl-5-methylthiophene-3-yl)-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (2,13 ml, 0.012 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (3.2 g, 0,0060 mol) in 30 ml of dichloromethane. The reaction mixture was cooled to 0°C, then slowly added methanesulfonamide (0.6 ml, 0,0073 mol). The reaction mixture was stirred at room temperature for 3 hours and then placed in ice water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with diluted hydrochloric acid, then with water and saturated salt solution, the organic layer was dried over sodium sulfate and concentrated, obtaining of 3.3 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid as a brown oil.

Stage 18: Synthesis of 3-{4-[3-(3,5-dimethylpyrazol-1-ylmethyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-ethoxymethyl}-5-methylthiophene-2-(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide

To a stirred solution of 3-(3,5-dimethylpyrazol-1-ylmethyl)-4,6-dimethy what-1H-pyrazolo[4,3-c]pyridine (0.45 g, 0,0017 mol) in N,N-dimethylformamide (10 ml) at

-15°C in a stream of dry nitrogen was added in portions sodium hydride (60% in mineral oil) (to 0.127 g, 0,0026 mol). After complete addition, the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was re-cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (1 g, 0,0016 mol) in 10 ml of N,N-dimethylformamide and stirred at room temperature for 24 hours. The mixture then was diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was separated, washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 1.5 g of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{4-[3-(3,5-dimethylpyrazol-1-ylmethyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-ethoxymethyl}-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 19: Synthesis of 3-{4-3-[(3,5-dimethylpyrazol-1-ylmethyl)-4,6-dimethylpyrazolo[4,3-C]pyridine-1-ylmethyl]-2-ethoxymethyl}-5-methylthiophene-2-(4,5-dimethylisoxazol-3-yl)amide

To (1.5 g, a 1.96 mmol) of the crude 3-{4-[3-(3,5-dimethylpyrazol-1-yl is ethyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-ethoxymethyl}-5-methylthiophene-2-(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide at room temperature was added 95%ethanol (10 ml) and 6 N. an aqueous solution of hydrochloric acid (6 ml). The reaction mixture was heated under reflux for 3 h Then the reaction mixture was concentrated in vacuum. The residue thus obtained was diluted with water, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (30 ml×3). The combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 300 mg (4,5-dimethylisoxazol-3-yl)amide 3-{4-[3-(3,5-dimethylpyrazol-1-ylmethyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-ethoxymethyl}-5-methylthiophene-2-sulfonic acid.

Molecular formula: C34H39N7O4S2

Molecular weight: 673,86.

1H NMR (DMSO-d6): of 1.02 (t, J=7.2 Hz, 3H)and 1.51 (s, 3H), 2,02 (s, 3H), 2.13 and (s, 3H), to 2.29 (s, 3H), 2,47 (s, 3H), 2,48 (s, 3H), was 2.76 (s, 3H), 3,22-of 3.27 (m, 2H), Android 4.04 (s, 2H), 5,59 (s, 2H), ceiling of 5.60 (s, 2H), of 5.82 (s, 1H), 6,69 (s, 1H), 6,91-6,93 (m, 1H), 7,00-7,02 (m, 1H), 7,29 (s, 1H), 7,43 (s, 1H), 10,70 (s, 1H).

Mass spectrum: (m-1) 674,2.

Example 16

(4,5-Dimethoxyethoxy-3-yl)amide 3-[2-methoxymethyl-4-(4,5,7-trimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-with Lanovoy acid

Stage 01: Synthesis of N-(3-acetyl-2,6-dimethylpyridin-4-yl)-4-methylbenzenesulfonamide

Totalization (52 g, 0.26 mol) was added to a stirred suspension of 3-acetyl-2,6-dimethyl-1H-pyridine-4-it (20 g, 0.12 mol) in acetonitrile (200 ml). After the fall of the initial ectothermy the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, and suspended solid substance was separated by filtration, obtaining 30 g of N-(3-acetyl-2,6-dimethylpyridin-4-yl)-4-methylbenzenesulfonamide.

Stage 02: Synthesis of 1-(4-amino-2,6-dimethylpyridin-3-ratanana

N-(3-acetyl-2,6-dimethylpyridin-4-yl)-4-methylbenzenesulfonamide (30 g, 0.10 mol) was added at 0°C to concentrated sulfuric acid (30 ml) and then the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and was poured into crushed ice. The pH value of the mixture was brought to pH 8 by addition of solid sodium carbonate and was extracted with dichloromethane (100 ml×3), combined organic phases are washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated, gaining 9 g of 1-(4-amino-2,6-dimethylpyridin-3-ratanana in the form of a solid substance with a low melting point.

Stage 03: Synthesis of 4.57-trimethyl-1H-[1,6]naphthiridine-2-it

1-(4-Amino-2,6-dimethylpyridin-3-ylatason (9 g, 0,054 mol) and (carletonville)triphenylphosphorane (21 g, 0.06 mol) was added to xylene (100 ml), the mixture was stirred and heated under reflux for 6 hours. The reaction mixture was evaporated in vacuo and to the thus obtained residue was added ethoxide sodium (2.1 g) and 20 ml of ethanol. The mixture was stirred, heated to reflux for 6 h, then was evaporated in vacuum and the residue was diluted with water followed by the addition with stirring of concentrated hydrochloric acid. The mixture then was extracted with simple ether. The ether extract was discarded. The aqueous phase was podslushivaet solid potassium carbonate and extracted with ethyl acetate, the organic layer was washed with water and saturated salt solution, dried over sodium sulfate and concentrated, getting to 0.662 g 4,5,7-trimethyl-1H-[1,6]naphthiridine-2-it.

Stage 04: Synthesis of 4-bromo-3-(methyl bromide)ethylbenzoic

To a solution of ethyl ester of 4-bromo-3-methylbenzoic acid (28 g, 0.11 mol) in 100 ml of carbon tetrachloride was added (22,65 g, 0.12 mol) N-bromosuccinimide and benzoyl peroxide (1.4 g 0,005 mol, 75% in water) and the mixture was heated under reflux for 10 hours. The reaction mixture was cooled to room temperature and filtered by the. The filtrate was concentrated and the residue, thus obtained, was purified, triturating with hexane (100 ml)to give a solid product which was filtered and dried under suction, receiving of 17.5 g of 4-bromo-3-(methyl bromide)ethylbenzoic.

Stage 05: Synthesis of ethyl ester of 4-bromo-3-methoxypyrazine acid

To a cooled (0°C) solution of 40 ml of methanol and 3 g (0.05 mol) of sodium methoxide at 0°C was added the solution (13 g, 0.04 mol) of ethyl ester of 4-bromo-3-bromomethylphenyl acid in 12 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature (28-30°C) for 2 h and then evaporated in vacuum. The obtained residue was acidified to pH 1 with diluted hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of ethyl ester of 4-bromo-3-methoxypyrazine acid.

Stage 06: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After the add is placed, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving (130 g) of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 07: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture is eremetical at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 08: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions at 0°C to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 09: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. Then the reaction mixture was stirred at 0°C for 3 hours the Crude p is a promotional mass then slowly loaded into the icy water, followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in 25 ml of methylene chloride was added at 0°C to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and PE is emisiuni sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C and then added dropwise to the reaction mixture of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C, was added (90 ml) of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Step 12: Synthesis of 3-harrows-N-(4,5-dim the Tyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 13: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy to the slots

To a stirred solution of ethyl ester of 4-bromo-3-methoxypyrazine acid (4 g, 0.014 mol) in dimethoxyethane (50 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (1 g, 0,0014 mol) followed by addition of 2M aqueous sodium carbonate (4.3 g in 20 ml water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. To the reaction mixture for 45 minutes, was added dropwise a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (3.1 g, 0,0076 mol in 25 ml of dimethoxyethane), and the reaction mixture then was heated under reflux for 60 minutes in 1 hour same procedure was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (3.1 g, 0,0076 mol in 25 ml of dimethoxyethane). After complete addition, the reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 hours, the Reaction mixture was cooled to room temperature and then was diluted with ethyl acetate (100 ml) and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sulfate is sodium and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 4:1 hexane/ethyl acetate as eluent, getting 5.5 g of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy acid as a pale yellow oily mass.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (0.7 g, 0.018 mol) was added to a mixed solution of tetrahydrofuran (15 ml) at 0°C in a stream of dry nitrogen followed by the addition of a solution of ethyl ester (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy acid (5.5 g, 0,009 mol) in 30 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, then the temperature was raised to room temperature and was stirred for 4 h, the Reaction mixture was then cooled to 0°C was added dropwise a solution of 50 ml of sodium hydroxide (1 g dissolved in 100 ml of water), keeping the temperature at 0°C. was Carried out by subsequent extraction with ethyl acetate (25 ml×2). The organic layer was separated and washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum, p is the ray of 2.7 g (4,5-dimethylisoxazol-3-yl)-2-methoxyethyl)amide 3-(2-ethoxymethyl-4-methylphenylhydrazine)-5-methylthiophene-2-sulfonic acid.

Stage 15: Synthesis of 4-(2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (2 ml, to 0.011 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-2-methoxyethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (2.6 g, 0,0051 mol) in 30 ml of dichloromethane. The reaction mixture was cooled to 0°C and then the reaction mixture was slowly added methanesulfonamide (0.5 ml, 0,0061 mol). After complete addition, the reaction mixture was stirred at room temperature for 3 h and then loaded into the icy water, followed by extraction with methylene chloride (50 ml×2). The combined organic extract was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated, obtaining 2.7 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid.

Stage 16: Synthesis of (4,5-dimethoxyethoxy-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-methoxymethyl-4-(4,5,7-trimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

To peremeshivaemogo 4,5,7-trimethyl-1H-[1,6]naphthiridine-2-it (0,065 g, 0,0034 mol) in N,N-dimethylformamide (10 ml) at -15°C in a stream of dry nitrogen was added in portions sodium hydride (60% in mineral oil) (0.25 g, 0,0052 mol). After complete addition, the reaction mixture was heated to ambient temperature and was stirred for 30 minutes, the Reaction mixture was re-cooled to 0°C was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (2.1 g, 0,0035 mmol) in 10 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 24 h and then was diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was separated, washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude compound, which was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 1 g (4,5-dimethoxyethoxy-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-methoxymethyl-4-(4,5,7-trimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 17: Synthesis of (4,5-dimethoxyethoxy-3-yl)amide 3-[2-methoxymethyl-4-(4,5,7-trimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethylene]-5-methylthiophene-2-sulfonic acid

p>

To (1.0 g, of 1.46 mmol) of (4,5-dimethoxyethoxy-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-methoxymethyl-4-(4,5,7-trimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid at room temperature was added 95%ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 h, then concentrated in vacuo, and the residue thus obtained was diluted with water. the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×3). The combined organic extracts were washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 100 mg (4,5-dimethoxyethoxy-3-yl)amide 3-[2-methoxymethyl-4-(4,5,7-trimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C30H32N4O5S2

Molecular weight: 592,74.

1H NMR (DMSO-d6): of 1.46 (s, 3H), 2,11 (s, 3H), 2.40 a (s, 3H), of 2.46 (s, 3H), 2,69 (s, 3H), 2,89 (s, 3H), 3,11 (s, 3H), 4,01 (s, 2H), 5,49 (s, 2H), is 6.61 (s, 1H), of 6.68 (s, 1H), 6,95 (s, 2H), 7,16 (s, 1H), 7,29 (s, 1H), 10,66 (s, 1H).

Mass spectrum: (m+1593,1.

Example 17

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione

Propionate (35 ml, 0,381 mol) was added at 0°C for 30 minutes to a solution of acid Melodrama (50 g, 0,345 mol) in pyridine (60 ml, 0,690 mol) and methylene chloride (200 ml), the temperature of the reaction mixture was allowed to rise to ambient temperature and was stirred for 1 h, the Reaction mixture was then acidified using 1 N. hydrochloric acid, and was extracted with methylene chloride (200 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, receiving 50 g of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of a solid crystalline substance.

Stage 02: Synthesis of 3-acetyl-6-ethyl-2-methyl-1H-pyridin-4-it

A mixture of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione (37,8 g, 0,189 mol) and 4-aminophen-3-EN-2-she (12.5 g, 0,126 mol) was heated under reflux at 120°C for 2 h, the Reaction mixture was cooled and the crude compound was purified by chromatography on a column of silica gel using with the offer of 10% methanol:ethyl acetate as eluent, receiving 6 g of 3-acetyl-6-ethyl-2-methyl-1H-pyridin-4-it is in the form of a yellow solid.

Stage 03: Synthesis of 1-(4-chloro-6-ethyl-2-methylpyridin-3-yl)ethanone

3-Acetyl-6-ethyl-2-methyl-1H-pyridin-4-one (5 g, or 0.027 mol) at 0°C was added to 10 ml of phosphorus oxychloride. The reaction mixture was heated under stirring to 50°C and kept at this temperature for 8 hours. The reaction mixture then was evaporated in vacuo, and the residue, thus obtained, was podslushivaet to pH 8 with a saturated solution of sodium bicarbonate, followed by extraction with methylene chloride (50 ml×2). The combined organic extracts were washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated, obtaining 3.2 g of 1-(4-chloro-6-ethyl-2-methylpyridin-3-yl)ethanone in the form of a yellow oil liquid.

Stage 04: Synthesis of 6-ethyl-3,4-dimethyl-1H-pyrazolo[4,3-c]pyridine

1-(4-chloro-6-ethyl-2-methylpyridin-3-yl)alanon (1.7 g, 0,0086 mol) was dissolved in ethanol (20 ml) was added hydrazinehydrate (2,15 ml of 0.038 mol). The reaction mixture was slowly heated to reflux and kept at the boil for 4 hours. The reaction mixture then was evaporated in vacuum and the residue, representing the crude compound was unloaded on the ice. The solid, thus obtained, Hotfile revival and dried under suction, receiving 1 g of 6-ethyl-3,4-dimethyl-1H-pyrazolo[4,3-c]pyridine.

Stage 05: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving 130 g of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 06: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tre the-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 07: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions at 0°C to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, organic the ski layer was dried over sodium sulfate and evaporated in vacuum, getting 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 08: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. the Reaction mixture was stirred at 0°C for 3 h and the crude reaction mass is then slowly discharged into ice-cold water followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in 25 ml of methylene chloride was added at 0°C to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. chlorotoluron the acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and with stirring, sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C and then adding to the reaction mixture dropwise of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C was added (90 ml) of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (2 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 11: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction with the ect was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Step 12: Synthesis of methyl ester (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid

To a stirred solution of methyl ester 4-bromo-3-methylbenzoic acid (4.72 in g, 0,0247 mol) in dimethoxyethane (50 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (1.45 g, 0.002 mol) followed by addition of 2M aqueous sodium carbonate (6.5 g in 30 ml water), the reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. the resulting mixture was added dropwise over 45 minutes a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5 g, 0.012 mol in 25 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes in 1 hour same procedure was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5 g, 0.012 mol in 25 ml of dimethoxyethane). The reaction mixture was heated OBR is Tim fridge for 4 h and stirred at room temperature for 12 hours The mixture was cooled and was diluted with ethyl acetate (100 ml) and water, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 4:1 hexane/ethyl acetate as eluent, obtaining 9.7 g of methyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid as a pale yellow oily mass.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1 g, was 0.026 mol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran (15 ml) followed by addition of methyl ester (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid (9.7 g, 0.019 mol) in 75 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, then the temperature was raised to room temperature and was stirred for 4 h, the Reaction mixture was cooled to 0°C was added dropwise a solution of sodium hydroxide (50 ml) (1 g dissolved in 100 ml of water is), maintaining the temperature at 0°C, the mixture was extracted with ethyl acetate (25 ml×2) and the organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel using a mixture of 1:3 hexane/ethyl acetate as eluent, gaining 5.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid.

Stage 14: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid

N-ethyldiethanolamine (3 ml of 0.017 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid (5.7 g, 0.012 mol) in 40 ml of dichloromethane. The reaction mixture was cooled to 0°C and then slowly added methanesulfonamide (1,16 ml, 0.014 mol). After complete addition, the reaction mixture was stirred at room temperature for 3 hours, the Reaction mixture was then placed in a mixture of ice and cold water followed by extraction with methylene chloride (50 ml×2). The combined extract was washed with diluted hydrochloric acid, then with water and saturated races is the thief of salt. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum, receiving 6 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(6-ethyl-3,4-dimethylpyrazolo[4,3-C]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 6-ethyl-3,4-dimethyl-1H-pyrazolo[4,3-c]pyridine (0,59 g, 3.5 mmol) in N,N-dimethylformamide (5 ml) at -15°C in a stream of dry nitrogen was added in portions sodium hydride (60% in mineral oil) (0.26 g, 5.4 mmol). After complete addition, the reaction mixture was heated to ambient temperature and was stirred for 30 minutes, the Reaction mixture was then cooled to 0°C was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid (2 g, 3.5 mmol) in 5 ml of N,N-dimethylformamide. The mixture was then stirred at room temperature for 24 h and then was diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was separated and washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 2 g (4,5-d is methylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(6-ethyl-3,4-dimethylpyrazolo[4,3-C]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid (2 g, of 3.13 mmol) at room temperature was added 95%ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was then concentrated in vacuum and the residue thus obtained was diluted with water, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution. After that, the pH of the solution was brought to pH 5 with acetic acid and then the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, receiving 300 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(6-ethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C28H1 N5O3S2

Molecular weight: 549,72.

1H NMR (DMSO-d6): of 1.26 (t, J=7.2 Hz, 3H), 1,49 (s, 3H), 1.93 and (s, 3H), and 2.14 (s, 3H), 2,47 (s, 3H), 2.63 in (s, 3H), 2,75-of 2.81 (m, 5H), 5,49 (s, 2H), of 6.68 (s, 1H), 6.89 in (s, 2H), 7,10 (s, 1H), 7,37 (s, 1H), 10,80 (s, 1H).

Mass spectrum: (m+1) 550,2.

Example 18

(4,5-dimethylisoxazol-3-yl)amide 3-(4,6-dimethyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 3-benzoyl-2,6-dimethyl-1H-pyridine-4-it

A mixture of 2,2,6-trimethyl[1,3]dioxin-4-it (15 ml, 0.10 mol) and 3-amino-1-phenylbut-2-EN-1-she (5.8 g, being 0.036 mol) was heated under reflux at 120°C for 6 hours, the Reaction mixture was purified by chromatography on a column of silica gel, elwira the desired product 10%methanol and ethyl acetate, receiving 2 g of 3-benzoyl-2,6-dimethyl-1H-pyridine-4-it.

Stage 02: Synthesis of (4-chloro-2,6-dimethylpyridin-3-yl)phenylmethanone

3-Benzoyl-2,6-dimethyl-1H-pyridin-4-one (2 g, 0,008 mol) at 0°C was added to 15 ml of phosphorus oxychloride. The mixture was heated under stirring to 100°C and kept under these conditions for 8 hours. Was processed, pariva phosphorus oxychloride in a vacuum. The obtained residue was podslushivaet to pH 8 with a saturated solution of sodium carbonate followed by extraction with methylene chloride (50 ml is 2). The combined extracts were washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated, obtaining 2 g of (4-chloro-2,6-dimethylpyridin-3-yl)phenylmethanone.

Stage 03: Synthesis of 4,6-dimethyl-3-phenyl-1H-pyrazolo[4,3-C]pyridine

(4-chloro-2,6-dimethylpyridin-3-yl)phenylmethanone (2 g, 0,008 mol) was placed in ethanol (15 ml), then added hydrazinehydrate (3 ml, 0.06 mol) and two drops of acetic acid. The temperature of the reaction mixture was slowly raised, heating under reflux, and heating was continued for 6 hours. The reaction mixture was completely evaporated in a vacuum. The crude mass was unloaded on the ice, the obtained solid was filtered and dried under suction, getting to 1.61 g of 4,6-dimethyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine.

Stage 04: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, is astoral in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving 130 g of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 05: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (35 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). Solid substances is about, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 06: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions at 0°C to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimethylisoxazol-3-ylamine in the form of a yellow solid.

Stage 07: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. the Reaction mixture was stirred at 0°C for 3 hours the Crude reaction mass was slowly dumped in ice cold water followed by extraction with chloroform 100 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate and was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Stage 08: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in 25 ml of methylene chloride was added at 0°C to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and p is remesiana sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C and then added dropwise to the reaction mixture of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C and added to 90 ml of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture of 25 ml of ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Step 10: Synthesis of 3-harrows-N-(4,5-dime the Il-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, 0:038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 11: Synthesis of methyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid

To a stirred solution of methyl ester 4-bromo-3-methylbenzoic acid (4.72 in g, 0,0247 mol) in dimethoxyethane (50 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (1.45 g, 0.002 mol) followed by addition of 2M aqueous sodium carbonate (6.5 g in 30 ml water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. To the mixture was added dropwise over 45 minutes a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5 g, 0.012 mol in 25 ml of dimethoxyethane) and then the reaction mixture was heated under reflux for 60 minutes in 1 hour same procedure was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5 g, 0.012 mol in 25 ml of dimethoxyethane). The reaction mixture was heated under reflux for 4 h and then stirred at room temperature for 12 hours the Mixture was cooled and was diluted with ethyl acetate (100 ml) and water, the organic layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified is on a column of silica gel, using a mixture of 4:1 hexane/ethyl acetate as eluent, obtaining 9.7 g of methyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid as a pale yellow oily mass.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1 g, was 0.026 mol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran (15 ml) followed by addition of methyl ester (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid (9.7 g, 0.019 mol) in 75 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, then the temperature was raised to room temperature and the mixture was stirred for 4 h, the Reaction mixture was cooled to 0°C was added dropwise a solution of sodium hydroxide (50 ml) (1 g dissolved in 100 ml of water), keeping the temperature at 0°C, followed by extraction with ethyl acetate (25 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 1:3 hexane/ethyl acetate as ale the NTA, getting 5.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid.

Stage 13: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid

N-ethyldiethanolamine (3 ml of 0.017 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid (5.7 g, 0.012 mol) in 40 ml of dichloromethane. The reaction mixture was cooled to 0°C and then the reaction mixture was slowly added methanesulfonamide (1,16 ml, 0.014 mol). After complete addition, the reaction mixture was stirred at room temperature for 3 hours the Reaction mixture was discharged into ice-cold water followed by extraction with methylene chloride (50 ml×2). The combined extract was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum, receiving 6 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4,6-dimethyl-3-phenylpyrazole[4,3-c]pyrid the n-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 4,6-dimethyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine (749 mg, 3.5 mmol) in dimethylformamide (15 ml) at -15°C under nitrogen atmosphere was added sodium hydride (60% in mineral oil) (0.24 g, 5 mmol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was again cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid (2 g, 3.5 mmol) in 10 ml of N,N-dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was separated and washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 2.2 g of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4,6-dimethyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-(4,6-dimethyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To (2.2 g, 2,95 mmol) neojidannogo the (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4,6-dimethyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid at room temperature was added ethanol (10 ml) and 6 N. an aqueous solution of hydrochloric acid (8 ml). The reaction mixture was stirred and heated for 3 h, then concentrated in vacuo. The residue thus obtained was diluted with water and then the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (25 ml×3) and the combined organic extract was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 1:1 hexane/ethyl acetate as eluent, receiving 300 mg (4,5-dimethylisoxazol-3-yl)amide 3-(4,6-dimethyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C32H31N5O3S2

Molecular weight: 597,76.

1H NMR (DMSO-d6): of 1.46 (s, 3H), 1.93 and (s, 3H), 2,11 (s, 3H), 2,47 (s, 3H), 2,48 (s, 3H), by 2.55 (s, 3H), 5,63 (s, 2H), 6,69 (s, 1H), 6.89 in-6,91 (m, 1H), 6,98-7,00 (m, 1H), 7,18 (s, 1H), 7,50-to 7.68 (m, 6H), is 10.75 (s, 1H).

Mass spectrum: (m+1) 598,2.

Example 19

(4,5-Dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carb is inovas acid

5-methylisoxazol-3-ylamine (100 g, 1,019 mol) was dissolved in pyridine (200 ml 2,545 mol) and then the resulting mixture was cooled to 0°C. To the reaction mixture were added 1 hour di-tert-butylboronic (245 g, 1.12 mol). After complete addition, the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated at 60-70°C in vacuum. The residue, thus obtained, was dissolved in ethyl acetate (500 ml). An ethyl acetate layer was washed with diluted hydrochloric acid, then with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining the crude product. The crude product was dissolved in hot toluene (200 ml), and after incubation for 2 hours at room temperature, crystallized solid, which was filtered off, washed with cold toluene (50 ml) and dried under suction, receiving 130 g of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid.

Stage 02: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

In a dry nitrogen atmosphere tert-butyl ester (5-methylisoxazol-3-yl)carbamino acid (20 g, 0.10 mol) was dissolved in hexane (150 ml) was added N,N,N',N'-tetramethylethylenediamine (5 ml, 0,221 mol). The reaction mixture then was cooled to -78°C. To the reaction mixture for 30 minutes was added n-utility (106 ml of 0.250 mol, 15%solution in hexane), maintaining the temperature of the reaction mixture at -78°C. the Reaction mixture was stirred for 1 hour and added methyliodide (12 ml, 0.15 mol). After complete addition, the reaction mixture was stirred at -10°C for 4 hours. Then the reaction mixture was extinguished with a saturated solution of ammonium chloride (60 ml). The solid, thus obtained, was filtered off, washed with cold hexane (50 ml) and dried under suction, obtaining 22 g of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid.

Stage 03: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Tert-butyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid (22 g, 0,1036 mol) was added in portions at 0°C to triperoxonane acid (22 ml, 0,3108 mol). After complete addition, the reaction mixture was heated to 60°C and was stirred for 2 hours. The reaction mixture was cooled to room temperature and was podslushivaet a saturated solution of sodium bicarbonate. The product was extracted with methylene chloride (100 ml×2). The organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum, obtaining 9 g of 4,5-dimetil oxazol-3-ylamine in the form of a yellow solid.

Stage 04: Synthesis of 5-methylthiophene-2-sulphonylchloride

A solution of 2-methylthiophene (50 g, 0.51 mol) in chloroform was added to a solution of chlorosulfonic acid (105 ml, 1.53 mol) in chloroform at a temperature from -5°C to 0°C. Then the reaction mixture was stirred at 0°C for 3 hours the Crude reaction mass was slowly unloaded into ice-cold water followed by extraction with chloroform (100 ml×2). The combined extract was washed with water and saturated salt solution. Finally, the organic layer was dried over anhydrous sodium sulfate and was evaporated in vacuum, obtaining 16 g of 5-methylthiophene-2-sulphonylchloride in the form of a brown liquid.

Stage 05: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

A solution of 5-methylthiophene-2-sulphonylchloride (16.0 g, of 0.081 mol) in 25 ml of methylene chloride at 0°C was added to a solution of 3-amino-4,5-dimethylisoxazole (6.2 g, by 0.055 mol) and dimethylaminopyridine (500 mg) in pyridine (40 ml). After complete addition, the temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. The reaction mixture was then concentrated in vacuo, the residue thus obtained was acidified using 1 N. hydrochloric acid, followed by extraction with methylene chloride (100 ml×2). United is xtracta washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated, obtaining 18 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid as a brown solid.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

In a stream of dry nitrogen and with stirring, sodium hydride (3.4 g, 0.07 mol, 60% dispersion in mineral oil) was added at 0°C to N,N-dimethylformamide (40 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid (16.5 g, to 0.060 mol). After complete addition, the temperature of the reaction mixture was slowly raised and the mixture was stirred at ambient temperature for 30 minutes, then cooled the reaction mixture to 0°C and then added dropwise to the reaction mixture of methoxyethoxymethyl (8,03 g, 0,064 mol). After complete addition, the temperature of the reaction mixture was slowly raised to ambient temperature and was stirred for 3 h Then the reaction mixture was cooled to 0°C, was added (90 ml) of ethyl acetate and stirred the reaction mixture for 20 min and then adding to the reaction mixture (25 ml) with ice water. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate (50 ml×2). United is xtracta washed with water and saturated salt solution and dried over sodium sulfate. The organic layer was concentrated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining of 18.2 g (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 07: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

In a dry nitrogen atmosphere a solution of (14 g, of 0.038 mol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid in tetrahydrofuran (80 ml) was cooled to -78°C. To the resulting solution was slowly added n-utility (60 ml, 0,097 mol, 15%solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 hour, then the temperature of the reaction mixture was slowly raised to 0°C and then the reaction mixture was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C and then added triisopropylsilyl (15 ml, holding 0.062 mol). After complete addition, the temperature was slowly raised to 0°C and the reaction mixture was stirred for 1 hour. Then the reaction mixture was cooled to -10°C and the reaction mixture was slowly added to a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×3). The combined extract was washed in the water and a saturated salt solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 15 g of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine in the form of a thick oily mass.

Stage 08: Synthesis of methyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid

To mix the complex solution of methyl ester 4-bromo-3-methylbenzoic acid (4.72 in g, 0,0247 mol) in dimethoxyethane (50 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (1.45 g, 0.002 mol) followed by addition of 2M aqueous sodium carbonate (6.5 g in 30 ml water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. To the mixture was added dropwise over 45 minutes a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5 g, 0.012 mol in 25 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes in 1 hour same procedure was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (5 g, 0.012 mol in 25 ml of dimethoxyethane). The reaction mixture was heated under reflux for 4 h, was stirred at on the th temperature for 12 h, then cooled and diluted with ethyl acetate (100 ml) and water. The organic layers were separated, the aqueous layer was extracted with ethyl acetate (50 ml×2) and the combined extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 4:1 hexane/ethyl acetate as eluent, obtaining 9.7 g of methyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid as a pale yellow oily mass.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (1 g, was 0.026 mol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran (15 ml) followed by addition of methyl ester (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid (9.7 g, 0.019 mol) in 75 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 1 h, then the temperature was raised to room temperature and was stirred for 4 h, the Reaction mixture was cooled to 0°C was added dropwise a solution of sodium hydroxide (50 ml) (1 g dissolved in 100 ml in the s), maintaining the temperature at 0°C. was Carried out by subsequent extraction with ethyl acetate (25 ml×2) and the organic layer was washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified on a column of silica gel using a mixture of 1:3 hexane/ethyl acetate as eluent, gaining 5.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid.

Step 10: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid

N-ethyldiethanolamine (3 ml of 0.017 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid (5.7 g, 0.012 mol) in 40 ml of dichloromethane. The reaction mixture was cooled to 0°C and then the reaction mixture was slowly added methanesulfonamide (1,16 ml, 0.014 mol). After complete addition, the reaction mixture was stirred at room temperature for 3 hours the Reaction mixture is then unloaded into ice-cold water followed by extraction with methylene chloride (50 ml×2). The combined extract was washed with diluted hydrochloric acid, then with water and saturated what astora salt. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum, receiving 6 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 5,7-diethyl-1H-[1,6]naphthiridine-2-it (0.74 g, 3.5 mol) in dimethylformamide (10 ml) at -15°C in a stream of dry nitrogen was added in portions sodium hydride (60% in mineral oil) (260 mg, 5.4 mmol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was then re-cooled to 0°C was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid (2 g, 3.5 mmol) in (10 ml), N,N-dimethylformamide and the mixture is then stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was separated and washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and evaporated in vacuum. The crude compound cleansing is whether on a column of silica gel, using a mixture of hexane:ethyl acetate as eluent, obtaining 1.6 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid (1.6 g, is 2.40 mmol) at room temperature was added ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 h, then concentrated in vacuo and the residue thus obtained was diluted with water. the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution. Then the mixture was extracted with ethyl acetate (25 ml×2) and the combined organic extracts were washed with water and saturated salt solution. Finally, the organic layer was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel using a mixture of 1:1 hexane/ethyl acetate as eluent, receiving 200 mg (4,5-dimetil oxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C30H32N4O4S2

Molecular weight: 576,74.

1H NMR (DMSO-d6): of 1.20 (t, J=7,6 Hz, 3H), 1,25 (t, J=7,6 Hz, 3H), of 1.46 (s, 3H), of 1.92 (s, 3H), 2,10 (s, 3H), 2,47 (s, 3H), 2,70 was 2.76 (m, 2H), 3.04 from-3,10 (m, 2H), 5,46 (s, 2H), 6,70-6,74 (m, 2H), 6,85-6,87 (m, 1H), 6,91-6,92 (m, 1H), 7,14-7,16 (m, 2H), by 8.22-of 8.25 (m, 1H), to 10.62 (s, 1H).

Mass spectrum: (m+1) 577,2.

Example 20

4-{4-[2-(4,5-Dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]-3-methoxymethylethoxy}-2-atelinae-6-carboxylic acid

Stage 01: Synthesis of ethyl ester of 4-[1-methoxycarbonylmethylene]benzoic acid

Ethyl ester of p-aminobenzoic acid (25 g, 0.15 mol) was added to a stirred solution of methylpropionamide (24 g, 0.18 mol) in toluene (200 ml) followed by addition of acetic acid (0.1 ml). After that the reaction mixture was heated under reflux for 24 hours with continuous removal of water using the apparatus of Dean-stark. Then the reaction mixture was cooled to room temperature and evaporated in vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, obtaining 3.0 g of ethyl ester of 4-[1-methoxycarbonylmethylene]benzoic acid in the form of oil.

Stage 02: Synthesis of ethyl ester of 2-ethyl-4-oxo-1,4-dihydroxy the Lin-6-carboxylic acid

Ethyl ester of 4-[1-methoxycarbonylmethylene]benzoic acid (3.0 g, 0.012 mol) was added to diphenyl ether (15 ml) and the reaction mixture was stirred and heated at 250°C for 3 hours. The reaction mixture was cooled to room temperature and was added (250 ml) of hexane and cooled to 15°C. the Crystallized product was filtered in vacuum, washed (100 ml) of hexane and dried under suction, receiving 450 mg of ethyl ester of 2-ethyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid in the form of a solid crystalline substance.

Stage 03: Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid

Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid was carried out according to the stage 02 example 01.

Stage 04: Synthesis of ethyl ester of 4-bromo-3-methoxypyrazine acid

Synthesis of ethyl ester of 4-bromo-3-methoxypyrazine acid was carried out according to the stage 05 of example 16.

Stage 05: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid was carried out according to the stage 04 example 01.

Stage 06: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid was carried out according to the article the Hai 05 example 01.

Stage 07: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Synthesis of 4,5-dimethylisoxazol-3-ylamine carried out according to the stage 06 example 01.

Stage 08: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Step 10: Synthesis of 5-methylthiophene-2-sulphonic acid (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 11: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Step 12: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy acid

To a stirred solution of ethyl ester of 4-bromo-3-methoxypyrazine acid (2.25 g, 8.2 mmol) in dimethoxyethane (25 ml) under nitrogen atmosphere was added bis(t is Ivanishin)palladium(II)chloride (522 mg, 0.7 mmol) followed by addition of 2M aqueous sodium carbonate (2,62 g in 13 ml of water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. was Added dropwise over 45 minutes a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (1.5 g, 3.7 mmol in 25 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes in 1 hour same thing was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (1.5 g, 3.7 mmol in 25 ml of dimethoxyethane), the reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 hours the Reaction mixture was diluted with 100 ml ethyl acetate and water, the layers were separated, the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, obtaining 2.8 g of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy acid as a pale yellow oily mass.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethyl)amide 3-(2-ethoxymethyl-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid was carried out according to the stage 12 example 01.

Stage 14: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid was carried out according to the stage 13 example 01.

Stage 15: Synthesis of ethyl ester of 4-(4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl)-3-methoxymethylethoxy)-2-atelinae-6-carboxylic acid

To a stirred solution of ethyl ester 2-ethyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (450 mg, 1.8 mmol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (130 mg, 2.7 mmol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (1 g, 1.8 mmol) in (10 ml), N,N-dime Informatica and stirred at room temperature for 24 hours The mixture then was diluted with ethyl acetate (30 ml), then 10 ml of cold water, the organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 1 g of the crude ethyl ester of 4-(4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy)-2-atelinae-6-carboxylic acid as a viscous oily mass.

Stage 16: Synthesis of ethyl ester of 4-{4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]-3-methoxymethylethoxy)-2-atelinae-6-carboxylic acid

To 1.0 g of ethyl ester of 4-(4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy)-2-atelinae-6-carboxylic acid at room temperature was added 95%ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel using a mixture of GE is San:ethyl acetate, receiving 200 mg of ethyl ester of 4-{4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]-3-methoxymethylethoxy}-2-atelinae-6-carboxylic acid.

Stage 17: Synthesis of 4-{4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]-3-methoxymethylethoxy)-2-atelinae-6-carboxylic acid

To the ethyl ether of 4-{4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]-3-methoxymethylethoxy}-2-atelinae-6-carboxylic acid (200 mg, 0.3 mmol) was added sodium hydroxide solution (50 mg in 2 ml water) and then adding (5 ml) of methanol. The reaction mixture was stirred at room temperature for 6 hours Then the reaction mixture was evaporated in vacuo, to the residue was added water and was extracted with diethyl ether. The aqueous layer was separated, cooled to 5°C and acidified to pH 2 with diluted hydrochloric acid and was extracted with ethyl acetate (50 ml×2). The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum, obtaining a solid brown color, which is triturated with hexane, filtered under vacuum, washed with hexane and dried under suction, receiving 45 mg of 4-{4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]-3-methoxymethylethoxy}-2-atelinae-6-carboxylic acid as a brown solid.

Mol the molecular formula: C 31H31N3O7S2

Molecular weight: 621,73.

1H NMR (DMSO-d6): a 1.25 (t, J=7,6 Hz, 3H), of 1.36 (s, 3H), of 2.15 (s, 3H), 2,47 (s, 3H), 2.91 in-2,97 (sq, J=7,6 Hz, 2H), 3,18 (s, 3H), of 4.12 (s, 2H), 5,44 (s, 2H), 6,94 (s, 1H), 7,21 (s, 2H), 7,41 (s, 1H), 7,53 (s, 1H), 7,94-of 7.96 (d, J=8,8 Hz, 1H), 8,15-8,18 (DD, J=8,8 Hz, 1H), 8,76 (s, 1H), 10,71 (user., 1H), of 13.05 (user., 1H).

Mass spectrum: (m+1) 622,1.

Example 21

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of l-thiophene-2-ivatan-1,3-dione

In 40 ml of N,N-dimethylformamide at 0°C was added sodium hydride (60% in mineral oil) (4,18 g to 0.17 mol). Then a solution obtained by dissolving 2-acetylthiophene (20 g, 0.16 mol) in dry ethyl acetate (31 ml, 0.32 mol)was added to the reaction mixture. The reaction mixture was stirred at room temperature for 12 hours the Reaction mixture was acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and evaporated, receiving 27 g of 1-thiophene-2-ivatan-1,3-dione.

Stage 02: Synthesis of 3-amino-1-thiophene-2-albut-2-EN-1-it

A mixture of 1-thiophene-2-ivatan-1,3-dione (26.5 g, 0.16 mol) and ammonium acetate (48.6 g, to 0.63 mol) in dry methanol (260 ml) was stirred at on the th temperature for 24 hours The reaction mixture was concentrated completely under vacuum and to the residue was added chilled water. The reaction mixture was podslushivaet to pH 8 using a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and evaporated, getting to 16.8 g of 3-amino-1-thiophene-2-albut-2-EN-1-it.

Stage 03: Synthesis of 2,6-dimethyl-3-(thiophene-2-carbonyl)-1H-pyridine-4-it

A mixture of 2,2,6-trimethyl[1,3]dioxin-4-it (28.6 g, 0.20 mol) and 3-amino-1-thiophene-2-albut-2-EN-1-it (16,8 g, 0.10 mol) was heated under reflux at 120°C for 6 hours, the Reaction mixture was purified by chromatography on a column of silica gel, elwira the desired product 10%methanol and ethyl acetate, obtaining 4.6 g of 2,6-dimethyl(thiophene-2-carbonyl)-1H-pyridine-4-it.

Stage 04: Synthesis of (4-chloro-2,6-dimethylpyridin-3-yl)thiophene-2-ylmethanone

2,6-Dimethyl-3-(thiophene-2-carbonyl)-1H-pyridin-4-one (4.6 g, 0.01 mol) was added to 30 ml of phosphorus oxychloride at 0°C. was Stirred and heated the reaction mixture at 100°C and held for 8 hours. Was processed, viparita phosphorus oxychloride in a vacuum, and the residue was podslushivaet to pH 8 with a saturated solution of sodium carbonate followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with water and saturated rastvorimoi. Was dried over anhydrous sodium sulfate and concentrated, obtaining 4.35 g (4-chloro-2,6-dimethylpyridin-3-yl)thiophene-2-ylmethanone.

Stage 05: Synthesis of 4,6-dimethyl-3-thiophene-2-yl-1H-pyrazolo[4,3-C]pyridine

(4-Chloro-2,6-dimethylpyridin-3-yl)thiophene-2-ylmethanone (4.35 g, 0.02 mol) was placed in ethanol (20 ml) and the reaction mixture was added hydrazinehydrate (6 ml, 0.185 mol) and two drops of acetic acid. Slowly raised the temperature and heated under reflux, while maintaining the boil for 6 hours. The reaction mixture was completely evaporated in a vacuum. The crude mass was unloaded on the ice, the obtained solid was filtered and dried under suction, getting 4,48 g of 4,6-dimethyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine.

Stage 06: Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid

Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid was carried out according to the stage 02 example 01.

Stage 07: Synthesis of ethyl ester of 4-bromo-3-methoxypyrazine acid

Synthesis of ethyl ester of 4-bromo-3-methoxypyrazine acid was carried out according to the stage 05 of example 16.

Stage 08: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid was carried out according to the stage 04 example 01.

Stage 09: Synthesis of tert-b is delovogo ether (4,5-dimethylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid was carried out according to the stage 05 example 01.

Step 10: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Synthesis of 4,5-dimethylisoxazol-3-ylamine carried out according to the stage 06 example 01.

Stage 11: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 14: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 15: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl)-3-methoxymethylethoxy acid

Synthesis of ethyl ester of (4-{2-[(4-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl)-3-methoxymethylethoxy acid was carried out according to the stage 13 example 16.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid was carried out according to the stage 14 example 16.

Stage 17: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl)-3-ethoxymethyleneamino ether methanesulfonate acid

4-{2-[(4,5-Dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy ether methanesulfonate acid was obtained according to stage 15 example 16.

Stage 18: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-C]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 4,6-dimethyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine (433 mg, 1.9 mmol) in N,N-dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (140 mg, 3 mmol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)with livemail]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (1 g, 1.8 mmol) in 10 ml of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water, the organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 2 g of the crude compound which was purified by chromatography on a column of silica gel, receiving 1 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 19: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-C]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid

To 1.0 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid at room temperature was added 95%ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×3). The combined organic extras the CT was washed with water and saturated salt solution, then was dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 100 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C31H31N5O4S3

Molecular weight: 633,80.

1H NMR (DMSO-d6): of 1.46 (s, 3H), 2,12 (s, 3H), 2,47 (s, 3H), 2.49 USD (s, 3H), of 2.66 (s, 3H), 3,14 (s, 3H), Android 4.04 (m, 2H), of 5.68 (s, 2H), 6,69-7,73 (m, 8H), 10,66 (user., 1H).

Mass spectrum: (m+1) 634,3.

Example 22

(4,5-Dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 1-thiophene-2-ivatan-1,3-dione

In 40 ml of N,N-dimethylformamide at 0°C was added sodium hydride (60% in mineral oil) (4,18 g to 0.17 mol). Then to the reaction mixture was added a solution obtained by dissolving 2-acetylthiophene (20 g, 0.16 mol) in dry ethyl acetate (31 ml, 0.32 mol). The reaction mixture was stirred at room temperature for 12 hours the Reaction mixture was acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Dried over surfacematerial and evaporated, getting 27 g of 1-thiophene-2-ivatan-1,3-dione.

Stage 02: Synthesis of 3-amino-1-thiophene-2-albut-2-EN-1-it

A mixture of 1-thiophene-2-ivatan-1,3-dione (26.5 g, 0.16 mol) and ammonium acetate (48.6 g, to 0.63 mol) in dry methanol (260 ml) was stirred at room temperature for 24 h the Reaction mixture was concentrated completely under vacuum and to the residue was added chilled water. The reaction mixture was podslushivaet to pH 8 using a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and evaporated, getting to 16.8 g of 3-amino-1-thiophene-2-albut-2-EN-1-it.

Stage 03: Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid

Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid was carried out according to the stage 02 example 01.

Stage 04: Synthesis of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid

Synthesis of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid was carried out according to the stage 03 example 01.

Stage 05: Synthesis of 6-ethyl-2-methyl-3-(thiophene-2-carbonyl)-1H-pyridine-4-it

A mixture of 2,2-dimethyl-5-propionyl[1,3]dioxane-4,6-dione (15,8 g, 0.08 mol) and 3-amino-1-thiophene-2-albut-2-EN-1-it (11 g, of 0.066 mol) was heated under reflux at 120°C for 6 hours, the Reaction mixture was cooled to room temperature and the eat rubbed with simple ether, the product was filtered in vacuum, washed with simple ether and dried under suction, receiving 6 g of 6-ethyl-2-methyl-3-(thiophene-2-carbonyl)-1H-pyridine-4-it.

Stage 06: Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)thiophene-2-ylmethanone

6-Ethyl-2-methyl-3-(thiophene-2-carbonyl)-1H-pyridin-4-one (6 g, 0,024 mol) was added at 0°C to 30 ml of phosphorus oxychloride. Was stirred and heated the reaction mixture to 100°C and held for 8 hours. Was processed, viparita phosphorus oxychloride in a vacuum, and the residue was podslushivaet to pH 8 with a saturated solution of sodium carbonate followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over anhydrous sodium sulfate and concentrated, obtaining 3 g of (4-chloro-6-ethyl-2-methylpyridin-3-yl)thiophene-2-ylmethanone in the form of a brown oil.

Stage 07: Synthesis of 6-ethyl-4-methyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine

(4-Chloro-6-ethyl-2-methylpyridin-3-yl)thiophene-2-ylmethanol (3 g, to 0.011 mol) was placed in ethanol (20 ml) and the reaction mixture was added hydrazinehydrate (9 ml, 0.185 mol) and two drops of acetic acid. Slowly raised the temperature and heated under reflux, while maintaining the boil for 6 hours, the Reaction mixture was completely evaporated in a vacuum. The crude mass was placed on ice, and the obtained solid was filtered and sushi is whether under suction, obtaining 1.7 g of 6-ethyl-4-methyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine.

Stage 08: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid was carried out according to the stage 04 example 01.

Stage 09: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid was carried out according to the stage 05 example 01.

Step 10: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Synthesis of 4,5-dimethylisoxazol-3-ylamine carried out according to the stage 06 example 01.

Stage 11: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 13: Synthesis of (4,5 dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 14: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-Metacritic and)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 15: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid was carried out according to the stage 15 example 15.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid was carried out according to the stage 16 example 15.

Stage 17: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid was carried out according to the stage 17 example 15.

Stage 18: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-C]pyridine-1-ylmethyl)Fe is Il]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 6-ethyl-4-methyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine (448 mg, 1.8 mmol) in N,N-dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (132 mg, 2.5 mmol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (1 g, 1.8 mmol) in (8 ml) of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 2 g of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 19: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-C]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

To 2 g of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-atok imethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid at room temperature was added ethanol (10 ml) and 6 N. an aqueous solution of hydrochloric acid (8 ml). The reaction mixture was stirred and heated for 3 hours the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (30 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 200 mg (4,5-dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C33H35N5O4S3

Molecular weight: 661,87.

1H NMR (DMSO-d6): 1,10 (t, J=6.8 Hz, 3H), 1,242 to 1.31 (m, 6H), of 1.47 (s, 3H), 2,12 (s, 3H), 2,47 (s, 3H), to 2.67 (s, 3H), 2,80-2,85 (sq, J=7,6 Hz, 2H), 3,23 of 3.28 (sq, J=6,8 Hz, 2H), 4,06 (s, 2H), 5,71 (s, 2H), 6,69 (s, 1H), 6,94-of 6.96 (d, J=7,6 Hz, 1H), 7,08-7,10 (d, J=7,6 Hz, 1H), 7.23 percent-of 7.25 (m, 1H), 7,35 (s, 1H), 7,45 (s, 2H), 7,71-7,73 (d, J=5,2 Hz, 1H), 10,63 (user., 1H).

Mass spectrum: (m+1) 662,3.

Example 23

(4,5-Dimethylisoxazol-3-yl)amide 3-{2-ethoxymethyl-4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 1-(4-methoxyphenyl)butane-1,3-d is it

In 30 ml at 0°C N,N-dimethylformamide was added sodium hydride (60% in mineral oil) (8.8 g, 0,219. mol) followed by a solution of dry ethyl acetate (15.5 g, 0,175 mol) and 1-(4-methoxyphenyl)ethanone (22 g, 0,145 mol). The reaction mixture was stirred at room temperature for 6 hours the Reaction mixture was acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and evaporated, obtaining 22 g of 1-(4-methoxyphenyl)butane-1,3-dione.

Stage 02: Synthesis of 3-amino-1-(4-methoxyphenyl)but-2-EN-1-it

A mixture of 1-(4-methoxyphenyl)butane-1,3-dione (22 g, 0,114 mol) and ammonium acetate (26,3 g, 0,342 mol) in dry methanol (150 ml) was stirred at room temperature for 24 h the Reaction mixture was concentrated completely under vacuum and to the residue was added chilled water. The reaction mixture was podslushivaet to pH 8 using a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and evaporated, obtaining 20 g of 3-amino-1-(4-methoxyphenyl)but-2-EN-1-it.

Stage 03: Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid

Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid was carried out with the stage according 02 example 01.

Stage 04: Synthesis of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid

Synthesis of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid was carried out according to the stage 03 example 01.

Stage 05: Synthesis of 6-ethyl-3-(4-methoxybenzoyl)-2-methyl-1H-pyridin-4-it

A mixture of 2,2,6-trimethyl-5-propionyl[1,3]dioxin-4-it (15 g, 0,075. mol) and 3-amino-1-(4-methoxyphenyl)but-2-EN-1-it (12 g, 0,062. mol) was heated under reflux at 120°C for 6 hours, the Reaction mixture was purified, triturating the crude reaction mixture with simple ether, separated thus, the solid was filtered under vacuum, washed with simple ether and dried under suction, receiving 2.4 g of 6-ethyl-3-(4-methoxybenzoyl)-2-methyl-1H-pyridin-4-it.

Stage 06: Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)-(4-methoxyphenyl)methanone

6-Ethyl-3-(4-methoxybenzoyl)-2-methyl-1H-pyridin-4-one (2.4 g) was added at 0°C to phosphorus oxychloride (15 ml). Was stirred and heated the reaction mixture to 100°C and held for 8 hours. Was processed, viparita phosphorus oxychloride in a vacuum, and the residue was podslushivaet to pH 8 with a saturated solution of sodium carbonate followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over anhydrous sodium sulfate and concentrated, obtaining of 2.44 g (4-chloro-6-ethyl-2-metile the one-3-yl)-(4-methoxyphenyl)methanone.

Stage 07: Synthesis of 6-ethyl-3-(4-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-C]pyridine

(4-Chloro-6-ethyl-2-methylpyridin-3-yl)-(4-methoxyphenyl)methanon (2,44 g, 0,0084 mol) was placed in ethanol (20 ml) and the reaction mixture was added hydrazinehydrate (3 ml) and two drops of acetic acid. Slowly raised the temperature and heated under reflux, while maintaining the boil for 6 hours. The reaction mixture was completely evaporated in a vacuum. The crude mass was placed on ice, and the obtained solid was filtered and dried under suction, receiving 1.7 g of 6-ethyl-3-(4-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine.

Stage 08: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid was carried out according to the stage 04 example 01.

Stage 08: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid was carried out according to the stage 05 example 01.

Stage 09: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Synthesis of 4,5-dimethylisoxazol-3-ylamine carried out according to the stage 06 example 01.

Step 10: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

One hundred of the Oia 11: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 13: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 14: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid was carried out according to the stage 15 example 15.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid was carried out according to the stage 16 example 15.

Stage 16: the synth is C 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid was carried out according to the stage 17 example 15.

Stage 17: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{2-ethoxymethyl-4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid

To a stirred solution of 6-ethyl-3-(4-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine (492 mg, 1.8 mmol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (132 mg, 2.5 mmol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (1 g, 1.8 mmol) in 10 ml of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 2 g of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{2-atok imethyl-4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 18: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-{2-ethoxymethyl-4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid

To 2 g of the crude (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{2-ethoxymethyl-4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid at room temperature was added ethanol (13 ml) and 6 N. aqueous solution of hydrochloric acid (10 ml). The reaction mixture was stirred and heated for 3 hours the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (30 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 70 mg (4,5-dimethylisoxazol-3-yl)amide 3-{2-ethoxymethyl-4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid.

Molecular formula: C36H39N5O5S2

Molecular weight: 685,87.

1H NMR (DMSO-d6): of 1.02 (t, J=7.2 Hz, 3H), of 1.27 (t, J=7.2 Hz, 3H), of 1.48 (s, 3H), 2,12 (s, 3H), of 2.45 (s, 3H), 2,48 (s, 3H), 2,79-2,85 (sq, J=7 Hz, 2H), 3,23-3,29 (sq, J=6,8 Hz, 2H), of 3.84 (s, 3H), 4,07 (s, 2H), 5,70 (s, 2H), 6,70-to 7.59 (m, 10H), 10,75 (user., 1H).

Mass spectrum: (m+1) 686,3.

Example 24

(4,5-Dimethylisoxazol-3-yl)amide 3-{4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 1-(4-methoxyphenyl)butane-1,3-dione

Synthesis of 1-(4-methoxyphenyl)butane-1,3-dione was carried out according to the stage 01 of example 23.

STAGE 02: Synthesis of 3-amino-1-(4-methoxyphenyl)but-2-EN-1-it

Synthesis of 3-amino-1-(4-methoxyphenyl)but-2-EN-1-it was carried out according to the stage 02 of example 23.

Stage 03: Synthesis of 6-ethyl-3-(4-methoxybenzoyl)-2-methyl-1H-pyridin-4-it

Synthesis of 6-ethyl-3-(4-methoxybenzoyl)-2-methyl-1H-pyridin-4-it was carried out according to the stage 05 of example 23.

Stage 04: Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)-(4-methoxyphenyl)methanone

Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)-(4-methoxyphenyl)methanone carried out according to the stage 06 of example 23.

Stage 05: Synthesis of 6-ethyl-3-(4-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine

Synthesis of 6-ethyl-3-(4-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine was carried out according to the stage 07 of example 23.

Stage 06: Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (5-methylisoxazol-3-yl)carbamino caloriecounter according to stage 04 example 01.

Stage 07: Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid

Synthesis of tert-butyl methyl ether (4,5-dimethylisoxazol-3-yl)carbamino acid was carried out according to the stage 05 example 01.

Stage 08: Synthesis of 4,5-dimethylisoxazol-3-ylamine

Synthesis of 4,5-dimethylisoxazol-3-ylamine carried out according to the stage 06 example 01.

Stage 09: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 11: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Step 12: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 13: Synthesis of methyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)self mail]-5-methylthiophene-3-yl}-3-methylbenzoic acid

Synthesis of methyl ester (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid was carried out according to the stage 08 of example 19.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 of example 19.

Stage 15: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid

Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid was carried out according to the stage 10 of example 19.

Stage 16: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid

To a stirred solution of 6-ethyl-3-(4-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine (642 mg, 2.4 mmol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (173 mg, 3.6 mmol). After the addition the reaction mixture was heated to a temperature which s environmental and kept for 30 minutes The reaction mixture was cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid (1.2 g, 2.4 mmol) in 10 ml of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 2 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 17: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-{4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-C]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid (2 g) at room temperature was added 95%ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo and the pH of the solution was brought to pH 8 by the use of what Finance saturated solution of sodium bicarbonate. The reaction solution is then acidified to pH 5 with acetic acid and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, receiving 170 mg (4,5-dimethylisoxazol-3-yl)amide 3-{4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid.

Molecular formula: C34H35N5O4S2

Molecular weight: 641,8.

1H NMR (DMSO-d6): of 1.29 (m, 3H), of 1.46 (s, 3H), of 1.94 (s, 3H), 2,11 (s, 3H), 2,47 (s, 3H), 2,79-to 2.85 (m, 2H), 3,85 (s, 4H), 5,62 (s, 2H), 6,68-to 7.59 (m, 11N), is 10.68 (user., 1H).

Mass spectrum: (m+1) 642,3.

Example 25

(5-Methylisoxazol-3-yl)amide 2-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-3-sulfonic acid

Stage 01: Synthesis of 1-phenylbutane-1,3-dione

Synthesis of 1-phenylbutane-1,3-dione was carried out according to the stage 01 of example 9.

Stage 02: Synthesis of 3-amino-1-phenylbut-2-EN-1-it

Synthesis of 3-amino-1-phenylbut-2-EN-1-it was carried out according to the stage 02 of example 9.

Stage 03: Synthesis of 5-(1-hydroxypropylamino)-2,2-dimethyl-1,3-dioxane-4,6-dione

Synthesis of 5-(1-hydroxypropyl) - Rev. DIN)-2,2-dimethyl-1,3-dioxane-4,6-dione was carried out according to the stage 03 of example 9.

Stage 04: Synthesis of 3-benzoyl-6-ethyl-2-methyl-1H-pyridin-4-it

Synthesis of 3-benzoyl-6-ethyl-2-methyl-1H-pyridin-4-it was carried out according to the stage 04 of example 9.

Stage 05: Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)phenylmethanone

Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)phenylmethanone carried out according to the stage 05 of example 9.

Stage 06: Synthesis of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine

Synthesis of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine was carried out according to the stage 06 of example 9.

Stage 07: Synthesis of 2-bromo-5-methylthiophene-3-sulphonylchloride

2-Bromo-5-methylthiophene (5 g, 0,0282 mol) was added at 15°C to a mixture of chlorosulfonic acid (4,7 ml, 0,0705 mol) and pentachloride phosphorus (g, mol). Maintained the reaction mixture at 15°C for 10 min the Crude reaction mass was slowly unloaded into ice-cold water followed by extraction simple diisopropyl ether (100 ml×2). The combined organic extract was washed with water and saturated salt solution. Dried the organic layer over anhydrous sodium sulfate and was evaporated in vacuum, obtaining 6.3 g of 2-bromo-5-methylthiophene-3-sulphonylchloride in the form of a brown liquid.

Stage 08: Synthesis of (5-methylisoxazol-3-yl)amide, 2-bromo-5-methylthiophene-3-sulfonic acid

2-Bromo-5-methylthiophene-3-sulphonylchloride (6.3 g, 0,0229 mol) in methylene chloride (50 ml) was added at 0°C to RA is Toro 3-amino-5-methylisoxazole (3,37 g, 0,0344 mol) in pyridine (50 ml) and dimethylaminopyridine (280 mg). The temperature was slowly raised to room temperature and was stirred for 6 hours. Concentrated the reaction mixture completely in vacuo, acidified reaction mixture with 1 N. hydrochloric acid followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated, receiving 6 g (5-methylisoxazol-3-yl)amide, 2-bromo-5-methylthiophene-3-sulfonic acid as a brown solid.

Stage 09: Synthesis ethoxymethyl(5-methylisoxazol-3-yl)amide, 2-bromo-5-methylthiophene-3-sulfonic acid

Sodium hydride (0.64 g, 0,0267 mol) was added at 0°C to a stirred solution of dimethylformamide (15 ml) followed by addition of (5-methylisoxazol-3-yl)amide, 2-bromo-5-methylthiophene-3-sulfonic acid (6.0 g, 0,0178 mol). Slowly raised the temperature and kept at ambient temperature for 30 minutes, then was cooled to 0°C followed by the addition at 0°C ethoxymethylene (2,02 g, 0,0214 mol). After complete addition, the temperature was slowly raised to ambient temperature and was stirred for 3 hours was Added to the reaction mixture of 90 ml of ethyl acetate, then with 25 ml of ice water. The organic layer was separated, water SNO is and was extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, receiving of 4.45 g ethoxymethyl(5-methylisoxazol-3-yl)amide, 2-bromo-5-methylthiophene-3-sulphonic acid in the form of a yellowish oil.

Step 10: Synthesis of ethoxymethyl(5-methylisoxazol-3-yl)amide 2-(4-formylphenyl)-5-methylthiophene-3-sulfonic acid

To mix the solution ethoxymethyl(5-methylisoxazol-3-yl)amide, 2-bromo-5-methylthiophene-3-sulfonic acid (3 g, 0,00076 mol) and 4-formylphenylboronic acid (1,026 g, 0,00684 mol) in toluene (60 ml) and ethanol (50 ml) under nitrogen atmosphere was added a 2M aqueous solution of sodium carbonate (2,417 g 11.4 ml of water). Stirred the reaction mixture under nitrogen atmosphere for 15 minutes, then added to the reaction mixture tetranitropentaerithrite(0) (0,791 g, 0,00068 mol). The reaction mixture was heated at 85°C for 6 hours the Reaction mixture was concentrated in vacuum. To the residue was added ethyl acetate (25 ml), then cooled water and extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated completely under vacuum. The crude compound was purified by chromatography on a column of silica gel, receiving 2.3 g ethoxymethyl(5-methylisoxazol the-3-yl)amide 2-(4-formylphenyl)-5-methylthiophene-3-sulfonic acid as an oily mass.

Stage 11: the Synthesis ethoxymethyl(5-methylisoxazol-3-yl)amide 2-(4-hydroxymethylene)-5-methylthiophene-3-sulfonic acid

To mix the solution ethoxymethyl(5-methylisoxazol-3-yl)amide 2-(4-formylphenyl)-5-methylthiophene-3-sulfonic acid (2.3 g, 0,0055 mol) in 35 ml of tetrahydrofuran at 0°C in a stream of nitrogen was added sodium borohydride (0,249 g, 0,0066 mol) followed by the addition of 2 drops of water. Stirred the reaction mixture at ambient temperature for 1 h, the Reaction mixture was evaporated in vacuo, to the residue was added 1 n solution of hydrochloric acid followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sodium sulfate and concentrated completely under vacuum. The crude product was purified by chromatography on a column of silica gel using a mixture of ethyl acetate:hexane as eluent, getting 740 mg ethoxymethyl(5-methylisoxazol-3-yl)amide 2-(4-hydroxymethylene)-5-methylthiophene-3-sulfonic acid.

Step 12: Synthesis of 4-{3-[ethoxymethyl(5-methylisoxazol-3-yl)sulfamoyl]-5-methylthiophene-2-yl)benzyl ether methanesulfonate acid

N-ethyldiethanolamine (0.6 ml, 0,00344 mol) was added to a solution of ethoxymethyl(5-methylisoxazol-3-yl)amide 2-(4-hydroxymethylene)-5-methylthiophene-3-sulfonic acid (740 mg, 0,00175 mol) in 15 ml dichloromethane. Cooled the reaction mixture to 0°C, Rea is operating and the mixture was added slowly methanesulfonanilide (0.2 ml, 0,00251 mol). The reaction mixture was stirred at room temperature for 3 hours the Reaction mixture was discharged into ice-cold water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with diluted hydrochloric acid, then with water and saturated salt solution. Dried the organic layer over sodium sulfate and concentrated, obtaining 1.24 g of 4-{3-[ethoxymethyl(5-methylisoxazol-3-yl)sulfamoyl]-5-methylthiophene-2-yl)benzyl ether methanesulfonate acid.

Stage 13: Synthesis ethoxymethyl(5-methylisoxazol-3-yl)amide 2-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-3-sulfonic acid

To a stirred solution of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine (452 mg, 0,00191 mol) in dimethylformamide (6 ml) at -0°C in an atmosphere of nitrogen was added in portions sodium hydride (60% in mineral oil) (69 mg, 0,00287 mol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{3-[ethoxymethyl(5-methylisoxazol-3-yl)sulfamoyl]-5-methylthiophene-2-yl}benzyl ether methanesulfonate acid (1.24 g, 0,00248 mol) in 6 ml of dimethylformamide and stirred at room temperature for 5 hours the Mixture then was diluted with ethyl acetate (40 ml), then 10 m the cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 1.35 g ethoxymethyl(5-methylisoxazol-3-yl)amide 2-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-3-sulphonic acid in the form of a viscous oily mass.

Stage 14: Synthesis of (5-methylisoxazol-3-yl)amide 2-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-3-sulfonic acid

To ethoxymethyl(5-methylisoxazol-3-yl)amide 2-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-3-sulfonic acid (1.35 g) at room temperature was added 95%ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (6 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo and the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution followed by extraction with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel using a mixture of hexane/ethyl acetate as eluent, getting 182 mg (5-methylisoxazol-3-yl)amide 2-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]-methylthiophene-3-sulfonic acid.

Molecular formula: C31H29N5O3S2

Molecular weight: 583,72.

1H NMR (DMSO-d6): of 1.28 (t, J=7,6 Hz, 3H), to 2.29 (s, 3H), 2,48 (s, 3H), 2,61 (s, 3H), 2,74-2,84 (sq, J=7.2 Hz, 2H), 5,69 (s, 2H), 7,31-the 7.65 (m, N), 11,55 (user., 1H).

Mass spectrum: (m+1) 584,3.

Example 26

3-{4-[2-(3,4-Dimethylisoxazol-5-ylsulphonyl)-5-methylthiophene-3-yl]benzyl}-2-ethoxy-3H-benzimidazole-4-carboxylic acid

Stage 01: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 02: Synthesis of (3,4-dimethylisoxazol-5-yl)amide 5-methylthiophene-2-sulfonic acid

5-methylthiophene-2-sulphonylchloride (10.5 g, 0,053 mol) in methylene chloride (50 ml) was added at 0°C to a solution of 3,4-dimethylisoxazol-5-ylamine (5 g, 0,044 mol) in pyridine (20 ml) and dimethylaminopyridine (500 mg). The temperature was slowly raised to room temperature and was stirred for 6 hours. Concentrated the reaction mixture completely in a vacuum, the reaction mixture was acidified with 1 N. hydrochloric acid followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated to give 10 g of a mixture of (3,4-dimethylisoxazol-5-yl)amide 5-methylthiophene-2-sulfones is th acid and in the form of a brown solid.

Stage 03: Synthesis of (3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)amide 5-methylthiophene-2-sulfonic acid

Sodium hydride (0,726 g, 0,0182 mol) was added at 0°C to a stirred solution of dimethylformamide (30 ml) followed by addition of (3,4-dimethylisoxazol-5-yl)amide 5-methylthiophene-2-sulfonic acid (3.3 g, 0.012 mol). The temperature was slowly raised and kept at ambient temperature for 30 minutes, then was cooled to 0°C followed by the addition at 0°C (2-hermeticity)trimethylsilane (2.6 g, 0.014 mol). After complete addition, the reaction temperature was slowly raised to ambient temperature and was stirred for 3 hours To the reaction mixture was added 90 ml of ethyl acetate, then with 25 ml of ice water. The organic layer was separated, the aqueous was extracted again with ethyl acetate (50 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 4.6 g of (3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)amide 5-methylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 04: Synthesis of 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-trimethylsilylethynyl)]-5-methylthiophenethylamine

Stage 05: Synthesis of anhydride 3-nitrophthalic acid

Mixed (50 g, 0,236 mol) 3-nitrophthalic acid (50 ml of 0.53 mol) of acetic anhydride. The reaction mixture was heated at 100-120°C for 20 min to obtain a pure solution, the reaction mixture was cooled to room temperature, obtaining a solid crystalline substance thus obtained to istoricheskii product is suspended in hexane and filtered under vacuum, washed with hexane, receiving 50 g of the anhydride of 3-nitrophthalic acid.

Stage 06: Synthesis of 3-nitrophthalimide acid

To a chilled solution of aqueous ammonia (30-35%, 200 ml) was added in portions over 15 minutes anhydride 3-nitrophthalic acid (45 g, 0.23 mol) and stirred the reaction mixture for 30 minutes, the Reaction mixture was acidified to pH 2 with external cooling of dilute hydrochloric acid. After 20 min, the separated solid substance was filtered under vacuum and washed with hexane. The product was dried in vacuum, obtaining 50 g 3-nitrophthalimide acid.

Stage 07: Synthesis of 2-amino-3-nitrobenzoic acid

To a stirred cold solution of potassium hydroxide (113 g, a 2.01 mol) in water (550 ml) at 5-10°C was slowly added bromine (11.5 ml, 0.22 mol). The reaction mixture was stirred at this temperature for 15 minutes. 3-Nitrophthalimide acid (45 g, 0.21 mol) was added in one portion. The reaction mixture was heated and stirred at 60-70°C for 4 hours. The reaction mixture was acidified with external cooling of dilute hydrochloric acid to pH 2. The solid product was filtered under vacuum, dried with hot air in an oven at 60-70°C, receiving 40 g of 2-amino-3-nitrobenzoic acid.

Stage 08: Synthesis of methyl ester of 2-amino-3-nitrobenzoic acid

To mix the cold is astory 2-amino-3-nitrobenzoic acid (20 g, 0.11 mol) in methanol (300 ml) was added at 0-5°C sulfuric acid (48 ml). The reaction mixture was heated under reflux for 12 hours, cooled to room temperature and the methanol was evaporated in vacuum. The reaction mixture was podslushivaet saturated solution (pH~7-8) of sodium bicarbonate. Were extracted with ethyl acetate (500 ml×2), dried over sodium sulfate and evaporated in vacuum, obtaining of 11.0 g of methyl ester of 2-amino-3-nitrobenzoic acid in the form of a solid crystalline substance is yellow.

Stage 09: Synthesis of methyl ester of 3-nitro-2-(2,2,2-triptoreline)benzoic acid

To a stirred cold solution of methyl ester 2-amino-3-nitrobenzoic acid (9.0 g, mol) in pyridine (90 ml) was added dropwise within 30 minutes at 0-5°C anhydride triperoxonane acid (9.0 ml, 0.06 mol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extinguished with ice water (100 ml) under stirring. Brought the pH to 7-8 with saturated sodium bicarbonate solution. The obtained solid was filtered under vacuum and washed with hexane. The obtained solid substance was dissolved in ethyl acetate, dried over sodium sulfate and evaporated in vacuum, obtaining 7.5 g of methyl ester of 3-nitro-2-(2,2,2-triptoreline)benzoic acid as a solid substance.

Stage 10: SinTe the methyl ester of 2-[(4-bromobenzyl)-(2,2,2-TRIFLUOROACETYL)amino]-3-nitrobenzoic acid

To a stirred solution of methyl ester of 3-nitro-2-(2,2,2-triptoreline)benzoic acid (7.0 g, 0,024 mol) in acetone (50 ml) was added anhydrous potassium carbonate (6.6 g, 0,048 mol). 4-Bromobenzylamine (8,9 g, 0.035 mol) in acetone (20 ml) was added dropwise at room temperature within 10 minutes. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated in vacuum. The crude product was placed in ethyl acetate (200 ml) and washed with water (100 ml×2). The organic layer was dried over sodium sulfate and evaporated in vacuum to obtain oil. The oil was cooled to 0-5°C for curing. The solid was stirred in hexane (70 ml), was filtered and dried under suction in a vacuum for 30 minutes, getting to 6.4 g of methyl ester of 2-[(4-bromobenzyl)-(2,2,2-TRIFLUOROACETYL)amino]-3-nitrobenzoic acid.

Stage 11: Synthesis of methyl ester of 2-(4-bromobenzylamine)-3-nitrobenzoic acid

To a stirred cold solution of methyl ester 2-[(4-bromobenzyl)-(2,2,2-TRIFLUOROACETYL)amino]-3-nitrobenzoic acid (6.4 g, 0.01 mol) in tetrahydrofuran (70 ml) was added sodium hydroxide solution (5 g in 20 ml water). The reaction mixture was stirred at room temperature for 7 hours. The tetrahydrofuran is evaporated and the reaction mixture was acidified with external cooling of the diluted water is the first hydrochloric acid solution to pH 2. Were extracted with ethyl acetate (200 ml×2), dried over sodium sulfate and evaporated in vacuum, obtaining 3.6 g of methyl ester of 2-(4-bromobenzylamine)-3-nitrobenzoic acid as a brown solid.

Step 12: Synthesis of methyl ester of 3-amino-2-(4-bromobenzylamine)benzoic acid

To a stirred solution of methyl ester of 2-(4-bromobenzylamine)-3-nitrobenzoic acid (2.6 g, 0,006 mol) in ethyl acetate (65 ml) was added chloride dihydrate tin (II) (6.5 g, 0,028 mol) and the reaction mixture was heated at 70°C for 1 hour. The reaction mixture was cooled and extinguished saturated aqueous sodium carbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layer was dried over sodium sulfate and evaporated, obtaining 2.0 g of methyl ester of 3-amino-2-(4-bromobenzylamine)benzoic acid as a brown oil.

Stage 13: Synthesis of methyl ester of 3-(4-bromobenzyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid

To a stirred solution of methyl ester 3-amino-2-(4-bromobenzylamine)benzoic acid (0.9 g, of 0.003 mol) in acetic acid (0.3 ml of 0.005 mol) was added tetrachlorocarbon (0.7 g, of 0.003 mol) and the reaction mixture was heated at 70-80°C for 1 hour. Was cooled to room temperature and the reaction mixture was added a saturated solution of bicarbonate NAT the Oia. The reaction mixture was extracted with ethyl acetate (50 ml×2). The organic layer was dried over sodium sulfate and evaporated in vacuo to obtain 1 g of methyl ester of 3-(4-bromobenzyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid in a solid green color.

Stage 14: Synthesis of methyl ester of 3-(4-{2-[(3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)sulfamoyl]-5-methylthiophene-3-yl}benzyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid

In a stream of dry nitrogen to 2.4 g (0,0062 mol) of methyl ester of 3-(4-bromobenzyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid was added to the sodium carbonate solution obtained by dissolving (1.1 g) in 8 ml of water. Then added with stirring (320 mg, 0,00055 mol) of bis(triphenylphosphine)palladium(II)chloride, followed by adding 10 ml of dimethoxyethane. To the reaction mixture was added dropwise over 30 minutes a solution of 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-trimethylsilylethynyl)]-5-methyldiphenylamine (3,15 g, 0,0068 mol) in 15 ml of dimethoxyethane. The reaction mixture was stirred and heated under reflux for 6 hours the Reaction mixture was cooled to room temperature and was added 50 ml of ethyl acetate followed by evaporation in vacuum. The obtained residue was dissolved in 100 ml ethyl acetate and washed with water and saturated salt solution, dried over sodium sulfate and evaporated in is the Aquum, receiving 2 g of the crude product as a brown oil, which was purified by chromatography on a column of silica gel, using hexane:ethyl acetate as eluent, obtaining 2.5 g of methyl ester of 3-(4-{2-[(3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)sulfamoyl]-5-methylthiophene-3-yl}benzyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid.

Stage 15: Synthesis of methyl ester of 3-{4-[2-(3,4-dimethylisoxazol-5-ylsulphonyl)-5-methylthiophene-3-yl]benzyl}-2-ethoxy-3H-benzimidazole-4-carboxylic acid

0.5 g (0,00069 mmol) of methyl ester of 3-(4-{2-[(3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)sulfamoyl]-5-methylthiophene-3-yl}benzyl)-2-ethoxy-3H-benzimidazole-4-carboxylic acid was dissolved in 15 ml of tetrahydrofuran followed by the addition of a solution of tetrabutylammonium (2 ml, 1 molar solution in tetrahydrofuran). The reaction mixture was heated at 90°C for 3 h Then the reaction mixture was cooled to room temperature, was added diluted hydrochloric acid and was extracted with ethyl acetate (50 ml×2), an ethyl acetate layer was washed with water and saturated salt solution, dried over sodium sulfate and evaporated in vacuum, obtaining 0.5 g of brown oily mass, which represents a methyl ester of 3-{4-[2-(3,4-dimethylisoxazol-5-ylsulphonyl)-5-methylthiophene-3-yl]benzyl}-2-ethoxy-3H-benzimidazole-4 the carb is new acid.

Stage 16: Synthesis of 3-{4-[2-(3,4-dimethylisoxazol-5-ylsulphonyl)-5-methylthiophene-3-yl]benzyl}-2-ethoxy-3H-benzimidazole-4-carboxylic acid

To methyl ether 3-{4-[2-(3,4-dimethylisoxazol-5-ylsulphonyl)-5-methylthiophene-3-yl]benzyl}-2-ethoxy-3H-benzimidazole-4-carboxylic acid (0.5 g, 0,0010 mol) was added a solution of lithium hydroxide (0.15 g in 2.5 ml water) followed by the addition of methanol (2.5 ml). The reaction mixture was stirred at ambient temperature for 6 hours Then the reaction mixture was evaporated in vacuo, to the residue thus obtained was added water and the resulting mixture was extracted with diethyl ether. The aqueous layer was separated, cooled to 5°C, acidified to pH 2 with diluted hydrochloric acid and was extracted with ethyl acetate (50 ml×2). The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum, obtaining a solid brown color, which is triturated with hexane, filtered under vacuum, washed with hexane and dried under suction, getting 108 mg of 3-{4-[2-(3,4-dimethylisoxazol-5-ylsulphonyl)-5-methylthiophene-3-yl]benzyl}-2-ethoxy-3H-benzimidazole-4-carboxylic acid.

Molecular formula: C27H26N4O6S2

Molecular weight: 566,65.

1H NMR (DMSO-d6): of 1.42 (t, J=7.2 Hz, 3H), of 1.46 (s, 3H), of 1.94 (s, 3H), 2,47 (s, 3H), 458-4,64 (square, J=7.2 Hz, 2H), of 5.68 (s, 2H), of 6.68 (s, 1H), 6,94-of 6.96 (d, J=8 Hz, 2H), 7,19 (t, J=8 Hz, 1H), 7,28 (user., 2H), 7,55-of 7.70 (m, 2H), 11,07 (user., 1H), of 13.18 (user., 1H).

Mass spectrum: (m+1) 567,1.

Example 27

(3,4-Dimethylisoxazol-5-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 1-thiophene-2-ivatan-1,3-dione

Synthesis of 1-thiophene-2-ivatan-1,3-dione was carried out according to the stage 01 of example 22.

Stage 02: Synthesis of 3-amino-1-thiophene-2-albut-2-EN-1-it

Synthesis of 3-amino-1-thiophene-2-albut-2-EN-1-it was carried out according to the stage 01 of example 22

Stage 03: Synthesis of 6-ethyl-2-methyl-3-(thiophene-2-carbonyl)-1H-pyridine-4-it

Synthesis of 6-ethyl-2-methyl-3-(thiophene-2-carbonyl)-1H-pyridine-4-it was carried out according to the stage 05 of example 22.

Stage 04: Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)thiophene-2-ylmethanone

Synthesis of (4-chloro-6-ethyl-2-methylpyridin-3-yl)thiophene-2-ylmethanone carried out according to the stage 06 of example 22.

Stage 05: Synthesis of 6-ethyl-4-methyl-3-thiophene-2-yl-1H-pyrazolo[4,3-C]pyridine

Synthesis of 6-ethyl-4-methyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine was carried out according to the stage 07 of example 22.

Stage 06: Synthesis of methyl ester of 4-bromo-3-bromomethylphenyl acid

28 g (0.11 mol) of ethyl ester of 4-bromo-3-methylbenzoic acid was dissolved in 120 ml of tetrachloro ETANA, to the resulting added 22,65 g (0.12 mol) of N-bromosuccinimide followed by the addition of 1.4 g (0,005 mol) of benzoyl peroxide (75% in water). The reaction mixture was stirred and heated under reflux for 2-3 hours, the Reaction mixture was cooled to 0°C with the formation of solid crystalline substance, which was filtered under vacuum and washed with 30 ml of carbon tetrachloride. Thus obtained filtrate was evaporated in vacuum. The residue was diluted with 300 ml of hexane and cooled to 0°C with the formation of solid crystalline substance, which was filtered in vacuum, washed with hexane, receiving of 17.5 g of ethyl ester of 4-bromo-3-bromomethylphenyl acid.

Stage 07: Synthesis of methyl ester of 4-bromo-3-ethoxymethyleneamino acid

To a cooled solution of 30 ml of ethanol and 7 g (0.10 mol) of ethoxide sodium at 0°C was added a solution of 17.5 g (0,054 mol) in 12 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature (28-30°C) for 2 h and then evaporated in vacuum. The obtained residue was acidified to pH 1 with diluted hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and evaporated in vacuum, obtaining 12.5 g of ethyl ester of 4-bromo-3-ethoxymethyleneamino acid.

Stage 08: Synthesis of 5-methylthiophene-2-Sul is vanilloid

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 09: Synthesis of (3,4-dimethylisoxazol-5-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (3,4-dimethylisoxazol-5-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 02 of example 74.

Step 10: Synthesis of (3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 03 of example 74.

Stage 11: Synthesis of 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-(2-trimethylsilylethynyl)]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-(2-trimethylsilylethynyl)]-5-methylthiophenethylamine carried out according to the stage 04 of example 74.

Step 12: Synthesis of methyl ester 4-{2-[(3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid

To a stirred solution of methyl ester 4-bromo-3-ethoxymethyleneamino acid (3 g, 0.01 to l mol) in dimethoxyethane (50 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (695 mg, 0,00099 mol) followed by addition of 2M aqueous sodium carbonate (3.15 g in 15 ml water). The reaction mixture was premesis is whether at room temperature for 10 min and then was heated at 60°C. Was added for 45 minutes dropwise a solution of 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-trimethylsilylethynyl)]-5-methyldiphenylamine (2 g of 0.005 mol in 25 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes in 1 hour again) was added for 45 minutes 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-trimethylsilylethynyl)]-5-methylthiophosphonate (2 g, 0.005 to mol in 25 ml of dimethoxyethane), the reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 hours, the Reaction mixture was diluted with ethyl acetate (100 ml) and water, the layers were separated, the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, obtaining 2.6 g of methyl ester of 4-{2-[(3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid as a pale yellow oily mass.

Stage 13: Synthesis of (3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Sociallyengaged (350 mg, of 0.92 mmol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran, followed doba the population methyl ester 4-{2-[(3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino acid (2.6 g, 4.7 mmol) in tetrahydrofuran. Stirred the reaction mixture at 0°C for 1 h, the temperature of the reaction mixture was raised to room temperature and was stirred for 4 h, the Reaction mixture was cooled to 0°C was added dropwise a solution of 30 ml of sodium hydroxide (1 g dissolved in 100 ml of water), keeping the temperature at 0°C, followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sodium sulfate and concentrated completely under vacuum, obtaining 2.2 g of (3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid.

Stage 14: Synthesis of 4-{2-[(3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

N-ethyldiethanolamine (2,13 ml, 0.012 mol) was added to a solution of (3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid (2.2 g, 4.1 mol) in 30 ml of dichloromethane. Cooled the reaction mixture to 0°C, the reaction mixture was added slowly methanesulfonanilide (0.45 ml, 5 mmol). Maintained the reaction mixture at room temperature for 3 hours the Reaction mixture was discharged into ice-cold water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with diluted chlorine is stevedorage acid, then water and saturated salt solution. Dried the organic layer over sodium sulfate and concentrated, obtaining 2.2 g of 4-{2-[(3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid.

Stage 15: Synthesis of (3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 6-ethyl-4-methyl-3-thiophene-2-yl-1H-pyrazolo[4,3-c]pyridine (0,447 g, 1.8 mmol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (132 mg, 3.3 mmol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-{2-[(3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (1 g, 1.8 mmol) in 10 ml of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 0.6 g crude (3,4-d is methylisoxazol-5-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 16: Synthesis of (3,4-dimethylisoxazol-5-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid

To 600 mg of the crude (3,4-dimethylisoxazol-5-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid was added at room temperature, ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was stirred and heated at 120°C for 6 hours the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (30 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 80 mg (3,4-dimethylisoxazol-5-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-c]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C27H26N4O6S2

Molecular weight: 661,87.

1H NMR (DMSO-d6): 1,00-1,05 (m, 3H), 1.30 and 1.32 to (m, 3H), of 1.42 (s, 3H), from 2.00 (s, 3H), of 2.46 (s, 3H), 2,82-2,88 (sq, J=7,6 Hz, 2H), 3.25 to 3,28 (sq, J=7.6 for the C, 2H), a 4.03 (s, 2H), 5,72 (s, 2H), 6,66-7,74 (m, 8H).

Mass spectrum: (m+1) 662,2.

Example 28

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-propylthiophene-2-sulfonic acid

Stage 01: Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone)

In a stream of dry nitrogen to a stirred solution of propionitrile (200 g, 3.6 mol) in toluene (1000 ml) was added n-butyl acetate (538, 6,46 mol) and then adding to the reaction mixture of sodium methoxide (197 g of 3.64 mol). After complete addition, the reaction mixture was heated and stirred at 90°C for 24 hours. Then the reaction mixture was cooled to room temperature (25°C). Separated solid was filtered, washed with hexane and dried in vacuum at 60°-65°C, getting 198 g of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone).

Stage 02: Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile

To a stirred solution of sodium salt of cyanobutane (70 g, 0,588 mol) in toluene (780 ml) was slowly added at 0-5°C sulfuric acid (52 g 0,5349 mol) and then was added ethylene glycol (72,93 g, 1,172 mol). The reaction mixture was heated under reflux in a period of 8.0 hours with the unit Dean-stark. The reaction mixture was cooled to 0°C is followed by the addition of 2M NaOH solution, the toluene layer was separated and washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuum, receiving 59 g of 2-(2-methyl[1,3]dioxolane-2-yl)propionitrile in the form of a yellowish liquid.

Stage 03: Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime

To a stirred solution of 4M aqueous sodium hydroxide solution (310 ml) in methanol (267 ml) was slowly added at 10°C, hydroxylamine hydrochloride (75 g, 3.0 mol), after adding to the reaction mixture at room temperature was added 2-(β-atlanticcity)propionamidoxime (65 g, 0,460 mol). The reaction mixture was then heated under reflux for 5 hours. The reaction mixture was cooled to room temperature, then methanol drove in vacuum, the residue thus obtained was extracted with ethyl acetate (100 ml×3). An ethyl acetate layer was washed with saturated salt solution, dried over sodium sulfate and evaporation of the layer of ethyl acetate under reduced pressure was obtained 34 g of 2-(β-atlanticcity)propionamidoxime in the form of oil.

Stage 04: Synthesis of 3-amino-4,5-dimethylisoxazole

To a stirred solution of 2-(β-atlanticcity)propionamidoxime (105 g of 0.60 mol) in n-propanol (1050 ml) was added slowly at 10-20°C sulfuric acid (96 g, 0,979 mol). The reaction mixture was heated with education is the principal fridge for 4 hours. n-Propanol drove in a vacuum, to the residue was added ethyl acetate (600 ml) and neutralized with an aqueous solution of sodium bicarbonate. Then the organic layer was separated, washed with water and saturated salt solution, dried over sodium sulfate and evaporated under reduced pressure, obtaining 40 g of the crude 3-amino-4,5-dimethylisoxazole, which again was led from a mixture of toluene/hexane, receiving 32 g of pure 3-amino-4,5-dimethylisoxazole.

Stage 05: Synthesis of 5-propylthiophene-2-sulphonylchloride

2-propylthiophene (5.0 g, 0,0396 mol) was added to a suspension of chlorosulfonic acid (6.6 ml, 0,099 mol) and pentachloride phosphorus (8,25 g, 0,0396 mol) at a temperature from 10°C to 15°C. Maintained the reaction mixture at 15°C for 10 min the Crude reaction mass was slowly unloaded into ice-cold water followed by extraction simple diisopropyl ether (50 ml×2). The combined extract was washed with water and saturated salt solution, dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining 7.0 g of 5-propylthiophene-2-sulphonylchloride in the form of a brown liquid.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-propylthiophene-2-sulfonic acid

5-Propylthiophene-2-sulphonylchloride (7.0 g, 0,0312 mol) in methylene chloride (25 ml) was added at 0°C to a solution of 3-amino-4,5-dimethylisoxazole (3,18 g, 0,0284 mol) in pyridine (5.8 ml) and dimethylamine is ridine (0,347 g). The temperature of the reaction mixture was slowly raised to room temperature and was stirred for 6 hours. Concentrated the reaction mixture completely in a vacuum, the reaction mixture was acidified with 1 N. hydrochloric acid followed by extraction with methylene chloride (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated, obtaining of 8.1 g (4,5-dimethylisoxazol-3-yl)amide 5-propylthiophene-2-sulfonic acid as a brown solid.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-propylthiophene-2-sulfonic acid

Potassium carbonate (6,14 g 0,044 mol) was added at 0°C to a stirred solution of dimethylformamide (30 ml) followed by addition of (4,5-dimethylisoxazol-3-yl)amide 5-propylthiophene-2-sulfonic acid (5,38 g, 0,0178 mol). The temperature was slowly raised and kept at ambient temperature for 30 minutes, then was cooled to 0°C followed by the addition at 0°C methoxyethoxymethyl (2.67 g, 0,0214 mol). After complete addition, the temperature was slowly raised to ambient temperature and was stirred for 3 hours To the reaction mixture was added 90 ml of ethyl acetate, then with 25 ml of ice water. The organic layer was separated, the water was again extracted with ethyl what cetecom (50 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, receiving of 4.2 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-propylthiophene-2-sulphonic acid in the form of a yellowish oil.

Stage 08: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-propylthiophenethylamine

(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-propylthiophene-2-sulfonic acid (4,2 g, to 0.011 mol) was dissolved in tetrahydrofuran (20 ml), the reaction mixture was cooled to -78°C under nitrogen atmosphere. In the reaction mixture when using the syringe was slowly added n-utility (17 ml, 0,0275 mol, 1.6 m solution in n-hexane). After complete addition, the reaction mixture was stirred at -78°C for 1 h, slowly raised the temperature to 0°C and was stirred for 30 minutes, the Reaction mixture was again cooled to -78°C, then added triisopropylsilyl (3 ml, 0,0132 mol). When you are finished adding slowly raised the temperature to 0°C and was stirred for 1 h, the Reaction mixture was cooled to -10°C was added a saturated solution of ammonium chloride followed by extraction with ethyl acetate (50 ml×2). The combined extract was washed with water and saturated salt solution. Was dried over sodium sulfate and conc who was narrowly in vacuum, receiving 4.5 g 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-propylthiophenethylamine in the form of a thick oily mass.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxy)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 1-(4-bromo-3-methylbenzyl)-5,7-diethyl-1H-[1,6]naphthiridine-2-she (1.0 g, 0,0026 mol) in dimethoxyethane (20 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (0,183 g, 0,00026 mol) followed by addition of 2M aqueous sodium carbonate (0,827 g 3.9 ml of water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. was Added dropwise over 45 minutes a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-propylthiophenethylamine (0,5616 g, 0,0013 mol in 10 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes in 1 hour same thing was repeated with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-propylthiophenethylamine (0,5616 g, 0,0013 mol in 10 ml of dimethoxyethane), the reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 hours, the Reaction mixture was diluted with ethyl acetate (50 ml) and water, the layers were separated, the water is Loy was extracted with ethyl acetate. The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum, obtaining 1.2 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid as a pale yellow oily mass.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-propylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid (1.2 g) at room temperature was added ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (4 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on silica gel using a mixture of hexane:ethyl acetate, getting 190 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-propylthiophene-2-sulfonic acid.

Stage 11: Synthesis of 3-aminomethylenemalonate

A mixture of methylpropionamide (50 g, 0,3842 mol) and ammonium acetate (148 g, 1,921 mol) in dry methanol (500 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated. The residue was podslushivaet to pH 8 and extracted with ethyl acetate. An ethyl acetate layer was washed with water, saturated salt solution, dried over sodium sulfate and concentrated, gaining 50 g 3-aminomethylenemalonate in the form of a light yellow liquid.

Step 12: Synthesis of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid

A mixture of 3-aminomethylenemalonate (50 g, 0,387 mol) and methylpropionamide (50 g, 0.384 mol) in 200 ml of o-xylene and 50 g 40 E molecular sieves was heated under reflux in an apparatus of the Dean-stark for 5 days. Molecular sieves were filtered off, the filtrate was concentrated and was purified on a column of silica gel, elwira a mixture of 50% dichloromethane:methanol, 20 g of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid as a white solid.

Stage 13: Synthesis of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid

Totalization (39 g, 0,197 mol) was added to a stirred suspension of 2,6-diethyl-4-oxo-1,4-dihydropyridines-3-methylcarbazole (25 g, 0,119 mol) in acetonitrile (250 ml). After the fall of the beginning of InEU ectothermy the mixture was heated under reflux for 2 hours. The mixture was cooled to room temperature and the suspended solid was separated by filtration, obtaining 20 g of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid.

Stage 14: Synthesis of methyl ester of 4-amino-2,6-diethylnicotinamide acid

Methyl 2,6-diethyl-4-(4-tosylamide)pyridine-3-methylcarbazole (40 g, 0,110 mol) was added at 0°C to concentrated sulfuric acid (57 ml, 1.10 mol) and then the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and poured on crushed ice. The mixture was brought to pH 8 with solid sodium carbonate and extracted DCM, the combined organic phase was washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated, gaining 19 g of methyl 4-amino-2,6-diethylpyrazine-3-methylcarbazole in the form of a white solid.

Stage 15: Synthesis of (4-amino-2,6-diethylpyrazine-3-yl)methanol

A solution of 4-amino-2,6-diethylpyrazine-3-methylcarbazole (20 g, 0,0962 mol) in tetrahydrofuran (150 ml) was added dropwise over 30 minutes to a stirred suspension of lithium aluminum hydride (7,3 g, 0,1923 mol) in tetrahydrofuran (150 ml), the reaction mixture is then stirred and heated under reflux for 5 hours, the Reaction mixture was cooled in a bath with ice was carefully added 2M aqueous solution of the hydroxide is sodium (50 ml), then water (20 ml), the mixture was stirred for 1 h, then was added tetrahydrofuran (150 ml). Insoluble substances were removed by filtration and washed with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuum, obtaining of 12.1 g (4-amino-2,6-diethylpyrazine-3-yl)methanol.

Stage 16: Synthesis of 4-amino-2,6-diethylpyrazine-3-carbaldehyde

A mixture of (4-amino-2,6-diethylpyrazine-3-yl)methanol (12.0 g, 0,0667 mol) and manganese dioxide (17,39 g, 0.2 mol) in toluene (150 ml) was stirred and heated under reflux for 10 hours. The hot reaction mixture was filtered and the solid washed with ethyl acetate (150 ml). The combined filtrate was concentrated by evaporation in a vacuum, getting to 11.7 g of 4-amino-2,6-diethylpyrazine-3-carbaldehyde as a yellow solid.

Stage 17: Synthesis of 5,7-diethyl-1H-[1,6]naphthiridine-2-it

A mixture of 4-amino-2,6-diethylpyrazine-3-carbaldehyde (11,7 g, 0,657 mol) and (ceratosolen)triphenylphosphorane (27,44 g, 0,07884 mol) in toluene (150 ml) was stirred and heated under reflux for 5 hours, the Reaction mixture was cooled to room temperature and the solvent was removed by evaporation. To the residue was added a solution of sodium methoxide (12,42 g, 0.23 mol) in methanol (150 ml) and the resulting solution was heated under reflux for 4 hours. Methanol UDA is Yali by evaporation and added water (100 ml). The mixture was acidified to pH 2 by adding concentrated hydrochloric acid. The mixture was then extracted with ethyl acetate (100 ml×2). The organic extract was discarded. The aqueous phase was then podslushivaet the addition of sodium carbonate. Then was extracted with dichloromethane (200 ml×3). The organic layer was washed with water, saturated salt solution, dried over sodium sulfate and concentrated, gaining 5.5 g of 5,7-diethyl-1H-[1,6]naphthiridine-2-it is in the form of a white solid.

Stage 18: Synthesis of 1-(4-bromo-3-methylbenzyl)-5,7-diethyl-1H-[1,6]naphthiridine-2-it

To a stirred solution of potassium carbonate (6,16 g, 0,04455 mol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added 5,7-diethyl-1H-[1,6]naphthiridine-2-he (3.0 g, 0,01485 mol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes and Then the reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-bromo-3-methylbenzylamino ether methanesulfonate acid (5,39 g, 0,01931 mol) in 10 ml of dimethylformamide and stirred at room temperature for 8 hours. The mixture then was diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 4.0 g of 1-(4-bromo-3-methylbenzyl)-5,7-diethyl-1H-[1,6]nattered is n-2-it is in the form of a brown solid.

Molecular formula: C32H36N4O4S2

Molecular weight: 604.

1H NMR (DMSO-d6): of 0.91 (t, J=7.2 Hz, 3H), 1.18 to of 1.27 (m, 6H), 1,45 (s, 3H), 1,61-1,66 (sq, J=7,6 Hz, 2H), 1,92 (s, 3H), 2,11 (s, 3H), 2.70 height is 2.80 (m, 4H), 3.04 from-3,10 (sq, J=7.2 Hz, 2H), 5,46 (s, 2H), of 6.71-7,16 (m, 6H), by 8.22-8,25 (d, J=9,36 Hz, 1H), 10,59 (s, 1H).

Mass spectrum: (m-1) 603,2.

Example 29

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-3-phenyl-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone)

Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone) was carried out according to the stage 01 of example 28.

Stage 02: Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile

Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile carried out according to the stage 02 of example 28.

Stage 03: Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime

Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime carried out according to the stage 03 of example 28.

Stage 04: Synthesis of 3-amino-4,5-dimethylisoxazole

Synthesis of 3-amino-4,5-dimethylisoxazole carried out according to the stage 04 of example 28.

Article is Diya 05: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 08: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 09: Synthesis of methyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl]-3-methylbenzoic acid

Synthesis of methyl ester (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid was carried out according to the stage 08 of example 19.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 of example 19.

Stage 11: Synthesis 4-12-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl)-3-methylbenzylamino ether methanesulfonate acid

Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid was carried out according to the stage 10 of example 19.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-dimethyl-2-oxo-3-phenyl-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 5,7-dimethyl-3-phenyl-1H-[1,6]naphthiridine-2-she (0.5 g, 0.002 mol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (150 mg, 0,0031 mol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid (1 g, 0.002 mol) in 10 ml of dimethylformamide and stirred at room temperature for 24 hours. The mixture then was diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sulfate on the model and was evaporated in vacuum, obtaining 1.3 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-dimethyl-2-oxo-3-phenyl-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-3-phenyl-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-dimethyl-2-oxo-3-phenyl-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid (1.3 g) at room temperature was added ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (6 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 200 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-3-phenyl-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulphonic acid in the form of a white solid.

Stage 14: Synthesis of et is gross ester of 2,6-dimethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid

A mixture of ethyl ester of 3-aminomethyl-2-ene acid (24,0 g, 0,184 mol) and methyl ester 3-oxomalonate acid (22,0 g to 0.17 mol) in 200 ml of o-xylene and 50 g 3E molecular sieves was heated under reflux in an apparatus of the Dean-stark within 2 days. The molecular sieve was filtered and the filtrate was concentrated, receiving semi-solid substance that is suspended in 25 ml of ethyl acetate and filtered, obtaining 9.0 g of ethyl ester of 2,6-dimethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid as a white solid.

Stage 15: Synthesis of ethyl ester of 2,6-dimethyl-4-(toluene-4-sulfonylamino)nicotinic acid

Totalization (36,0 g, 0.18 mol) was added to a stirred suspension of ethyl ester of 2,6-dimethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid (20,0 g, 0.10 mol) in acetonitrile (200 ml), after the fall of the initial ectothermy the mixture was heated under reflux for 2 hours. The mixture was cooled to room temperature and the suspended solid was separated by filtration, getting 37,0 g of ethyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid.

Stage 16: Synthesis of ethyl ester of 4-amino-2,6-diethylnicotinamide acid

Ethyl ester of 2,6-dimethyl-4-(toluene-4-sulfonylamino)nicotinic acid (37,0 g, 0.10 mol) was added at 0°C to concentrated sulfuric acid (57 ml, 1.15 mol) and ZAT is m the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and poured on crushed ice. The mixture was brought to pH 8 with solid sodium carbonate and was extracted with dichloromethane (100 ml×2), the combined organic phase was washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated, obtaining 20.6 g of ethyl ester of 4-amino-2,6-diethylnicotinamide acid.

Stage 17: Synthesis of (4-amino-2,6-dimethylpyridin-3-yl)methanol

To a stirred cold solution of ethyl ester of 4-amino-2,6-diethylnicotinamide acid (18.0 g, 0,0928 mol) in tetrahydrofuran (130 ml) was added by portions at 0°C alumoweld lithium (7,044 g, 0,1856 mol). The reaction mixture was stirred at room temperature for 15 min, then was heated under reflux for 6 hours. The reaction mixture was cooled to 0°C and added portions of aqueous sodium hydroxide solution (10 g in 100 ml water). The organic layer decantation and the aqueous layer was extracted with tetrahydrofuran (500 ml×2). The combined organic layer was evaporated, receiving 12.0 g (4-amino-2,6-dimethylpyridin-3-yl)methanol as a solid crystalline substance.

Stage 18: Synthesis of 4-amino-2,6-dimethylpyridin-3-carbaldehyde

To a solution of (4-amino-2,6-dimethylpyridin-3-yl)methanol (5.0 g, 0,0329 mol) in toluene (80 ml) was added manganese dioxide (8,58 g, 0,0987 mol). The reaction mixture is agrawala under reflux for 6 hours. The reaction mixture was cooled to room temperature, filtered through a layer hyflow and the residue was washed with toluene. The organic filtrate was evaporated, getting 5.29 g of 4-amino-2,6-dimethylpyridin-3-carbaldehyde as a white solid.

Stage 19: the Synthesis of 5,7-dimethyl-3-phenyl[1,6]naphthiridine-2-ylamine

A mixture of 4-amino-2,6-dimethylpyridin-3-carbaldehyde (3 g, 0.02 mol), sodium methoxide (2.14 g, 0.04 mol) and phenylacetonitrile (2,34 g, 0.02 mol) was heated at 60°C for 2 hours Volatiles were removed by evaporation and the residue was distributed between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate and concentrated in vacuum, obtaining 4.3 g of 5,7-dimethyl-3-phenyl[1,6]naphthiridine-2-ylamine.

Stage 20: the Synthesis of 5,7-dimethyl-3-phenyl-1H-[1,6]naphthiridine-2-it

A solution of sodium nitrite (6.0 g) in water (20 ml) was added dropwise over 45 minutes to a solution of 5,7-dimethyl-3-phenyl[1,6]naphthiridine-2-ylamine (4.3 g, 0.02 mol), 30 ml of water and 11 N. hydrochloric acid (10 ml). The reaction mixture was stirred for another 1 h, and then suspended solid white substance was separated by filtration and dried in vacuum, obtaining 4.35 g of 5,7-dimethyl-3-phenyl-1H-[1,6]naphthiridine-2-it.

Molecular formula: C34H32N4O4S2

Molecular weight: 624.

1H NMR (DMSO-d6): for 1.49 (s, 3H), 1.93 and (s, 3H), 2,12 (s, 3H), 2,47 (s, 3H), 2,48 (s, 3H), and 2.8 (s, 3H), 5,54 (s, 2H), of 6.71 (s, 1H), 6,88-6,94 (m, 2H), 7,15 (s, 1H), 7,21 (s, 1H), 7,40-7,49 (m, 3H), 7,79-7,81 (m, 2H), 8,24 (s, 1H), to 10.62 (user., 1H).

Mass spectrum: (m+1) 623,2.

Example 30

(3,4-dimethylisoxazol-5-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 02: Synthesis of (3,4-dimethylisoxazol-5-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (3,4-dimethylisoxazol-5-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 02 of example 26.

Stage 03: Synthesis of (3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 03 of example 26.

Stage 04: Synthesis of 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-trimethylsilylethynyl)]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-trimethylsilylethynyl)]-5-methylthiophenethylamine carried out according to the stage 04 of example 26.

Stage 05: Synthesis of 3-aminomethylenemalonate

Synthesis of 3-aminomethylenemalonate carried out according to the stage frimer 28.

Stage 06: Synthesis of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid

Synthesis of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid was carried out according to the stage 12 of example 28.

Stage 07: Synthesis of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid

Synthesis of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid was carried out according to the stage 13 of example 28.

Stage 08: Synthesis of methyl ester of 4-amino-2,6-diethylnicotinamide acid

Synthesis of methyl ester of 4-amino-2,6-diethylnicotinamide acid was carried out according to the stage 14 of example 28.

Stage 09: Synthesis of (4-amino-2,6-diethylpyrazine-3-yl)methanol

Synthesis of (4-amino-2,6-diethylpyrazine-3-yl)methanol was carried out according to the stage 14 of example 28.

Step 10: Synthesis of 4-amino-2,6-diethylpyrazine-3-carbaldehyde

Synthesis of 4-amino-2,6-diethylpyrazine-3-carbaldehyde was carried out according to the stage 15 of example 28.

Stage 11: the Synthesis of 5,7-diethyl-1H-[1,6]naphthiridine-2-it

Synthesis of 5,7-diethyl-1H-[1,6]naphthiridine-2-it was carried out according to the stage 16 of example 28.

Step 12: Synthesis of 1-(4-bromo-3-methylbenzyl)-5,7-diethyl-1H-[1,6]naphthiridine-2-it

At 0°C under nitrogen atmosphere was added 5,7-diethyl-1H-[1,6]naphthiridine-2-he (3.0 g, 0,01485 mol). After the addition the reaction mixture was heated to a temperature of OCD the global environment and kept for 30 minutes Then the reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-bromo-3-methylbenzylamino ether methanesulfonate acid (5,39 g, 0,01931 mol) in 10 ml of dimethylformamide and stirred at room temperature for 8 hours. The mixture then was diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 4.0 g of 1-(4-bromo-3-methylbenzyl)-5,7-diethyl-1H-[1,6]naphthiridine-2-it is in the form of a brown solid.

Stage 13: Synthesis of (3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 1-(4-bromo-3-methylbenzyl)-5,7-diethyl-1H-[1,6]naphthiridine-2-she (1.0 g, 0,0026 mol) in dimethoxyethane (20 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (0,183 g, 0,00026 mol) followed by addition of 2M aqueous sodium carbonate (0,827 g 3.9 ml of water). The reaction mixture was stirred at room temperature for 10 minutes and then was heated at 60°C. was Added dropwise over 45 minutes a solution of 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-trimethylsilylethynyl)]-5-methyldiphenylamine (0,58 g, 0,0013 mol in 10 ml of dimethoxyethane) and the reaction mixture was heated with education is the principal refrigerator for 60 minutes After 1 h the same procedure was repeated with the subsequent addition of 45 minutes 3-harrows-N-(3,4-dimethyl-3-isoxazolyl)-N-[(2-trimethylsilylethynyl)]-5-methyldiphenylamine (0,58 g, 0,0013 mol in 10 ml of dimethoxyethane), the reaction mixture was heated under reflux for 4 hours and stirred at room temperature for 12 hours, the Reaction mixture was diluted with ethyl acetate (50 ml) and water, the layers were separated, the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum, obtaining of 1.9 g of (3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid as a pale yellow oily mass.

Stage 14: Synthesis of (3,4-dimethylisoxazol-5-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

1.9 grams (0,00269 mol) of (3,4-dimethylisoxazol-5-yl)-(2-trimethylsilylethynyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid was dissolved in 10 ml of tetrahydrofuran followed by the addition of a solution of tetrabutylammonium (8.1 ml, 1 molar solution in tetrahydrofuran). The reaction mixture was heated at 55°C for 3 hours After that re is clonney the mixture was cooled to room temperature, added diluted hydrochloric acid and was extracted with ethyl acetate (50 ml×2), an ethyl acetate layer was washed with water and saturated salt solution, dried over sodium sulfate and evaporated in vacuum, obtaining oil mass brown (1.0 g). The crude compound was purified by chromatography on a column of silica gel, getting 122 mg (3,4-dimethylisoxazol-5-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid.

Molecular formula: C30H32N4O4S2

Molecular weight: 576.

1H NMR (DMSO-d6): of 1.20 (t, J=7.2 Hz, 3H), 1,25 (t, J=7.2 Hz, 3H), of 1.42 (s, 3H), 1.93 and (s, 3H), of 1.98 (s, 3H), of 2.45 (s, 3H), 2,70-2,74 (sq, J=7,6 Hz, 2H), 3.04 from-3,10 (sq, J=7,6 Hz, 2H), 5,46 (s, 2H), 6,70-7,35 (m, 6H), by 8.22-of 8.25 (d, J=8,8 Hz, 1H), 11,07 (user., 1H).

Mass spectrum: (m-1) 575,2.

Example 31

(4,5-dimethylisoxazol-3-yl)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone)

Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone) was carried out according to the stage 01 of example 28.

Stage 02: Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile

Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)is propionitrile carried out according to the stage 02 of example 28.

Stage 03: Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime

Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime carried out according to the stage 03 of example 28.

Stage 04: Synthesis of 3-amino-4,5-dimethylisoxazole

Synthesis of 3-amino-4,5-dimethylisoxazole carried out according to the stage 04 of example 28.

Stage 05: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 08: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 09: Synthesis of (4,5-dimethylisoxazol-yl)-(2-methoxyethoxymethyl)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid

To a stirred solution of 4-(4-bromo-3-methylbenzyl)-5-methyl-2-phenyl-2,4-dihydro[1,2,4]triazole-3-one (2 g, 0,00558 mol) in dimethoxyethane (10 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (0.39 g, 0,000558 mol) followed by addition of 2M aqueous sodium carbonate (1.77 g of 8.3 ml of water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. was Added dropwise over 45 minutes a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (1,125 g, 0,00558 mol in 5 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes in 1 hour repeated the same procedure with the subsequent addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (1,125 g, 0,00558 mol in 5 ml of dimethoxyethane), the reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 hours, the Reaction mixture was diluted with ethyl acetate (50 ml) and water, the layers were separated, the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, receiving 3.5 g (4,5-dimethylisoxazol-3-yl)-(2-methoxy shall taximeter)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid (2 g) at room temperature was added ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 400 mg (4,5-dimethylisoxazol-3-yl)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid in the form of a white solid.

Stage 11: Synthesis of the hydrochloride of ethyl ether imide acetic acid

Cooled to 0°C solution of acetonitrile (50 g, to 1.21 mol) and ethanol (55,66 g, 1,21 mol) for 2 hours was introduced dry gaseous HCl (44.5 kg). PEFC is the completion of introduction of the reaction mixture was stirred at 0°C for 6 h and then kept at room temperature for 6 hours. The reaction mixture was evaporated in vacuum, obtaining 30 g of white crystalline solids, representing the hydrochloride of the ethyl ester imide acetic acid. It is further used as such.

Step 12: Synthesis of ethyl ester [1-amoxicilian]carbamino acid

To a cooled to 0°C solution of the hydrochloride of ethyl ether imide acetic acid in dichloromethane (30 g, 0,248 mol) in a stream of nitrogen was added diisopropylethylamine (80 g, 0,642 mol) and the reaction mixture was stirred at 0°C for 30 minutes Then to the reaction mixture for 45 minutes, was added dropwise ethylchloride (26,3 g, 0,2492 mol). Then the reaction mixture was stirred at room temperature for 3 hours, the Reaction mixture was filtered under vacuum and the filtrate was concentrated in vacuum, receiving 50 g of ethyl ester [1-amoxicilian]carbamino acid in the form of oil.

Stage 13: Synthesis of 5-methyl-2-phenyl-2,4-dihydro[1,2,4]triazole-3-one

To 20 g (0.125 mol) ethyl ester [1-amoxicilian]carbamino acid was added toluene (100 ml). To the reaction mixture was added 12.4 g (0,114 mol) of phenylhydrazine and the reaction mixture was heated under reflux for 2 h at 45°C, then the reaction mixture was cooled to room temperature and then was added 12.7 g (0.125 mol) of triethylamine, and then the reaction mixture was heated to reverse this b is the IR for 6 hours. The reaction mixture was evaporated in vacuum and the crude product was re led from simple diethyl ether, obtaining a solid crystalline substance, which was filtered under vacuum and dried under suction, getting 9.5 g of 5-methyl-2-phenyl-2,4-dihydro[1,2,4]triazole-3-one.

Stage 14: Synthesis of 4-(4-bromo-3-methylbenzyl)-5-methyl-2-phenyl-2,4-dihydro[1,2,4]triazole-3-one

To a stirred solution of 5-methyl-2-phenyl-2,4-dihydro[1,2,4]triazole-3-one (1.85 g, 0.01 mol) in dimethylformamide (10 ml) at 0°C in an atmosphere of nitrogen was added in portions sodium hydride (60% in mineral oil) (617 mg, 0,0017 mol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes and Then the reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-bromo-3-methylbenzylamino ether methanesulfonate acid (2.86 g, 0,010 mol) in 10 ml of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 3.4 g of 4-(4-bromo-3-methylbenzyl)-5-methyl-2-phenyl-2,4-dihydro[1,2,4]triazole-3-one as a brown solid.

Molecular formula: C27H27N5O4S2

M is molecular weight: 549.

1H NMR (DMSO-d6): of 1.55 (s, 3H), a 1.96 (s, 3H), of 2.18 (s, 3H), and 2.27 (s, 3H), of 4.90 (s, 2H), 6,74 (s, 1H), 6,95-6,97 (d, J=7,6 Hz, 1H),? 7.04 baby mortality-7,06 (d, J=7,6 Hz, 1H), 7,17 (s, 1H), 7.23 percent (t, J=7,6 Hz, 1H), 7,47 (t, J=7,6 Hz, 2H), 7,92-7,94 (d, J=7,6 Hz, 2H), of 10.58 (user., 1H).

Mass spectrum: (m-1) 548,1.

Example 32

(4,5-Dimethylisoxazol-3-yl)amide 5-methyl-3-[2-methyl-4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone)

Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone) was carried out according to the stage 01 of example 28.

Stage 02: Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile

Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile carried out according to the stage 02 of example 28.

Stage 03: Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime

Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime carried out according to the stage 03 of example 28.

Stage 04: Synthesis of 3-amino-4,5-dimethylisoxazole

Synthesis of 3-amino-4,5-dimethylisoxazole carried out according to the stage 04 of example 28.

Stage 05: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-su is theilhard carried out according to the stage 07 example 01.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 08: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid

To a stirred solution of 4-(4-bromo-3-methylbenzyl)-5-propyl-2-pyridin-2-yl-2,4-dihydro[1,2,4]triazole-3-one (0.5 g, 0.001 mol) in dimethoxyethane (5 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (0.09 g, 0,00012 mol) followed by addition of 2M aqueous sodium carbonate solution (0.4 g of 2.16 ml of water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. was Added on the aplam 45 minutes a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (0.26 g, 0.0001 mol ml dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes in 1 hour repeated the same procedure with the further addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (0.26 g, 0.0001 mol ml dimethoxyethane), the reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 hours, the Reaction mixture was diluted with ethyl acetate (20 ml) and water the layers were separated, the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, receiving 0,78 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid in the form of a brown oil.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methyl-3-[2-methyl-4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid (0,78 g) at room temperature was added ethanol (10ml) and 6 N. an aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 40 mg (4,5-dimethylisoxazol-3-yl)amide 5-methyl-3-[2-methyl-4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid in the form of a white solid.

Stage 11: Synthesis of hydrochloride complex of ethyl ether imide butyric acid

Cooled to 0°C solution of butyronitrile (50 g, 0,726 mol) and ethanol (33,33 g, 0,724 mol) was injected dry gaseous HCl (to increase the weight of the reaction mixture up to 26 g) (26,44 g, 0,724 mol), after complete addition, the reaction mixture was stirred at 0°C for 6 h and then kept at room temperature for 6 hours, the Reaction mixture was evaporated in vacuum, obtaining 35 g of white crystalline solids, representing hydrochloride complex of ethyl ether imide butyric acid. It was palaeopathology as such.

Step 12: Synthesis of ethyl ester [1-ethoxymethylene]carbamino acid

To a cooled to 0°C solution of hydrochloride complex of ethyl ether imide butyric acid (25 g, 0.18 mol) in dichloromethane (125 ml) in a stream of nitrogen was added diisopropylethylamine (55 g, of 0.58 mol) and the reaction mixture was stirred at 0°C for 30 minutes Then to the reaction mixture for 45 minutes, was added dropwise ethylchloride (17 g, 0,156 mol). Then the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered under vacuum and the filtrate was concentrated in vacuum, obtaining 24 g of ethyl ester [1-ethoxymethylene]carbamino acid in the form of oil.

Stage 13: Synthesis of 5-propyl-2-pyridin-2-yl-2,4-dihydro[1,2,4]triazole-3-one

To 10 g (0.5 mol) of ethyl ester [1-ethoxymethylene]carbamino acid was added toluene (20 ml). To the reaction mixture was added to 5.3 g (0,048 mol) pyridine-2-Algeria and heated the reaction mixture at 45°C for 30 min, then the reaction mixture was cooled to room temperature, then added to 5.4 g (0,053 mol) of triethylamine and then the reaction mixture was heated under reflux for 6 hours, the Reaction mixture was evaporated in vacuum and the crude product was re led from simple diethyl ether, obtaining a solid crystalline substance, which otherthrow the Ali in vacuo and dried under suction, obtaining 2.2 g of 5-propyl-2-pyridin-2-yl-2,4-dihydro[1,2,4]triazole-3-one.

Stage 14: Synthesis of 4-(4-bromo-3-methylbenzyl)-5-methyl-2-phenyl-2,4-dihydro[1,2,4]triazole-3-one

To a stirred solution of 5-propyl-2-pyridin-2-yl-2,4-dihydro[1,2,4]triazole-3-one (1 g, of 0.004 mol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (294 mg, 0,0073 mol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes and Then the reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-bromo-3-methylbenzylamino ether methanesulfonate acid (1.64 g, 0,0058 mol) in 10 ml of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (20 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 2 g of 4-(4-bromo-3-methylbenzyl)-5-methyl-2-phenyl-2,4-dihydro[1,2,4]triazole-3-one as a brown solid.

Molecular formula: C28H30N6O4S2

Molecular weight: 578.

1H NMR (DMSO-d6): of 0.94 (t, J=7,6 Hz, 3H), of 1.29 (s, 3H), of 1.64-1.69 in (square, 2H), 1,96 (s, 3H), of 2.18 (s, 3H), by 2.55 (t, J=7,6 Hz, 3H), 4,91 (s, 2H), 6,74 (s, 1H), 6,95-7,16 (m, 4H), 7,92-to 7.99 (m, 2H), 8,49-of 8.50 (d, 2H), to 10.62 (, 1H).

Mass spectrum: (m-1) 577,2.

Por what measures 33

(4,5-dimethylthiazol-2-yl)amide 3-[4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of 3-bromothiophene-2-sulphonylchloride

Synthesis of 3-bromothiophene-2-sulphonylchloride carried out according to the stage 10 example 02.

Stage 02: Synthesis of (4,5-dimethylthiazol-2-yl)amide 3-bromothiophene-2-sulfonic acid

3-Bromothiophene-2-sulphonylchloride (20 g, 0,076 mol) was added to a solution of 4,5-dimethylthiazol-2-ylamine (15 g, 0,071 mol) in 40 ml of sodium hydroxide solution (6 g, 0.15 mol) at room temperature and was stirred for 6 hours. Concentrated the reaction mixture completely in a vacuum, the reaction mixture was acidified with 1 N. hydrochloric acid followed by extraction with dichloromethane (50 ml×3). The combined extract was washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated, obtaining a mixture of products, which was dissolved in methanol sodium hydroxide solution and the reaction mixture was stirred and heated at 50°C for 6 hours, the Reaction mixture was cooled to room temperature and evaporated in vacuum. The residue thus obtained was acidified with diluted hydrochloric acid to pH 2, followed by extraction with methylene chloride (100 ml×3). The combined extract industry is Ali water, saturated salt solution and dried over anhydrous sodium sulfate, was evaporated in vacuum, obtaining 9 g of brown solid, which represents (4,5-dimethylthiazol-2-yl)amide 3-bromothiophene-2-sulfonic acid.

Stage 03: Synthesis of (4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid

To a solution of (4,5-dimethylthiazol-2-yl)amide 3-bromothiophene-2-sulfonic acid (8 g, of 0.022 mol) in 40 ml of acetone and 10 ml of dimethylformamide at 0°C was added potassium carbonate (5 g, being 0.036 mol). The reaction mixture was stirred at room temperature for 30 minutes, the Reaction mixture was cooled to 0°C, using a bath of ice and salt. 2-Methoxyethoxymethyl (5 g, 0.040 mol) was added dropwise over 30 minutes at 0°C. the Reaction mixture was stirred in a bath of ice and salt for 30 min and then at room temperature for 4 h the Mixture was diluted with ethyl acetate (100 ml), then 30 ml of ice water and the organic layer was separated, washed with water and saturated salt solution, and finally dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 3 g (4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulphonic acid in the form of a yellow oil.

Stage 05: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3(4-formylphenyl)thiophene-2-sulfonic acid

To mix the solution (3 g, 6.8 mmol) of (4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)amide 3-bromothiophene-2-sulfonic acid and 1.2 g (8 mmol) 4-forevernow acid dimethoxyethane (30 ml) under nitrogen atmosphere was added a 2M aqueous solution of sodium carbonate (2.16 g in 10 ml water). Stirred the reaction mixture for 15 minutes, then the reaction mixture was added bis(triphenylphosphine)palladium(II)chloride (400 mg, of 0.68 mmol). The reaction mixture was heated at 85°C for 6 hours, the Reaction mixture was cooled to room temperature and was added 50 ml of ethyl acetate. Concentrated the reaction mixture in vacuo, to the residue was added ethyl acetate (100 ml), then cooled with water to further extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated completely under vacuum. The crude compound was purified by chromatography on a column of silica gel, receiving 2.5 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid as an oily mass.

Stage 06: Synthesis of (4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid

Sodium borohydride (400 mg, 10 mmol) was added at 0°C in a stream of nitrogen to a stirred solution of tetrahydrofuran followed by addition of the (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid (2.5 g, 5.3 mmol) in 15 ml of tetrahydrofuran. Stirred the reaction mixture at 0°C for 1 h, has raised the temperature of the reaction mixture to room temperature and was stirred for 4 hours Spent processing added at 0°C solution of sodium hydroxide (1 g dissolved in 100 ml of water) followed by extraction with ethyl acetate (50 ml×2). Dried the organic layer over sodium sulfate and concentrated completely under vacuum, obtaining 2.3 g (4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid in the form of an oily liquid.

Stage 07: Synthesis of 4-{2-[(4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)sulfamoyl]thiophene-3-yl}benzyl ether methanesulfonate acid

N-ethyldiethanolamine (2 ml, to 10.8 mmol) was added to a solution of (4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid (2.3 g, 4.9 mmol) in 15 ml dichloromethane. Cooled the reaction mixture to 0°C, then the reaction mixture was slowly added a solution of methanesulfonamide (0.5 ml, 6.1 mmol) in 10 ml of dichloromethane. The reaction mixture was stirred at room temperature for 3 hours was Carried out by processing of adding to the reaction mixture was ice-cold water followed by extraction with methylene chloride (25 ml×2). The combined extracts were washed with diluted hydrochloric acid, ZAT is m water and saturated salt solution. Dried the organic layer over sodium sulfate and concentrated in vacuum, obtaining 1.8 g of 4-{2-[(4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)sulfamoyl]thiophene-3-yl}benzyl ether methanesulfonate acid in the form of a viscous liquid.

Stage 08: Synthesis of (4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid

To a stirred solution of 5-propyl-2-pyridin-2-yl-2,4-dihydro[1,2,4]triazole-3-one (700 mg, 3.4 mmol) in dimethylformamide (5 ml) at 0°C in a stream of dry nitrogen gas was added in portions sodium hydride (60% in mineral oil (252 mg, 5.2 mmol). After addition the temperature was raised to room temperature and maintained for 30 minutes, Again cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)sulfamoyl]thiophene-3-yl}benzyl ether methanesulfonate acid (1.8 g, 3.5 mmol) in 5 ml of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of water at 0°C and extracted with ethyl acetate (50 ml×2) and the combined extracts were washed with water and saturated salt solution. Dried the organic layer over sodium sulfate and concentrated in vacuum, obtaining 2 g (4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)am is Yes 3-[4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid resin.

Stage 09: Synthesis of (4,5-dimethylthiazol-2-yl)amide 3-[4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid

To 2 g (4,5-dimethylthiazol-2-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid at room temperature was added 95%ethanol (15 ml) and 10 ml of 6 N. aqueous solution of hydrochloric acid. The reaction mixture was heated under reflux for 6 hours the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 5 with sodium bicarbonate solution and the mixture was extracted with ethyl acetate (50 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified flash chromatography on silica gel using a mixture of hexane:ethyl acetate, receiving 180 mg of yellowish solid substance representing (4,5-dimethylthiazol-2-yl)amide 3-[4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid.

Molecular formula: C26H26N6O3S3

Molecular weight: 566.

1H NMR (DMSO-d6): 0,93 (3, 3H), of 1.64 (m, 2H), 2,07 (s, 3H), 2,12 (s, 3H), by 2.55 (t, J=3.2 Hz, 2H), 4,96 (s, 2H), 7,20-8,50 (m, 10), 12,46 (user., 1H).

Mass spectrum: (m-1) 565,12.

Example 34

Isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

Stage 01: Synthesis of 3-bromothiophene-2-sulphonylchloride

Synthesis of 3-bromothiophene-2-sulphonylchloride carried out according to the stage 10 example 02.

Stage 02: Synthesis of (3-methoxy-5-methylpyrazine-2-yl)amide 3-bromothiophene-2-sulfonic acid

To a stirred cold solution of 3-methoxy-5-methylpyrazine-2-ylamine (2.5 g, 0.018 mol) in pyridine (30 ml) was added dimethylaminopyridine (0.3 g, 0.002 mol), then 3-bromothiophene-2-sulphonylchloride (6.5 g, 0,025 mol). The reaction mixture was heated and stirred at 60°C for 24 hours. The pyridine was evaporated in vacuum. The crude product was placed in ethyl acetate and washed with saturated sodium bicarbonate solution. An ethyl acetate layer was dried over sodium sulfate and concentrated in vacuum, obtaining 4.4 g (3-methoxy-5-methylpyrazine-2-yl)amide 3-bromothiophene-2-sulfonic acid as a brown solid.

Stage 03: Synthesis isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-bromothiophene-2-sulfonic acid

To a stirred cold solution of (3-methoxy-5-methylpyrazine-2-yl)amide 3-bromothiophene-2-sulfonic acid (5.5 g, 0.015 mol) in dimethylformamide (30 ml) at 0°C was added on the of sodium hydride (60% in mineral oil, 0,870 g, 0.018 mol). The reaction mixture was stirred at room temperature for 30 minutes. At 0°C was added isobutylparaben (2.4 g, is 0.017 mol). The reaction mixture was stirred at room temperature for 3 hours. Added ethyl acetate (150 ml) and water (50 ml). The organic layer was washed with water (50 ml×3). The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 5 g isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-bromothiophene-2-sulphonic acid in the form of a brownish oil.

Stage 04: Synthesis isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid

4-forevernow acid (1,61 g to 0.011 mol) in 20 ml of ethanol was added isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-bromothiophene-2-sulfonic acid (5 g, of 0.01 l mol) in toluene (20 ml) followed by addition of 2M sodium carbonate solution (3.4 g in 6 ml of water to 0.032 mol) and was stirred for 15 minutes. Added tetranitropentaerithrite(0) (0,53 g, 0,00045 mol) and the reaction mixture was heated and stirred at 110°C-120°C for 6 hours. To the reaction mixture were added ethyl acetate (50 ml), the reaction mixture was concentrated in vacuum. Was added water (100 ml) and was extracted with ethyl acetate (100 ml). The organic layer was dried over sodium sulfate and concentrated in vacuum, receiving 6 g of butoxycarbonyl(3-methoxy-5-methylpyrazine-2-yl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid.

Stage 05: Synthesis isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid

To mix the solution isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-(4-formylphenyl)thiophene-2-sulfonic acid (5 g, to 0.011 mol) in tetrahydrofuran (30 ml) was added at 0°C and sodium borohydride (0.6 g, is 0.017 mol) and stirred at room temperature for 60 minutes. The reaction mixture was cooled to 0°C and the reaction mixture was added dilute sodium hydroxide solution (0.5 g in 50 ml). The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum, obtaining of 3.9 g isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid in the form of a brown oil.

Stage 06: Synthesis of 4-{2-[isobutoxide(3-methoxy-5-methylpyrazine-2-yl)sulfamoyl]thiophene-3-yl}benzyl ether methanesulfonate acid

To mix the solution isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-(4-hydroxymethylene)thiophene-2-sulfonic acid (1.5 g, 3 mmol) in dichloromethane (20 ml) at 0°C was added triethylamine (1.0 ml, 6 mmol) and was stirred for 5 min, then at 0°C methanesulfonate (0.3 ml, 3.7 mmol). The reaction mixture is PE is amasyali at room temperature for 3 hours. The reaction mixture was extinguished with water (15 ml). The organic layer was separated and dried over sodium sulfate, concentrated in vacuum, obtaining 1.5 g of 4-{2-[isobutoxide(3-methoxy-5-methylpyrazine-2-yl)sulfamoyl]thiophene-3-yl}benzyl ether methanesulfonate acid.

Stage 07: Synthesis isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-C]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

To a stirred solution of 6-ethyl-4-methyl-3-phenyl-1H-pyrazolo[4,3-c]pyridine (0,640 g, 2.7 mmol) in dimethylformamide (5 ml) at 0°C under nitrogen atmosphere was added sodium hydride (50%, 0.2 g, 4 mmol) and was stirred for 30 minutes at room temperature. Then the reaction mixture was cooled to 0°C was added 4-{2-[isobutoxide(3-methoxy-5-methylpyrazine-2-yl)sulfamoyl]thiophene-3-yl}benzyl ether methanesulfonate acid (1.5 g, 2.7 mmol) in dimethylformamide (5 ml). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and 10 ml of water. The organic layer was separated and washed with water (10 ml×3), saturated salt solution, dried over sodium sulfate and concentrated in vacuum, obtaining 1 g of crude isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic key is lots in the form of a viscous liquid.

Stage 08: Synthesis of (3-methoxy-5-methylpyrazine-2-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-C]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid

To isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (1 g) was added methanol (10 ml) and sodium hydroxide (500 mg in 5 ml water). The reaction mixture was heated and stirred at 50°C for 1 hour. The methanol was evaporated and neutralized with diluted hydrochloric acid (pH~6.5 in). Was extracted with dichloromethane (50 ml), dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel using ethyl acetate and hexane, receiving 50 mg isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid.

Molecular formula: C32H30N6O3S2

Molecular weight: 610.

1H NMR (DMSO-d6): of 1.24 to 1.31 (t, J=7,6 Hz, 3H), 2,24 (s, 3H), 2,47 (s, 3H), 2,80-2,85 (sq, J 7.2 Hz, 2H), and 3.72 (s, 3H), 5,71 (s, 2H), 7,08-to 7.09 (d, J=5,2 Hz, 1H), 7,26-7,28 (d, J=8 Hz, 2H), 7,44-7,46 (d, J=8,4 Hz, 2H), of 7.48-7,55 (m, 5H), 7,65-to 7.68 (DD, J=8 Hz, 2H), 7,86-7,87 (d, J=5,2, 1H).

Mass spectrum: (m+1) 611,27.

Example 35

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine--ylmethyl)-2-forfinal]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone)

Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone) was carried out according to the stage 01 of example 28.

Stage 02: Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile

Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile carried out according to the stage 02 of example 28.

Stage 03: Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime

Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime carried out according to the stage 03 of example 28.

Stage 04: Synthesis of 3-amino-4,5-dimethylisoxazole

Synthesis of 3-amino-4,5-dimethylisoxazole carried out according to the stage 04 of example 28.

Stage 05: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol the-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 08: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-forfinal]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 1-(4-bromo-3-terbisil)-5,7-diethyl-1H-[1,6]naphthiridine-2-she (2 g, 5.1 mmol) in dimethoxyethane (20 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (370 mg, 0.51 mmol) followed by addition of 2M aqueous sodium carbonate (1.7 g in 8 ml of water). The reaction mixture was stirred at room temperature for 10 min and then was heated at 60°C. was Added dropwise over 45 minutes a solution of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (1 g, 2.5 mmol in 15 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes in 1 hour repeated the same procedure with the further addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (1 g, 2.5 mmol in 15 ml of dimethoxyethane), the reaction mixture was heated under reflux for 4 h and stirred at whom atoi temperature for 12 hours The reaction mixture was diluted with ethyl acetate (100 ml) and water, the layers were separated, the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, receiving 2 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-forfinal]-5-methylthiophene-2-sulfonic acid as a pale yellow oily mass.

Stage 010: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-forfinal]-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-forfinal]-5-methylthiophene-2-sulfonic acid (2 g) at room temperature was added ethanol (15 ml) and 6 N. aqueous solution of hydrochloric acid (10 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. OS is atok was purified by chromatography on a column of silica gel, using a mixture of hexane:ethyl acetate, receiving 200 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-forfinal]-5-methylthiophene-2-sulfonic acid as a yellow solid.

Stage 11: Synthesis of 3-aminomethylenemalonate

Synthesis of 3-aminomethylenemalonate carried out according to the stage 11 of example 28.

Step 12: Synthesis of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid

Synthesis of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid was carried out according to the stage 12 of example 28.

Stage 13: Synthesis of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid

Synthesis of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid was carried out according to the stage 13 of example 28.

Stage 14: Synthesis of methyl ester of 4-amino-2,6-diethylnicotinamide acid

Synthesis of methyl ester of 4-amino-2,6-diethylnicotinamide acid was carried out according to the stage 14 of example 28.

Stage 15: Synthesis of (4-amino-2,6-diethylpyrazine-3-yl)methanol

Synthesis of (4-amino-2,6-diethylpyrazine-3-yl)methanol was carried out according to the stage 14 of example 28.

Stage 16: Synthesis of 4-amino-2,6-diethylpyrazine-3-carbaldehyde

Synthesis of 4-amino-2,6-diethylpyrazine-3-carbaldehyde was carried out according to the stage 15 of example 28.

Stage 17: Synthesis of 5,7-diethyl-1H-[16]naphthiridine-2-it

Synthesis of 5,7-diethyl-1H-[1,6]naphthiridine-2-it was carried out according to the stage 16 of example 28.

Stage 18: Synthesis of 1-bromo-4-methyl bromide-2-fermental.

To a solution of 1-bromo-2-fluoro-4-methylbenzene (5 g, was 0.026 mol) in carbon tetrachloride (40 ml) was added N-bromosuccinimide (5.6 g, 0,037 mol) followed by addition of 400 mg of azoisobutyronitrile (AIBN), then the reaction mixture was heated under reflux for 6 hours, the Reaction mixture was cooled to 0°C and was filtered in a vacuum; the filtrate was evaporated in vacuum, receiving 6 g of 1-bromo-4-methyl bromide-2-fervently in the form of a yellow oil. It is further used as such.

Stage 19: Synthesis of 1-(4-bromo-3-terbisil)-5,7-diethyl-1H-[1,6]-naphthiridine-2-it

To a stirred solution of 5,7-diethyl-1H-[1,6]naphthiridine-2-it (1 g, of 0.005 mol) in dimethylformamide (10 ml) at ambient temperature under nitrogen atmosphere was added potassium carbonate (1 mg, 0,0072 mol) followed by addition of 1-bromo-4-methyl bromide-2-fervently (1.4 g, 0,0052 mol) in 10 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 16 hours. The mixture is then filtered and the residue was washed with ethyl acetate, the combined organic phase was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 2 g of 1-(4-bromo-3-terbisil)-5,7-diethyl-1H-[1,6]-naphthiridine-2-it is in the form of a yellow oil.

<> Molecular formula: C32H30N6O3S2

Molecular weight: 580.

1H NMR (DMSO-d6): of 1.20 (t, J=7,6 Hz, 3H), 1,25 (t, J=7,6 Hz, 3H), 1,49 (s, 3H), 2,10 (s, 3H), 2,48 (s, 3H), 2,67-2,75 (sq, J=7.2 Hz, 2H), 3,05-3,10 (sq, J=7.2 Hz, 2H), 5,51 (s, 2H), 6,72-6,74 (d, J=10 Hz, 1H), for 6.81 (s, 1H), 6,95-6,97 (d, J=7,6 Hz, 1H), 7,13-7,16 (m, 3H), 8,24 compared to 8.26 (d, J=10 Hz, 1H), of 10.72 (user., 1H).

Mass spectrum: (m-1) 579,13.

Example 36

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-isobutoxide]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone)

Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone) was carried out according to the stage 01 of example 28.

Stage 02: Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile

Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile carried out according to the stage 02 of example 28.

Stage 03: Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime

Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime carried out according to the stage 03 of example 28.

Stage 04: Synthesis of 3-amino-4,5-dimethylisoxazole

Synthesis of 3-amino-4,5-dimethylisoxazole carried out with the public hearing stage 04 of example 28.

Stage 05: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 08: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 09: Synthesis of methyl ester 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-isobutoxide acid

To a stirred solution of methyl ester 4-bromo-3-isobutoxide acid (1.0 g, 0,00348 mol) in dimethoxyethane (15 ml) under nitrogen atmosphere was added bis(triphenylphosphine)palladium(II)chloride (0,243 g, 3.4 mmol) followed by addition of 2M aqueous sodium carbonate (0,811 g 3.8 ml of water). Reacciona the mixture was stirred at room temperature for 10 min and then was heated at 60°C. Was added dropwise over 45 minutes a solution of 3-harrows-N-(4,5-Dimethyl-3~isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methyldiphenylamine (700 mg, 0,003465 mol in 15 ml of dimethoxyethane) and the reaction mixture was heated under reflux for 60 minutes in 1 hour repeated the same procedure with the further addition of 45 minutes 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophosphonate (700 mg, 0,003465 mol in 15 ml of dimethoxyethane), the reaction mixture was heated under reflux for 4 h and stirred at room temperature for 12 hours, the Reaction mixture was diluted with ethyl acetate (100 ml) and water, the layers were separated, the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and concentrated in vacuum. The crude compound was purified by chromatography on a column of silica gel, obtaining 1.8 g of methyl ester of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-isobutoxide acid as a pale yellow oily mass.

Step 10: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-isobutoxy)-5-methylthiophene-2-sulfonic acid

Alumoweld lithium (0.15 g, to 0.0039 mol) at 0°C in a stream of nitrogen was added to the mixed solution tetrahydrofur is on (15 ml) followed by addition of methyl ester 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-isobutoxide acid (1.5 g, 0,0026 mol) in 20 ml of tetrahydrofuran. The reaction mixture was stirred at 0°C for 15 minutes. Raised the temperature of the reaction mixture to room temperature and was stirred for 4 h, the Reaction mixture was cooled to 0°C was added dropwise a solution of 50 ml of sodium hydroxide (1 g dissolved in 100 ml of water), keeping the temperature at 0°C, followed by extraction with ethyl acetate (25 ml×2). The organic layer was dried over sodium sulfate and concentrated completely under vacuum, obtaining 1.4 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-isobutoxy)-5-methylthiophene-2-sulfonic acid.

Stage 11: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-isobutoxyethanol ether methanesulfonate acid

N-ethyldiethanolamine (0,67 g, 0,005204 mol) was added to a solution of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-isobutoxy)-5-methylthiophene-2-sulfonic acid (1.4 g, 0,0026 mol) in 10 ml of dichloromethane. Cooled the reaction mixture to 0°C, the reaction mixture was slowly added methanesulfonamide (0,351 g, 0,003122 mol). The reaction mixture was stirred at room temperature for 3 hours the Reaction mixture was discharged into ice-cold water followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed of razbam the military hydrochloric acid, then water and saturated salt solution. Dried the organic layer over sodium sulfate and concentrated, obtaining 1.5 g of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-isobutoxyethanol ether methanesulfonate acid.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-isobutoxide]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 5,7-dimethyl-1H-[1,6]naphthiridine-2-it (0,0423 g, 0,002435 mol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (146 mg, 0,00365 mol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-isobutoxyethanol ether methanesulfonate acid (1.5 g, 0,002435 mol) in 10 ml of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining the crude material which was purified of chromatogra what s on a column of silica gel, using a mixture of hexane:ethyl acetate, gaining 0.7 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-isobutoxide]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-isobutoxide]-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-isobutoxide]-5-methylthiophene-2-sulfonic acid (0.7 g) at room temperature was added ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 120 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-isobutoxide]-5-methylthiophene-2-sulphonic acid in the form of a white solid substances is A.

Stage 14: Synthesis of ethyl ester of 2,6-dimethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid

Synthesis of ethyl ester of 2,6-dimethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid was carried out according to the stage 14 of example 29.

Stage 15: Synthesis of ethyl ester of 2,6-dimethyl-4-(toluene-4-sulfonylamino)nicotinic acid

Synthesis of ethyl ester of 2,6-dimethyl-4-(toluene-4-sulfonylamino)nicotinic acid was carried out according to the stage 15 of example 29.

Stage 16: Synthesis of ethyl ester of 4-amino-2,6-diethylnicotinamide acid

Synthesis of ethyl ester of 4-amino-2,6-diethylnicotinamide acid was carried out according to the stage 16 of example 29.

Stage 17: Synthesis of (4-amino-2,6-dimethylpyridin-3-yl)methanol

Synthesis of (4-amino-2,6-dimethylpyridin-3-yl)methanol was carried out according to the stage 17 of example 29.

Stage 18: Synthesis of 4-amino-2,6-dimethylpyridin-3-carbaldehyde

Synthesis of 4-amino-2,6-dimethylpyridin-3-carbaldehyde was carried out according to the stage 18 of example 29.

Stage 19: the Synthesis of 5,7-dimethyl-1H-[1,6]naphthiridine-2-it

A mixture of 4-amino-2,6-dimethylpyridin-3-carbaldehyde (6,1 g 0,041 mol) and (ceratosolen)triphenylphosphorane (35,38 g, 0,101 mol) in xylene (150 ml) was stirred and heated under reflux for 6 hours the Reaction mixture was cooled to room temperature and the solvent was removed by evaporation. To the residue add the Lyali solution of sodium methoxide (of 7.75 g, 0.144 mol) in methanol (150 ml) and the resulting solution was heated under reflux for 4 hours, the Methanol was removed by evaporation and added water (200 ml). The mixture was acidified to pH 1-2 by addition through the funnel hydrochloric acid. The mixture was then extracted with ethyl acetate (ml) and the extract was discarded. The aqueous phase was then podslushivaet the addition of sodium carbonate. Then carried out the extraction with dichloromethane (200 ml×3). The organic layer was washed with water, saturated salt solution, dried over sodium sulfate and concentrated, obtaining 1.6 g of 5,7-dimethyl-1H-[1,6]naphthiridine-2-it is in the form of a white solid.

Stage 20: Synthesis of 4-bromo-3-hydroxybenzoic acid

4.7 g of copper bromide was dissolved in 5 ml of 48%Hydrobromic acid and heated under reflux for 30 minutes. Then in another flask and 6 ml of 48%Hydrobromic acid was cooled to 0°C. To 5 g (0,032679 mol) 4-amino-3-hydroxybenzoic acid was added under stirring (2,61 g, 0,03782 mol) of a solution of sodium nitrite (dissolved in 20 ml of water). Stirred the reaction mixture for 30 min at 0°C, then the resulting solution was added dropwise in 30 minutes to an activated solution of sodium bromide. After complete addition, the reaction mixture was heated under reflux for 1 h the Reaction mixture was cooled to room temp the atmospheric temperature and then filtered through a layer hyflow, the filtrate was extracted with ethyl acetate (50 ml×3). The organic layer was washed with water, saturated salt solution, dried over sodium sulfate and concentrated, obtaining 1 g of 4-bromo-3-hydroxybenzoic acid.

Stage 21: Synthesis of methyl ester of 4-bromo-3-hydroxybenzoic acid

4-Bromo-3-hydroxybenzoic acid (1 g, of 0.004 mol) was dissolved in 20 ml of methanol, the resulting solution was cooled to 0°C and then added 0.2 ml of concentrated sulfuric acid. After complete addition, the reaction mixture was heated under reflux for 6 h, then methanol was evaporated in vacuum. To the residue was added water and was extracted with simple diethyl ether. The organic layer was washed with sodium bicarbonate solution, then with water and saturated salt solution, finally, the organic layer was dried over sodium sulfate and concentrated, obtaining 1.3 g of methyl ester of 4-bromo-3-hydroxybenzoic acid.

Stage 22: Synthesis of methyl ester of 4-bromo-3-isobutoxide acid

Methyl ester of 4-bromo-3-hydroxybenzoic acid (1.3 g, of 0.005 mol) was dissolved in 10 ml of dimethylformamide followed by the addition of potassium carbonate (1.7 g, 0.01 mol). Then to the reaction mixture (1 g, to 0.007 mol) was added isobutyramide and the reaction mixture was heated and stirred at 90°C for 10 h, the Reaction mixture was cooled to room so the temperature and the reaction mixture was filtered under vacuum, to the filtrate was added water and was extracted with ethyl acetate (20 ml×3). The organic layer was washed with water, saturated salt solution, dried over sodium sulfate and concentrated, obtaining 1 g of methyl ester of 4-bromo-3-isobutoxide acid in the form of oil.

Molecular formula: C31H34N4O5S2

Molecular weight: 606.

1H NMR (DMSO-d6): 0,812-of 0.82 (d, J=is 6.78 Hz, 6H), of 1.47 (s, 3H), 1,79-to 1.82 (m, 1H), 2,10 (s, 3H), of 2.44 (s, 3H), of 2.46 (s, 3H), 2,70 (s, 3H), 3,59-3,61 (d, J=6,4 Hz, 2H), 5,46 (s, 2H), 6,53-6,55 (d, J=8 Hz, 1H), of 6.71-6,74 (m, 2H), 7,00? 7.04 baby mortality (m, 2H), 7,22 (s, 2H), 8,19-8,21 (d, 1H), 10,55 (user., 1H).

Mass spectrum: (m-1) 605,1.

Example 37

(4,5-Dimethylisoxazol-3-yl)amide 3-{4-[3-(4-chlorophenyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone)

Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone) was carried out according to the stage 01 of example 28.

Stage 02: Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile

Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile carried out according to the stage 02 of example 28.

Stage 03: Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime

Synthesis of N-is hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime carried out according to the stage 03 of example 28.

Stage 04: Synthesis of 3-amino-4,5-dimethylisoxazole

Synthesis of 3-amino-4,5-dimethylisoxazole carried out according to the stage 04 of example 28.

Stage 05: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 06: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 07: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Stage 08: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 13: Synthesis of methyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid

Synthesis of methyl ester (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid was carried out according to the stage 08 p is the emer 19.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 of example 19.

Stage 15: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid

Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid was carried out according to the stage 10 of example 19.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{4-[3-(4-chlorophenyl)-4,6-dimethylpyrazolo[4,3-C]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid

To a stirred solution of 3-(4-chlorophenyl)-4,6-dimethyl-1H-pyrazolo[4,3-c]pyridine (516 mg, 0.002 mol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (150 mg, 0,0031 mol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)self mail]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid (1.0 g, 0.002 mol) in 10 ml of dimethylformamide and stirred at room temperature for 24 h the Mixture was then diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 1.6 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{4-[3-(4-chlorophenyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-{4-[3-(4-chlorophenyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-{4-[3-(4-chlorophenyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid (1.6 g) at room temperature was added ethanol (10 ml) and 6 N. aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. OST is OK purified by chromatography on a column of silica gel, using a mixture of hexane:ethyl acetate, receiving 200 mg (4,5-dimethylisoxazol-3-yl)amide 3-{4-[3-(4-chlorophenyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulphonic acid in the form of a white solid.

Stage 14: Synthesis of 1-(4-chlorophenyl)butane-1,3-dione

In 50 ml of N,N-dimethylformamide at 0°C was added sodium hydride (60% in mineral oil) (3.88 g, 0,097 mol) followed by a solution of dry ethyl acetate (6.8 g, 0,07727 mol) and 4-chloromethylketone (10.0 g, 0,065 mol). The reaction mixture was stirred at room temperature for 12 hours the Reaction mixture was acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and evaporated, getting 13,0 g of yellow solid, which represents 1-(4-chlorophenyl)butane-1,3-dione.

Stage 15: Synthesis of 3-amino-1-(4-chlorophenyl)but-2-EN-1-it

A mixture of 1-(4-chlorophenyl)butane-1,3-dione (27,0 g, 0,136 mol) and ammonium acetate (31,6 g, 0.41 mol) in dry methanol (200 ml) was stirred at room temperature for 24 h the Reaction mixture was concentrated completely under vacuum and to the residue was added chilled water. The reaction mixture was podslushivaet to pH 8 using a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate (100 ml×2). About the United extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and evaporated, receiving of 32.0 g of 3-amino-1-(4-chlorophenyl)but-2-EN-1-it.

Stage 16: Synthesis of 3-(4-chlorbenzoyl)-2,6-dimethyl-1H-pyridine-4-it

A mixture of 2,2,6-trimethyl[1,3]dioxin-4-it (to 11.56 g of 0.081 mol) and 3-amino-1-(4-chlorophenyl)but-2-EN-1-she (10.0 g, 0,059 mol) was heated under reflux at 120°C for 6 hours, the Reaction mixture was purified by chromatography on a column of silica gel, elwira the desired product 10%methanol and ethyl acetate, obtaining 3.1 g of 3-(4-chlorbenzoyl)-2,6-dimethyl-1H-pyridine-4-it.

Stage 17: Synthesis of (4-chloro-2,6-dimethylpyridin-3-yl)-(4-chlorophenyl)methanone

3-(4-chlorbenzoyl)-2,6-dimethyl-1H-pyridin-4-one (3.1 g, 0.012 mol) was added at 0°C to 20 ml of phosphorus oxychloride. Was stirred and heated the reaction mixture at 100°C and held for 8 hours. Was processed, viparita phosphorus oxychloride in a vacuum, and the residue was podslushivaet to pH 8 with a saturated solution of sodium carbonate followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over anhydrous sodium sulfate and concentrated, obtaining 3.2 g of (4-chloro-2,6-dimethylpyridin-3-yl)-(4-chlorophenyl)methanone.

Stage 18: Synthesis of 3-(4-chlorophenyl)-4,6-dimethyl-1H-pyrazolo[4,3-c]pyridine

(4-Chloro-2,6-dimethylpyridin-3-yl)-(4-chlorophenyl)methanon (3.4 g, 0.012 mol) was placed in ethanol (10 ml)and the reaction the mixture was added hydrazinehydrate (5.8 ml, 0.185 mol) and two drops of acetic acid. The temperature was slowly raised and the mixture was heated under reflux, while maintaining the boil for 6 hours. The reaction mixture was completely evaporated in a vacuum. The crude mass was placed on ice, and the obtained solid was filtered and dried under suction, receiving 700 mg of 3-(4-chlorophenyl)-4,6-dimethyl-1H-pyrazolo[4,3-c]pyridine.

Molecular formula: C32H30ClN5O3S2

Molecular weight: 631,5.

1H NMR (DMSO-d6): 1,45 (s, 3H), 1.93 and (s, 3H), 2,11 (s, 3H), 2,47 (s, 3H), 2.49 USD (s, 3H), of 2.54 (s, 3H), 5,63 (s, 2H), of 6.68 (s, 1H), 6.90 to-6,99 (m, 2H), 7,17 (s, 1H), 7,51 (s, 1H), 7,58-of 7.60 (d, J=8,4 Hz, 2H), 7.68 per-of 7.70 (d, J=8,4 Hz, 2H), at 10.64 (user., 1H).

Mass spectrum: (m-1) 630,1.

Example 38

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(3,4-diethyl-6-methylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone)

Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone) was carried out according to the stage 01 of example 28.

Stage 02: Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile

Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile carried out according to the stage 02 of example 28.

Stage 03: Synthesis of N-hydroxy-2-(2-methyl[,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime

Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime carried out according to the stage 03 of example 28.

Stage 04: Synthesis of 3-amino-4,5-dimethylisoxazole

Synthesis of 3-amino-4,5-dimethylisoxazole carried out according to the stage 04 of example 28.

Stage 05: Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid

Synthesis of ethyl ester of 4-bromo-3-bromomethylphenyl acid was carried out according to the stage 02 example 01.

Stage 06: Synthesis of ethyl ester of 4-bromo-3-methoxypyrazine acid

Synthesis of ethyl ester of 4-bromo-3-methoxypyrazine acid was carried out according to the stage 04 of example 20.

Stage 07: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 08: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Step 10: Synthesis of 3-harrows-N-(4,5-dimeth the l-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 11: Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy acid

Synthesis of ethyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methoxymethylethoxy acid was carried out according to the stage 15 example 21.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-2-methoxyethyl)amide 3-(2-ethoxymethyl-4-hydroxymethylene)-5-methylthiophene-2-sulfonic acid was carried out according to the stage 16 example 21.

Stage 13: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid

Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid was carried out according to the stage 16 example 21.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(3,4-diethyl-6-methylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-methoxymethyl]-5-metaltype the-2-sulfonic acid

To a stirred solution of 3,4-diethyl-6-methyl-1H-pyrazolo[4,3-c]pyridine (536 mg, 2.8 mmol) in dimethylformamide (10 ml) at 0°C under nitrogen atmosphere was added in portions sodium hydride (60% in mineral oil) (204 mg, 4.2 mmol). After the addition the reaction mixture was heated to ambient temperature and maintained for 30 minutes, the Reaction mixture was cooled to 0°C, the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-ethoxymethyleneamino ether methanesulfonate acid (1.5 g, 2.8 mmol) in 10 ml of dimethylformamide and stirred at room temperature for 16 hours the Mixture then was diluted with ethyl acetate (40 ml), then 10 ml of cold water. The organic layer was washed with water and saturated salt solution, then dried over sodium sulfate and evaporated in vacuum, obtaining 1.5 g of the crude compound. The crude compound was purified by chromatography on a column of silica gel, receiving 1.0 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(3,4-diethyl-6-methylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 15: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(3,4-diethyl-6-methylpyrazolo[4,3-C]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid

1.5 the (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(3,4-diethyl-6-methylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid at room temperature was added 95%ethanol (10 ml) and 6 N. an aqueous solution of hydrochloric acid (8 ml). The reaction mixture was heated under reflux for 3 hours, the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with dichloromethane (25 ml×3). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on silica gel using a mixture of hexane:ethyl acetate, receiving 90 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(3,4-diethyl-6-methylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid.

Stage 16: Synthesis of 5-aminoet-4-EN-3-one

A mixture of heptane-3,5-dione (8 g, 0,062 mol) and ammonium acetate (14,43 g, 0,187 mol) in dry methanol (50 ml) was stirred at room temperature for 24 h the Reaction mixture was concentrated completely under vacuum and to the residue was added chilled water. The reaction mixture was podslushivaet to pH 8 using a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate (100 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over sodium sulfate and evaporated, receiving 6 g 5-aminoet-4-EN-3-one.

Stage 17: Synthesis of 2-ethyl-6-methyl-3-propionyl 1H-pyridine-4-it

mesh 2,2,6-trimethyl[1,3]dioxin-4-it (13,4 g, 0,094 mol) and 5-aminoet-4-EN-3-one (6 g, 0,047 mol) was heated under reflux at 120°C for 6 hours, the Reaction mixture was purified by chromatography on a column of silica gel, elwira the desired product 10%methanol and ethyl acetate, receiving of 3.9 g of 2-ethyl-6-methyl-3-propionyl 1H-pyridine-4-it.

Stage 18: Synthesis of 1-(4-chloro-2-ethyl-6-methylpyridin-3-yl)propane-1-it

2-Ethyl-6-methyl-3-propionyl 1H-pyridin-4-one (3.9 g) was added at 0°C to 20 ml of phosphorus oxychloride. Was stirred and heated the reaction mixture at 100°C and kept for 6 hours. Was processed, pariva phosphorus oxychloride in a vacuum, and the residue was podslushivaet to pH 8 with a saturated solution of sodium carbonate followed by extraction with methylene chloride (50 ml×2). The combined extracts were washed with water and saturated salt solution. Was dried over anhydrous sodium sulfate and concentrated, obtaining 2,95 g of 1-(4-chloro-2-ethyl-6-methylpyridin-3-yl)propane-1-it.

Stage 19: the Synthesis of 3,4-diethyl-6-methyl-1H-pyrazolo[4,3-c]pyridine

1-(4-chloro-2-ethyl-6-methylpyridin-3-yl)propane-1-he (2,95 g) was placed in ethanol (20 ml) and the reaction mixture was added hydrazinehydrate (6 ml) and two drops of acetic acid. The temperature was slowly raised and the mixture was heated under reflux, while maintaining the boil for 6 hours. The reaction mixture was completely evaporated in a vacuum. The crude mass was poured the ice, the obtained solid was filtered and dried under suction, getting 1.68 g of 3,4-diethyl-6-methyl-1H-pyrazolo[4,3-c]pyridine.

Molecular formula: C30H35N5O4S2

Molecular weight: 593.

1H NMR (DMSO-d6): 1,29-of 1.36 (m, 6H), for 1.49 (s, 3H), and 2.14 (s, 3H), 2,48 (s, 3H), of 2.54 (s, 3H), 3,07-3,13 (m, 5H), is 4.03 (s, 2H), 5,59 (s, 2H), 6,70 (s, 1H), 6,92-7,01 (m, 2H), 7,34 (s, 1H), of 7.48 (s, 1H), 10,75 (user., 1H).

Mass spectrum: (m-1) 592,2.

Example 39

(4,5-Dimethylisoxazol-3-yl)amide 3-[4-(4-ethoxy-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

Stage 01: Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone)

Synthesis of sodium salt of 3-hydroxy-2-methylbut-2-onitrile (sodium salt of 3-cyano-2-butanone) was carried out according to the stage 01 of example 28.

Stage 02: Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile

Synthesis of 2,2-(2-methyl[1,3]dioxolane-2-yl)propionitrile carried out according to the stage 02 of example 28.

Stage 03: Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime

Synthesis of N-hydroxy-2-(2-methyl[1,3]dioxolane-2-yl)propionamide or 2-(β-atlanticcity)propionamidoxime carried out according to the stage 03 of example 28.

Stage 04: Synthesis of 3-amino-4,5-demetrise is casola

Synthesis of 3-amino-4,5-dimethylisoxazole carried out according to the stage 04 of example 28.

Stage 07: Synthesis of 5-methylthiophene-2-sulphonylchloride

Synthesis of 5-methylthiophene-2-sulphonylchloride carried out according to the stage 07 example 01.

Stage 08: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 08 example 01.

Stage 09: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 example 01.

Step 10: Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine

Synthesis of 3-harrows-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-5-methylthiophenethylamine carried out according to the stage 10 example 01.

Stage 13: Synthesis of methyl ester of (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid

Synthesis of methyl ester (4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzoic acid was carried out according to the stage 08 of example 19.

Stage 14: Synthesis of (4,5-dimethylisoxazol the l-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid

Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-(4-hydroxymethyl-2-were)-5-methylthiophene-2-sulfonic acid was carried out according to the stage 09 of example 19.

Stage 15: Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl)-3-methylbenzylamino ether methanesulfonate acid

Synthesis of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid was carried out according to the stage 10 of example 19.

Step 12: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-chloro-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To a stirred solution of 4-chloro-5,7-diethyl-1H-[1,6]naphthiridine-2-she (0.5 g, 2.2 mmol) in dimethylformamide (10 ml) at ambient temperature under nitrogen atmosphere was added potassium carbonate (437 mg, 3.2 mmol) and the reaction mixture was added dropwise a solution of 4-{2-[(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)sulfamoyl]-5-methylthiophene-3-yl}-3-methylbenzylamino ether methanesulfonate acid (1,17 g, 2 mmol) in 10 ml of dimethylformamide and stirred at room temperature for 16 hours, the Reaction mixture was then filtered and the residue was washed with ethyl acetate (40 ml), the combined organic layer was washed with water and saturated Rast is or salt, then was dried over sodium sulfate and evaporated in vacuum, obtaining 1.2 g of the crude substance, which was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, obtaining 0.8 g (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-chloro-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulphonic acid in the form of a viscous oily mass.

Stage 13: Synthesis of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-ethoxy-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To mix the solution (800 mg, 1.15 mmol) of (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-chloro-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid in 8 ml of ethanol at room temperature was added ethoxide sodium (120 mg, 1.7 mmol). After complete addition, the reaction mixture was stirred and heated at 40°C for 1 hour. Then the reaction mixture was cooled to room temperature and evaporated in vacuum. To the residue was added water and brought the pH to 2 with aqueous hydrochloric acid followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with water and saturated salt solution, and finally dried over sodium sulfate and evaporated in vacuum receiving 700 mg (4,5-dime isoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-Hexi-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulphonic acid in the form of oil.

Stage 14: Synthesis of (4,5-dimethylisoxazol-3-yl)amide 3-[4-(4-ethoxy-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid

To (4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(4-ethoxy-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid (0.3 g) at room temperature was added ethanol (5 ml) and 6 N. aqueous solution of hydrochloric acid (3 ml). The reaction mixture was heated under reflux for 2 hours the Reaction mixture was concentrated in vacuo, the pH of the solution was brought to pH 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (25 ml×2). The combined organic extract was washed with water and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel, using hexane:ethyl acetate, receiving 80 mg (4,5-dimethylisoxazol-3-yl)amide 3-[4-(4-ethoxy-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid as a brown solid.

Stage 11: Synthesis of 3-aminomethylenemalonate

Synthesis of 3-aminomethylenemalonate carried out according to the stage 11 of example 28.

Step 12: Synthesis of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid

Synthesis of methyl ester of 2,6-diethyl-4-oxo-1,4-hydropyridine-3-carboxylic acid was carried out according to the stage 12 of example 28.

Stage 13: Synthesis of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid

Synthesis of methyl ester of 2,6-diethyl-4-(toluene-4-sulfonylamino)nicotinic acid was carried out according to the stage 13 of example 28.

Stage 14: Synthesis of methyl ester of 4-amino-2,6-diethylnicotinamide acid

Synthesis of methyl ester of 4-amino-2,6-diethylnicotinamide acid was carried out according to the stage 14 of example 28.

Stage 19: Synthesis of ethyl ether 5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro[1,6]naphthiridine-3-carboxylic acid

Diethylmalonate (15 ml, 0,093 mol) and methyl-4-amino-2,6-diethylpyrazine-3-carboxylate (19,0 g, 0.09 mol) was added to a solution of ethoxide sodium (7 g, 0.10 mol) in ethanol (60 ml)and the reaction mixture was heated at 150°C and a pressure of 100 psi for 20 hours in an autoclave. The reaction mixture was allowed to cool, the volatiles were removed by evaporation and the resulting semi-solid substance was rubbed with a simple ester, getting a solid white color, which was separated by filtration and dissolved in water. The resulting solution was then acidified using 1 N. hydrochloric acid, getting a solid white color, which was filtered and dried under suction, receiving 11 g of 5,7-diethyl-4-hydroxy--oxo-1,2-dihydro-1,6-naphthiridine-3-ethylcarboxylate in the form of a white solid.

Stage 20: the Synthesis of 5,7-diethyl-4-hydroxy-1H-[1,6]naphthiridine-2-it

5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro-1,6-naphthiridine-3-ethylcarboxylate (11 g) was dissolved in a mixture of water (11 ml), 1,4-dioxane (22 ml) and concentrated hydrochloric acid (11 ml) and the reaction mixture was heated under reflux for 3 hours. The reaction mixture was then cooled, the suspended solid was filtered, washed with ethanol and simple with ether, and dried under suction, obtaining 4.3 g of 5,7-diethyl-4-hydroxy-1,6-naphthiridine-2(1H)-it is in the form of a white solid.

Stage 21: Synthesis of 4-chloro-5,7-diethyl-1,6-naphthiridine-2(1H)-it

4.3 g (0.019 mol) of 5,7-diethyl-4-hydroxy-1,6-naphthiridine-2(1H)-it was dissolved in 22 ml of phosphorus oxychloride and the reaction mixture was heated under reflux for 24 hours. The reaction mixture was concentrated, the residue was dissolved in concentrated hydrochloric acid (16 ml) and 22 ml of water and heated under reflux for 4 hours. The reaction mixture was diluted with water and podslushivaet solid sodium bicarbonate. The obtained solid substance was separated by filtration, washed with water and dried under suction, obtaining 3.0 g of 4-chloro-5,7-diethyl-1,6-naphthiridine-2(1H)-it is in the form of a solid orange color.

Molecular formula: C32H36N4O5S2

Forefront of the regular weight: 620.

1H NMR (DMSO-d6): 1,16-of 1.27 (m, 6H), 1,47 of 1.50 (m, 6H), of 1.92 (s, 3H), 2,12 (s, 3H), 2,48 (s, 3H), 2,67-2,72 (sq, J=7.2 Hz, 2H), 3,20-3,26 (sq, J=7.2 Hz, 2H), 4,21-4.26 deaths (sq, J=6,8 Hz, 2H), 5,46 (s, 2H), 6,10 (s, 1H), 6,70 (, 1H), 6,84-6,91 (m, 2H), 7,11-7,16 (m, 2H), 10,26 (s, 1H).

Mass spectrum: (m-1) 619,2

The following compounds can also be obtained using the techniques shown on reaction scheme I, II and III, as shown above:

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl)phenyl]-5-methyl-furan-2-sulfonic acid (compound 40),

(4-ethyl-5-methylisoxazol-3-yl)amide 5-methyl-3-[4-(7-oxo-2-propyl-4,5,6,7-tetrahydroimidazo-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 41),

3-{4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]benzyl}-4-oxo-2-propyl-3,4-dihydroquinazolin-5-carboxylic acid (compound 42),

(4,5-dimethylisoxazol-3-yl)amide 5-methyl-3-[4-(3,4,5,7-tetramethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 43),

(4,5-dimethylisoxazol-3-yl)amide 2[4-(4,5-diethyl-3,7-dimethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl)phenyl]pyridine-3-sulfonic acid (compound 44),

2-butyl-5-chloro-3-{4-[5-(4,5-dimethylisoxazol-3-ylsulphonyl)-3-methylisoxazol-4-yl]benzyl}-3H-imidazole-4-carboxylic acid (compound 45),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(2-methyl-5,6,7,8-tetrahydroquinolin-4-intoximeter)phenyl]benzo[b]thiophene-2-sulfonic key is lots (compound 46),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)phenyl]benzo[b]thiophene-2-sulfonic acid (compound 47),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl)phenyl]-4,5,6,7-tetrahydrobenzo[b]thiophene-2-sulfonic acid (compound 48),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-chloro-4-(5,7-dimethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl)phenyl]benzofuran-2-sulfonic acid (compound 49),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-chloro-4-(3,5-dipropyl-1,2,4-triazole-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 50),

(5-methyl-4-propylenoxide-3-yl)amide 3-{2-chloro-4-[5,7-diethyl-3-(5-methylthiophene-2-yl)-2-oxo-2H-1,6-naphthiridine-1-ilmatieteen-2-sulfonic acid (compound 51),

(4,5-dimethylisoxazol-3-yl)amide of 4-[4-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine-3-ylmethyl)phenyl]-3-methylisoxazol-5-sulfonic acid (compound 52),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-chloro-4-(3-isobutyl-6-methoxy-2-methylinosine-4-intoximeter)phenyl]-5-methylthiophene-2-sulfonic acid (compound 53),

(4-butyl-5-methylisoxazol-3-yl)amide 3-[2-chloro-4-(4-oxo-2-propyl-1,3-diazaspiro[4,5]Dec-1-EN-3-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 54),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-chloro-4-(5-phenyl-2-propyl-2H-1,2,4-triazole-3-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 55),

(4,5-demetrise Sasol-3-yl)amide of 4-methyl-2-[4-(7-oxo-2-propyl-4,5,6,7-tetrahydroimidazo-1-ylmethyl)phenyl]pyridine-3-sulfonic acid (compound 56),

(5-methoxy-thiazolo[5,4-b]pyridine-2-yl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 57),

(2,4-dimethoxypyrimidine-5-yl)amide 2-[4-(5,7-dimethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl)phenyl]pyridine-3-sulfonic acid (compound 58),

(2,4-dimethoxypyrimidine-5-yl)amide 3-{4-[4,6-dimethyl-3-(5-methylthiophene-2-yl)pyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}thiophene-2-sulfonic acid (compound 59),

isoxazol-3-alamid 3-{4-[4,6-dimethyl-3-(5-methylthiophene-2-yl)pyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid (compound 60),

(5-ethyl-1,3,4-thiadiazole-2-yl)amide 3-[4-(6-methoxy-2,3-dimethylindoline-4-intoximeter)phenyl]thiophene-2-sulfonic acid (compound 61),

(1H-tetrazol-5-yl)amide 3-{4-[3-(3-chlorophenyl)-5,7-diethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl]phenyl}thiophene-2-sulfonic acid (compound 62),

(4,5-dimethylisoxazol-3-yl)amide 3-{4-[4,6-dimethyl-3-(3-triptoreline)pyrazolo[4,3-c]pyridine-1-ylmethyl]-2-hydroxyphenyl}-5-methylthiophene-2-sulfonic acid (compound 63),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-(2-hydroxyethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 64),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-chloro-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-methoxyphenyl]-5-methylthiophene-2-sulfonic acid (compound 65),

(4,5-dimethylisoxazol-3-alamid 3-[4-(3-1,3-benzodioxol-5-yl-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-(2-methoxyethoxy)phenyl]-5-methylthiophene-2-sulfonic acid (compound 66),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-[4,6-dimethyl-3-(5-methylthiophene-2-yl)pyrazolo[4,3-c]pyridine-1-ylmethyl]-2-(2-oxopyrrolidin-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 67),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-phenylpyrazole[4,3-c]pyridine-1-ylmethyl)-2-(3,5-dimethylpyrazol-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 68),

(4,5-dimethylisoxazol-3-yl)amide 3-{4-[3-(3-isobutoxy)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-methoxyphenyl}-4,5-dimethylthiophene-2-sulfonic acid (compound 69),

(4,5-dimethylisoxazol-3-yl)amide 3-{4-[3-(3-chlorophenyl)-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl]-2-ethoxyphenyl}-5-ethylthiophen-2-sulfonic acid (compound 70),

(4-chloro-5-methylisoxazol-3-yl)amide 3-{4-[4-(4-methoxyphenyl)-5,7-dimethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl]-2-propoxyphenyl}-5-methylthiophene-2-sulfonic acid (compound 71),

(4,5-dimethylisoxazol-3-yl)amide 3-{4-[5,7-dimethyl-4-(4-methylpiperazin-1-yl)-2-oxo-2H-1,6-naphthiridine-1-ylmethyl]-2-methoxyphenyl}-5-methylthiophene-2-sulfonic acid (compound 72),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-methoxy-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-(2-methoxyethoxy)phenyl]-5-methylthiophene-2-sulfonic acid (compound 73),

ethyl ester of 4-{4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]benzyloxy}-6-methyl-2-propylresorcinol acid (compound 74),

4-{4-2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]benzyloxy}-6-methyl-2-propylenimine acid (compound 75),

methyl ester of 3-{4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]benzyl}-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylic acid (compound 76),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(6-oxo-4-phenyl-2-propyl-6H-pyrimidine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 77),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(2,4-dimethyl-7-oxo-6,7-dihydro-5H-pyrido[2,3-d]pyrimidine-8-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 78),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(4-ethyl-6-oxo-2-propyl-6h-pyrimidine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 79),

(4,5-dimethylisoxazol-3-yl)amide 3-{4-[(3-cyano-5,7-dimethyl-1,6-naphthiridine-2-ylamino)methyl]phenyl}thiophene-2-sulfonic acid (compound 80),

(4,5-dimethylisoxazol-3-yl)amide 3-{4-[4,6-dimethyl-3-(5-methylthiophene-2-yl)pyrazolo[4,3-c]pyridine-1-ylmethyl]-2-ethoxymethyl}-5-methylthiophene-2-sulfonic acid (compound 81),

(4-isobutyl-5-methylisoxazol-3-yl)amide 3-{2-chloro-4-[5,7-diethyl-3-(5-methylthiophene-2-yl)-2-oxo-2H-1,6-naphthiridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid (compound 82),

ethyl ester of 4-{4-[2-(5-ethyl-4-methylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]benzyloxy}-6-methyl-2-propylresorcinol acid (compound 83),

(4,5-dimethylisoxazol-3-yl)amide 3-{2,6-dichloro-4-[4,6-dimethyl-3-(5-methylthiophene-2-yl)pyrazolo[4,3-c]pyridine-1 and the methyl]phenyl}-5-methylthiophene-2-sulfonic acid (compound 84),

(4-ethyl-5-methylisoxazol-3-yl)amide 3-{2-chloro-4-[3-methyl-6-thiophene-2-ylmethyl-4-(3-triptoreline)pyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid (compound 85),

(5-ethyl-4-methylisoxazol-3-yl)amide 3-[4-(6-cyclopropylmethyl-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-propylphenyl]-5-methylthiophene-2-sulfonic acid (compound 86),

(4,5-dimethylisoxazol-3-yl)amide 3-(4-{6-[2-(3-chlorophenyl)-ethyl]-3,4-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl}-2 hydroxyphenyl)-5-methylthiophene-2-sulfonic acid (compound 87),

(4,5-dimethylisoxazol-3-yl)amide 3-{2-(2-hydroxyethyl)-4-[3-methyl-6-(4-methylbenzyl)-4-(5-methylthiophene-2-yl)pyrazolo[4,3-c]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid (compound 88),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(4-cyclopropylmethyl-6-isobutylpyrazine[4,3-c]pyridine-1-ylmethyl)-2-methoxyphenyl]-5-methylthiophene-2-sulfonic acid (compound 89),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-cyclopropyl-4,6-dimethylpyrazolo[4,3-c]pyridine-1-ylmethyl)-2-forfinal]-5-methylthiophene-2-sulfonic acid (compound 90),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-[4-(3-chlorophenyl)-6-methyl-3-cryptomaterial[4,3-c]pyridine-1-ylmethyl]-2-(2-methoxyethoxy)phenyl]-5-methylthiophene-2-sulfonic acid (compound 91),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-chloro-6-methyl-4-propylpyrazole[4,3-c]pyridine-1-ylmethyl)-2-were]-4,5-dimethylthiophene-2-sulfona the Oh of the acid (compound 92),

(5-ethyl-4-methylisoxazol-3-yl)amide 3-{4-[3-(4-butoxyphenyl)-6-methyl-4-cryptomaterial[4,3-c]pyridine-1-ylmethyl]-2-chlorophenyl}-5-ethylthiophen-2-sulfonic acid (compound 93),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(7-isobutyl-2-oxo-5-phenyl-2H-1,6-naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 94),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(7-benzyl-2-oxo-5-propyl-2H-1,6-naphthiridine-1-ylmethyl)-2-chlorophenyl]-5-ethylthiophen-2-sulfonic acid (compound 95),

(4,5-dimethylisoxazol-3-yl)amide 3-{2,6-dichloro-4-[7-cyclopropylmethyl-5-(5-methylthiophene-2-yl)-2-oxo-2H-1,6-naphthiridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid (compound 96),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,5-dimethyl-2-oxo-7-thiophene-2-ylmethyl-2H-1,6-naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 97),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-chloro-4-(7-ethyl-2-oxo-5-thiophene-2-ylmethyl-2H-1,6-naphthiridine-4-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 98),

(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5-cyclopropylmethyl-7-ethyl-2-oxo-2H-1,6-naphthiridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid (compound 99),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-chloro-4-(7-cyclopropylmethyl-2-oxo-4-o-tolyl-5-trifluoromethyl-2H-1,6-naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 100),

(4,5-dimethylisoxazol-3-yl)amide 3-{2-C is chlorophyllose-4-[5,7-dimethyl-2-oxo-4-(pyridine-4-yloxy)-2H-1,6-naphthiridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid (compound 101),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-chloro-4-(5,7-dimethyl-2-oxo-3-pyridin-2-yl-2H-1,6-naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 102),

(4,5-dimethylisoxazol-3-yl)amide 3-[2-chloro-4-(5,7-diethyl-4-methyl-2-oxo-3-phenyl-2H-1,6-naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 103),

(S)-2-({4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]-3-ethoxymethylene}pentanediamine)-3-matlakala acid (compound 104).

The screening model to determine the potential for in vivo

Animals:

Male SD rats (300-350 g) were anestesiologi with a mixture of ketamine/xylazine (or ketamine/diazepam). After tracheal intubation, rats were ventolinbuy room air in a volume of 10 ml/kg of body weight and respiratory rate of 70 breaths/minute. Animals were warmed by homeomorphically overall system. The left jugular vein was Coulibaly intravenous drugs, and the right femoral artery for measurement of systemic blood pressure and heart rate. After stabilization of blood pressure (approximately 15 minutes) was administered atropine (0.4 mg/kg) and mecamylamine (3 mg/kg) for inhibition of the autonomic nervous reflexes.

The efficiency of receptor AT the shot rats

Blood pressure increased to approximately 45 mm Hg Kee is Noah infusion of human Ang II (50 ng/kg/min) for 2.5-3 hours. To block all the receptors ETA, prior to infusion of Ang-II was administered selective ETA antagonist (ZD1611, 1.5 mg/kg). When the blood pressure was stabilized, the investigated compound was administered by infusion over 30 minutes at three increasing speed of introduction of the drug. Blood samples were collected at the beginning and end of each speed the introduction of drugs to determine plasma concentrations of the drug. Similarly, blood samples were taken at intervals for 2 hours after completion of infusion of the drug. The number of animals on each connection was 6-8. Blood pressure was recorded during the whole experiment. PK/PD modeling is then used to study the pharmacodynamics (i.e. the capacity and efficiency of in vivo using unbound plasma concentration and the data on the effect (blood pressure).

Potential receptor ETA at shot rats

Blood pressure was increased by a constant infusion of human big ET-1 (0.05 ng/kg/min) for 2.5-3 hours. To block all the receptors AT, prior to the infusion of big ET-1 was administered Losartan. When the blood pressure was stabilized, the investigated compound was administered by infusion over 30 minutes at three increasing speed of introduction of medicinal medium spans the VA. Blood samples were taken during the beginning and end of each speed the introduction of drugs to determine plasma concentrations. Similarly, blood samples were taken at intervals for 2 hours after completion of infusion of the drug. The number of animals on each connection was 6-8. Blood pressure was recorded during the whole experiment. PK/PD modeling is then used to study the pharmacodynamics (i.e. the capacity and efficiency of in vivo using unbound plasma concentration and the data on the effect (blood pressure).

Figure 1: Percentage of inhibition induced by angiotensin II (Ang-II) and big endothelin 1 (bET 1) increase blood pressure in rats SD compound of example 15.

The screening model to determine the potential for in vitro

Functional test AT

The CHO cells, stably superexpression full-receptor AT man, was cultured in DMEM (Gibco) with 10% FCS (Hyclone) and selection supported, using 0.5 mg/ml G418 (Gibco). Cells at 70%confluence were treated with trypsin and re-suspended in medium and counted. 20000 cells/well were cultivated in black 384-well polystyrene tablets with clear reasons and left for 16 hours for adhesion. To the cells was added to the dye Flou-4 (TEFLABS, USA) in HBSS (Gibco) for 1 hour, the meters were washed in HBSS and the cells were added to 0.6 µl of the diluted compounds in dimethyl sulfoxide in 30 μl of HBSS in the liquid processing system Multimek (Beckman, USA). The cells were then placed in fluorometrically spectrophotometer to read the tablets (FLIPR, Molecular Devices, USA) was added to 20 μl of the peptide angiotensin-II as an agonist (EC80) in HBSS.

The output of Sa was observed within 2 minutes, and the maximum peak height was measured at various concentrations of compounds and was built according to the equation

y=A+((B-A)/1+((C/x)^D))),

and was calculated IC50where

A mean plateau base curve, i.e. the final value of the minimum y,

B means the top plateau of the curve, there is a finite maximum y,

C is the value of x in the middle of the curve. It represents the value of log EC50when A+B=100,

D means the angular coefficient, x is the known initial values of x, y means originally known y-values.

Functional test ETA

The CHO cells, stably superexpression full-receptor ETA man, was cultured in DMEM (Gibco) with 10% FCS (Hyclone) and selection supported, using 0.5 mg/ml G418 (Gibco). Cells at 70%confluence were treated with trypsin and re-suspended in medium and counted. 20000 cells/well were cultivated in black 384-well polystyrene tablets with clear reasons and left for 16 hours for adhesion. To the cells was added to the dye Flou-4 (TEFLABS, USA) in HBSS (Gibco) for 1 hour, then washed in HBSS and the cell is added 0.6 μl of the diluted compounds in dimethyl sulfoxide in 30 μl of HBSS in the liquid processing system Multimek (Beckman, USA). The cells were then placed in fluorometrically spectrophotometer to read the tablets (FLIPR, Molecular Devices, USA) was added to 20 μl of the peptide endothelin-1 as an agonist in HBSS (EC80).

The output of Sa was observed within 2 minutes, and the maximum peak height was measured at various concentrations of compounds and was built according to the equation

y=A+((B-A)/1+((C/x)^D))),

and was calculated IC50where

A mean plateau base curve, i.e. the final value of the minimum y,

B means the top plateau of the curve, there is a finite maximum y,

C is the value of x in the middle of the curve. It represents the value of log EC50when A + B = 100,

D means the angular coefficient, x is the known initial values of x, y means originally known y-values.

In General, the potential of the compounds according to the present invention is from 1 nm to 10 μm for AT and from 10 nm to 50 μm for ETA: Examples of individual values IC50are as follows:

ExampleIC50(AT1)(nm)IC50(ETA) (μm)
31252,92
429 6,2
622,90,562
724,60,814
820,82,87
1511,40,503
187,981,43
217,470,464
2225,20,454
2322,10,248
2427,41,89
2611718,9
27the 15.60,646
2915,90,292
3018,93,32
34189? 7.04 baby mortality/td>
3527,6to 2.57
3658,30,758
371530,407
3817,21,04
3925,10,781

These values show that the balance of selectivity between AT vs. ETA is good for the compounds according to the present invention, which is unexpected relative to the prior art.

1. The compound of the formula

where R3 has any of the formulas

where R1 is selected from

where
R2, each independently, signifies hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy-C1-C8alkyl, C1-C8alkoxy;
R4 means a five - or six-membered monocyclic ring system having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazolyl or thiazolyl, each of which may be optionally substituted by one or more of the following substituents: With1-C8alkylamine 1-C8alkoxy;
R5 and R6 independently denote hydrogen or C1-C8alkyl;
R7 and R8 together form cyclopentene ring;
R9 independently means1-C8alkyl;
R9a is independently means1-C8alkylsulphonyl or phenylcarbinol;
R10 denotes hydrogen;
R11 independently mean C1-C8-alkyl or C1-C8alkoxy;
R12 denotes hydrogen or -- COOR17;
R13 independently denotes hydrogen, phenyl and 6-membered heteroaryl containing one heteroatom selected from N;
R17 denotes hydrogen;
R23 means
(a)1-C8alkyl, phenyl, 5-membered heteroaryl containing 1-2 heteroatoms selected from S, N, where any phenyl and heteroaryl residues optionally substituted with halogen, C1-C8the alkyl or C1-C8alkoxy;
R24 means1-C8alkyl;
R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl;
R29 means -(CH2)w-COOR17; where w=0;
R31 denotes hydrogen;
including its pharmaceutically acceptable salt.

2. The compound according to claim 1, which is selected from the group of compounds including
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(2-butyl-4-oxo-13-diazaspiro[4.4]non-1-EN-3-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid (compound 1),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-C]p is ridin-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 2),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenylsulfonyl-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 3),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-benzoyl-6-ethyl-2-methylpyridin-4-intoximeter)phenyl]thiophene-2-sulfonic acid (compound 4),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 5),
(4,5-dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-3,4-dimethylpyrazolo[4,3-C]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 6),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 7),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-4-phenoxy-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 8),
(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-C]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 9),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(2-methylinosine-4-intoximeter)phenyl]thiophene-2-sulfonic acid (compound 10),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid (compound 11),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(3-acetyl-2,6-dimethylene the Jn-4-intoximeter)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid (compound 12),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-paraolimpiyskogo[4,3-C]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid (compound 13),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-C]pyridine-1-ylmethyl)-2-ethoxymethyl]-5-methylthiophene-2-sulfonic acid (compound 14),
(4,5-dimethylisoxazol-3-yl)amide 3-{4-[3-(3,5-dimethylpyrazol-1-ylmethyl)-4,6-dimethylpyrazolo[4,3-C]pyridine-1-ylmethyl]-2-ethoxymethyl}-5-methylthiophene-2-sulfonic acid (compound 15),
(4,5-dimethoxyethoxy-3-yl)amide 3-[2-methoxymethyl-4-(4,5,7-trimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 16),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(6-ethyl-3,4-dimethylpyrazolo[4,3-C]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid (compound 17),
(4,5-dimethylisoxazol-3-yl)amide 3-(4,6-dimethyl-3-phenylpyrazole[4,3-C]pyridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid (compound 18),
(4,5-dimethylisoxazol-3-yl)-(2-methoxyethoxymethyl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid (compound 19),
4-{4-[2-(4,5-dimethylisoxazol-3-ylsulphonyl)-5-methylthiophene-3-yl]-3-methoxymethylethoxy}-2-atelinae-6-carboxylic acid (compound 20),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(4,6-dimethyl-3-thiophene-2-alprazola[4,3-C]pyridi the-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid (compound 21),
(4,5-dimethylisoxazol-3-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-C]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 22),
(4,5-dimethylisoxazol-3-yl)amide 3-{2-ethoxymethyl-4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-C]pyridine-1-ylmethyl]phenyl}-5-methylthiophene-2-sulfonic acid (compound 23),
(4,5-dimethylisoxazol-3-yl)amide 3-{4-[6-ethyl-3-(4-methoxyphenyl)-4-methylpyrazolo[4,3-C]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid (compound 24),
(5-methylisoxazol-3-yl)amide 2-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-C]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-3-sulfonic acid (compound 25),
3-{4-[2-(3,4-dimethylisoxazol-5-ylsulphonyl)-5-methylthiophene-3-yl]benzyl}-2-ethoxy-3H-benzimidazole-4-carboxylic acid (compound 26),
(3,4-dimethylisoxazol-5-yl)amide 3-[2-ethoxymethyl-4-(6-ethyl-4-methyl-3-thiophene-2-alprazola[4,3-C]pyridine-1-ylmethyl)phenyl]-5-methylthiophene-2-sulfonic acid (compound 27),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-propylthiophene-2-sulfonic acid (compound 28),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-3-phenyl-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-sulfonic acid (compound 29),
(3,4-dimethylisoxazol-5-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-methylthiophene-2-Sul the background acid (compound 30),
(4,5-dimethylisoxazol-3-yl)amide 5-methyl-3-[2-methyl-4-(3-methyl-5-oxo-1-phenyl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 31),
(4,5-dimethylisoxazol-3-yl)amide 5-methyl-3-[2-methyl-4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 32),
(4,5-dimethylthiazol-2-yl)amide 3-[4-(5-oxo-3-propyl-1-pyridin-2-yl-1,5-dihydro[1,2,4]triazole-4-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 33),
isobutoxide(3-methoxy-5-methylpyrazine-2-yl)amide 3-[4-(6-ethyl-4-methyl-3-phenylpyrazole[4,3-C]pyridine-1-ylmethyl)phenyl]thiophene-2-sulfonic acid (compound 34),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-forfinal]-5-methylthiophene-2-sulfonic acid (compound 35),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(5,7-dimethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-isobutoxide]-5-methylthiophene-2-sulfonic acid (compound 36),
(4,5-dimethylisoxazol-3-yl)amide 3-{4-[3-(4-chlorophenyl)-4,6-dimethylpyrazolo[4,3-C]pyridine-1-ylmethyl]-2-were}-5-methylthiophene-2-sulfonic acid (compound 37),
(4,5-dimethylisoxazol-3-yl)amide 3-(4-(3,4-diethyl-6-methylpyrazolo[4,3-C]pyridine-1-ylmethyl)-2-methoxymethyl]-5-methylthiophene-2-sulfonic acid (compound 38),
(4,5-dimethylisoxazol-3-yl)amide 3-[4-(4-ethoxy-5,7-diethyl-2-oxo-2H-[1,6]naphthiridine-1-ylmethyl)-2-were]-5-metaltype the-2-sulfonic acid (compound 39).

3. A method of obtaining a compound according to claim 1, comprising at least one of the following stages:
a) interaction of thiophene with sulfurylchloride with getting thienylallylamine,
b) interaction of thienylallylamine with the primary amine with getting sulfonamida,
c) N-protection sulfonamida to obtain N-protected sulfonamida,
d) litvinovna halogenated or dehalogenating N-protected sulfonmethane, the subsequent interaction with the corresponding borate derivative to obtain N-protected sulfonamida boric acid,
e) N-protected sulfonamide boric acid further interacts with halogen-substituted complex alkilany ether aromatic carboxylic acids or aromatic aldehyde with getting aristotelova of ester or aldehyde,
f) recovering aristotelova of ester or aldehyde with getting aristotelova alcohol,
g) converting the hydroxy-group aristotelova alcohol aristotile derivative having a leaving group,
h) interaction aristotile derivative having a leaving group with a nucleophile, and
i) removing the protective group from the N-protected sulfonamida.

4. Pharmaceutical composition having the properties of receptor antagonists dual action receptor A1 and ETA, containing as an active ingredient the compound according to claim 1, in a mixture with a pharmaceutical adjuvant, diluent or carrier.

5. The use of compounds according to claim 1 for obtaining a medicinal product having the properties of receptor antagonists dual action receptor AT1 and ETA.

6. The use of compounds according to claim 1, having the properties of a receptor antagonist double-acting receptors AT1 and ETA to obtain drugs for the treatment of hypertension.

7. A method of treating hypertension by introducing to a mammal an effective amount of a compound according to claim 1.

8. A method of treating hypertension by introducing to a mammal an effective amount of a receptor antagonist double-acting receptors AT1 and ETA, which has a higher affinity for AT1 than ETA, representing a compound according to claim 1.



 

Same patents:

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 2,8-dimethyl-5-[2-(6-methyl-pyridyl-3)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole salts of general formula (1) exhibiting antidepressive and antihypoxic activity where n=1, 2 Y = (CH2COOH)2, HOOCCH(OH)CH2COOH, (HOOCCH2)2C(OH)COOH. Besides, the invention concerns a pharmaceutical agent.

EFFECT: ensured production of new biologically active compounds exhibiting antidepressive and antihypoxic activity.

6 cl, 5 ex, 2 tbl

FIELD: medicine, pharmaceutics.

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

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

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a condensed cyclic aromatic compound having the formula [2] given below: , where each R1 R2, R3, R5-R8, R10-R13, R15-R18, R20 denotes a hydrogen atom, R4, R9, R14, R19 denote phenyl, optionally substituted with two substitutes selected from tertbutyl. The invention also relates to use of said compound as an organic light-emitting layer in an organic light-emitting device.

EFFECT: obtaining a substance which can be used to make a light-emitting device which is durable and has high radiation efficiency.

2 cl, 6 ex, 2 tbl, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to new amino acid derivatives of formula (I), , in which R-groups have the following value: -R1 is -H;-R2 is -C(O)R15 or -SO2R15; -R3 is -H;-R4 is -H or -(1-4C)alkyl; -R6 is -H; -R7 is -H; -R8 is -H, cyanogroup, halogen, nitrogroup; -(1-6C)alkyl optionally substituted by amino group, hydroxyl or halogen; -heteroaryl representing a 5 or 6-members aromatic ring containing one or more heteroatoms N optionally substituted by -(1-4C) alkyl; -C(R16)NOR16, -C(O)N(R17)2, -C(O)R18 or -C(O)OR19; -R9 is -H; -R10 is -H or -(1-4C)alkyl; -R11 is -H; -R12 is -H; -R13 is -H; -R14 is -H; -R15 is -H; -(1-6C)alkyl, -(2-6C)alkynyl, -O(2-6C)alkyl) all optionally substituted by one or more, halogen, cyanogroup or 5-members heteroaryl where 5-members heteroaryl represents an aromatic ring containing one or more heteroatoms selected from a group including N, O or S; -(hetero)aryl representing 5 or 6-members aromatic ring system containing one or more heteroatoms selected from group including N, O or S, optionally substituted by -(1-4C)alkyl, halogen or NH2; -NH2, -(di)(1-4C)alkylamihogroup, -(1-4C)alkylamihogroup or -NR16OR16; R16 is -H or -(1-4C)alkyl; -R17 is -H or -(1-6C)alkyl optionally substituted by halogen, or 5 or 6-members heteroaryl or aryl optionally substituted by halogen, -(1-4C)alkyl or -(1-4C)alkoxygroup where heteroaryl represents an aromatic ring containing one or more heteroatoms selected from the group including N, O or S; -R18 is -H or -(1-4C)alkyl; -R19 is -H or -(1-6C)alkyl.

EFFECT: compounds of this invention are high-specific to glucocorticoid receptor and can be used for treating inflammatory diseases.

6 cl, 58 ex

FIELD: medicine.

SUBSTANCE: invention refers to aryl-izoxazole-4-yl-imidazo[1,5-a]pyridine derivatives of formula I and to their pharmaceutically acceptable acid addition salts. In formula I , R1 represents hydrogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom, cyano or -(CO)-Ra; Ra represents lower alkoxy or NR'R" where each of R' and R" independently represents hydrogen atom, 6-members heterocycloalkyl with the 1st heteroatom selected from O, or lower alkyl substituted by C3-C7-cycloalkyl. The invention also refers to a drug exhibiting affinity and selectivity to GABA(A) α5-receptor binding sites, containing one or more compounds of formula I and to an application of the compound of the invention in producing the drug exhibiting affinity and selectivity to GABA(A) α5-receptor binding sites.

EFFECT: improved efficacy of the drug.

7 cl, 2 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I): in which the radicals R1, R2, R3 and R4 independently represent hydrogen atom, halogen atom, hydroxy group, amino group, nitro group, an alkyl, alkenyl, cycloalkyl or aralkyl radical. And all these radicals can to be optionally substituted by haloalkyl or hydroxyalkyl, or radicals R2 and R3 in combination can represent a part of an aryl rings; R5 represents hydrogen atom, halogen atom, hydroxy group or thiol group, an alkyl, alkenyl, alkinyl, aryl, cycloalkyl, aralkyl radical or a 5-merous heteroaromatic ring containing 1, 2 heteroatoms selected from nitrogen and oxygen; the radicals R6 and R7 independently represent hydrogen atom, an alkyl or aryl radical; and X represents a group of formula where represents a bond or CH2, V represents O, W represents NH, a Y represents OH, or to its pharmaceutically acceptable salts, and besides to pharmaceutical composition based on said compound showing an inhibitory action on peptide deformylase (PDF).

EFFECT: new compounds which attract a great interest as new antibiotics are produced and described.

11 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of structural formula IIIm: or pharmaceutically acceptable salt thereof, where: R81 is selected from a group comprising hydrogen, halogen, possibly substituted C1-6alkyl, possibly substituted C2-6alkenyl, possibly substituted C2-6alkynyl, possibly substituted cycloalkyl, possibly substituted heterocycloalkyl, possibly substituted aryl, possibly substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR68, -SR68, -NR69R68, -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR69R68, -C(S)NR69R68, -S(O)2NR69R68; -NR69C(O)R68, -NR69C(S)R68, -NR69S(O)2R68, -NR69C(O)NH2, -NR69C(O)NR69R68, -NR69C(S)NH2, -NR69C(S)NR69R68, -NR69S(O)2NH2, -NR69S(O)2NR69R68, -S(O)R68 and -S(O)2R68, R83 is selected from a group comprising hydrogen, fluro and chloro; R112 is selected from a group comprising possibly substituted C2-6alkyl, possibly substituted aryl, possibly substituted heteroaryl and -NR79 R80; R68 is selected from a group comprising possibly substituted C1-6alkyl, possibly substituted C2-6alkenyl, but provided that when R68 is possibly substituted C2-6alkenyl, then one of its alkene carbons is not bonded with N, S, O, S(O), S(O)2, C(O) or C(S) from -OR68, -SR68, -NR69R68, -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR69R68, -C(S)NR69R68, -S(O)2NR69R68, -NR69C(O)R68, -NR69C(S)R68, -NR69S(O)2R68, -NR69C(O)NH2, -NR69C(O)NR69R68, -NR69C(S)NH2, -NR69C(S)NR69R68, -NR69S(O)2NH2, -NR69S(O)2NR69R68, -S(O)R68 or -S(O)2R68, possibly substituted C2-6alkynyl, but provided that when R68 is possibly substituted C2-6alkynyl, then one of its alkyne carbons is not bonded with N, S, O, S(O), S(O)2, C(O) or C(S) from -OR68, -SR68, -NR69R68, -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR69R68, -C(S)NR69R68, -S(O)2NR69R68, -NR69C(O)R68, -NR69C(S)R68, -NR69S(O)2R68, -NR69C(O)NH2, -NR69C(O)NR69R68, -NR69C(S)NH2, -NR69C(S)NR69R68, -NR69S(O)2NH2, -NR69S(O)2NR69R68, -S(O)R68 or -S(O)2R68, possibly substituted cycloalkyl, possibly substituted heterocycloalkyl, possibly substituted aryl and possibly substituted heteroaryl; R69 is selected from a group comprising hydrogen and possibly substituted C1-6alkyl; and R79 and R80 independently denote hydrogen or possibly substituted C1-6alkyl or R79 and R80 together with the nitrogen atom to which they are bonded form a possibly substituted 5-7-member heterocycloalkyl. Described also is a composition and a set for modulating protein kinase based on said compounds and use of said compounds in preparing a medicinal agent.

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

71 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic derivatives of general formula (I) where R1 denotes hydrogen, halogen, cyano, lower alkoxy or lower alkyl; R2 denotes aryl or a 5- or 6-member heteroaryl; R3 denotes hydrogen, aryl, a 5- or 6-member heteroaryl, where aryl, cycloalkyl, heterocycloalkyl or 5- or 6-member heteroaryl groups for R2 and R3 may be unsubstituted or substituted with halogen, cyano, lower alkyl, possibly substituted with one or more halogens, lower alkoxy, S(O)2-alkyl, -C(O)R', where R' is a lower alkyl, lower alkoxy; as well as pharmaceutically acceptable salts thereof. The invention also relates to a medicine based on said compounds for treating and preventing diseases mediated by the mGIuR5 receptor and use of compounds of formula (I) in preparing medicines.

EFFECT: novel compounds which are metabotropic glutamate receptor antagonists are obtained and described.

17 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compound has antibacterial activity and can be used as a medicinal agent. In formula ,

R1 is hydrogen, halogen, C1-4alkyl; R2 is selected from hydrogen, halogen, C1-4alkyl; R3 is selected from hydrogen, halogen, cyano, C1-4alkyl; W is -N(R6)-; X is a single bond; ring A is an unsaturated or partially saturated ring containing 5-6 atoms, one or two of which are independently selected from nitrogen and sulphur; or an unsaturated or partially saturated bicyclic ring containing 9-10 atoms, one, two or three of which are selected from nitrogen and sulphur; R4 and R5 are substitutes on a carbon atom and are independently selected from a halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, formyl, hydroxy iminomethyl, C1-4alkoxyminomethyl, C1-4alkyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkoxy)carbamoyl, N-(C1-4alkyl)-N-(C1-4alkoxy)carbamoyl, C1-4alkylS(O)a, where a equals 0-2, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, C1-4alkylsulphonylamino, (saturated or unsaturated carbocycle containing 3-7 atoms)-R10- or (saturated, partially saturated or unsaturated ring containing 5-6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R11-; where R4 and R5 can independently and optionally substituted at the carbon atom with one or more R12; R6 is hydrogen; n equals 1-4; where values of R4 can be identical or different; m equals 0-4; where values of R5 can be identical or different; R12 is selected from azido, halogen, cyano, hydroxy, amino, carboxy, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkylS(O)a, where a equals 0-2, (saturated or unsaturated cabocycle containing 3-7 atoms)-R14- or (saturated, partially saturated or unsaturated ring containing 5 or 6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R15-; where R12 can independently and optionally be substituted at the carbon atom with one or more R9; R10, R11, R14 and R15 are independently selected from a single bond, -C(O)-, -N(R19)C(O)- or -C(O)N(R20)-; where R19 and R20 are independently selected from hydrogen or C1-4alkyl; R16 is selected from halogen, cyano, hydroxy, carboxy, methyl and methoxy. The invention also relates to a pharmaceutical composition, having antibacterial activity, containing the disclosed compound as an active ingredient, use of the disclosed compound to prepare a medicinal agent and a method of producing the compound of formula (I).

EFFECT: high activity of the compounds.

22 cl, 52 tbl, 721 ex

FIELD: medicine, pharmaceutics.

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

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

50 cl, 18 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

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

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

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

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

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: medicine, pharmaceutics.

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

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

36 cl, 10 tbl, 44 ex

FIELD: chemistry.

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

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

Aromatic compound // 2416608

FIELD: chemistry.

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

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

62 cl, 2717 ex, 432 tbl

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

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