Derivatives of n-heteroaryl-pyridinesulfonamide, methods for their production (options), pharmaceutical composition, method of combating one or more effects of endothelin

 

(57) Abstract:

The invention relates to derivatives of N-heteroaryl-pyridinesulfonamide General formula I, in which one of the A1and A3represents nitrogen and the other represents CH; each of the A3and A4represents CH; Ar represents a phenyl group which is either not replaced, or has one Deputy; W, X, Y, Z can be nitrogen or a CH group; R1is hydrogen or halogen, and their pharmaceutically acceptable salts. The compounds possess endothelin-receptor antagonistic activity and are useful in the treatment of diseases or conditions in which a significant causal role of elevated or abnormal levels of endothelin. In addition, the invention relates to methods of making the compounds and using the compounds in drug therapy. 7 C. and 10 C.p. f-crystals.

The invention relates to new heterocyclic compounds and, in particular, to new N - heterocyclyl-sulfonamides and their pharmaceutically acceptable salts, which possess endothelin-receptor antagonistic activity. These compounds are of value in cases where it is desired such antagonistic activity, for example, as tools researched which includes, but not limited to, hypertension, pulmonary hypertension, heart disease or diseases associated with disorders of cerebral blood circulation and kidney disease in mammals (including humans), in which elevated or abnormal levels of endothelin play a significant role in causing the disease. The invention relates also to pharmaceutical compositions of the new compounds (and their salts) for use in the treatment of specified diseases or conditions, and to methods for commercial production of new compounds. In addition, the invention relates to the use of new compounds in the treatment of one or more of these diseases or conditions. It also provides a method of treating one or more of these diseases or conditions using these compounds.

Endothelin represent the number of endogenous peptides of 21 amino acids, including three isoforms, endothelin - 1, endothelin-2 and endothelin-3. Endothelin are formed by splitting Trp21-Val22communication of relevant proendothelin using the proposed enzyme that promotes transformation in endothelin. Endothelin are among some of the most potent vasoconstrictors that have high prodolliet, transudate and chemotaxis, as well as interact with a number of other vasoactive funds. They also have a direct impact on the heart. This biological profile endothelina consistent with their pathophysiological role in cardiovascular system. Endothelin also have effects on other physiological systems, including the respiratory tract, gastrointestinal tract, reproductive system, kidneys, liver, Central nervous system, the neuroendocrine system and the blood.

Endothelin differ from a number of tissue and cell sources, including the vascular endothelium, smooth muscle, blood vessels, kidneys, liver, uterus, respiratory tract, colon and leukocytes. The selection can be stimulated by hypoxia, stress, physical trauma and a wide range of hormones or cytokines. Found to have elevated levels of endothelin in the number of illnesses in humans, including hypertension, pulmonary hypertension, pre-eclampsia, congestive heart failure, myocardial infarction, angina, acute and chronic renal failure, severe ischemia, subarachnoid Georgiou, atherosclerosis, hypercholesterolemia, cardiogenic and endotoxic shock, diabetes, b is respiratory failure, cirrhosis of the liver, Crohn's disease, ulcerative colitis, some carcinoma and postoperative state.

In European patent applications, publications 558258 and 569193, and in international patent application, publication number WO 94/27979 described some N- (isoxazolyl) sulfonamides, and in European patent application, publication number 640596 described some N- (pyridazinyl) sulfonamides are referred to as antagonists endothelioma receptors.

Although there are a number of endothelin-receptor antagonists, continues to exist a need for alternative antagonists. This invention is based, in particular, on this need and made by the authors of the discovery of unexpected antagonism of receptor endothelin shown some of the N-heterocyclic sulfonamides.

According to one aspect of the invention features a compound of formula I (shown below, together with the other chemical formulae identified by Roman numerals), in which one of the A1AND2AND3and4denotes nitrogen, and the remainder of the A1AND2AND3and4denote CH, Ar denotes a phenyl group which is either not samail, hydroxy(1 - 6C)alkyl, N-[(1-4C)alkyl]amino(1-6C)alkyl, N,N-[di(1 - 4C)alkyl]amino-(1-6C)alkyl, carboxy (1-6C)alkyl, (1 - 6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkylcarboxylic (1-6C) alkyl, carbarnoyl (1-6C)alkyl, N- (1-6C)allylcarbamate (1-6C) alkyl, di-N- (1-6C)alkyl-carbarnoyl (1-6C)alkyl, N-(1-6C) allylcarbamate (1-6C)alkyl, carboxy (1-6C)alkoxy, carboxy (1-6C)alkylthio, (1-6C)alkoxycarbonyl (1-6C)alkoxy, (1-6C) alkoxycarbonyl (1-6C)alkylthio, carbarnoyl (1-6C)alkoxy, (1-6C) allylcarbamate (1-6C)alkoxy, di(1-6C)allylcarbamate (1-6C) alkoxy, carbarnoyl(1-6C)alkylthio, (1-6C)allylcarbamate (1-6C) alkylthio, di(1-6C)allylcarbamate (1-6C)alkylthio, (2-6C)alkenyl, carboxy (2-6C)alkenyl, (2-6C)quinil, carboxy (2-6C)quinil, halogen (2-6C)alkyl, trifluoromethyl, trichloromethyl, tribromoethyl, (1 - 6C)alkoxy, hydroxy (1-6C)alkoxy, diploid (1-6C)alkoxy, triploid (1-6C)alkoxy, (2-6C)alkenylamine (1-6C)alkyl, (2 - 6C)alkenylamine, (1-4C)alkoxy (1-6)alkyl, (1-6C)alkoxycarbonyl (1-6C)alkoxy (1-6C)alkyl, carboxy (1-6C)alkoxy (1-6C)alkyl, hydroxy (1-6C)alkoxy (1-6C)alkyl, (1-4C)alkylthio (1-6C) alkyl, (1-4C)alkylsulfonyl (1-6C)alkyl, (1-4C)alkylsulfonyl (1-6C)alkyl, (1-4C)alkylenedioxy, (3-6C)cycloalkyl, (3-8C)cycloalkyl (1-6C) alkyl, phenyl, phenyl (1-6C)alkyl, phenoxy, phenyl (1-6C)alkoxy, pyridyl(1-6C)alkoxy (1 - 6C)alkyl, halogen, hydroxy, mercapto, cyano, nitro, Carbo is benzoyl, (1-6C)alkylthio, (1 - 6C)alkylsulfonyl, (1-6C)alkylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, (1-6C)alkanolamine, TRIFLUOROACETYL, triptorelin, N-[(1-4C)alkyl] - triptoreline, benzamide, N-[(1-4C)alkyl] benzamido, carbarnoyl, (1-4C)allylcarbamate, di(1 - 4C)alkyl - carbarnoyl, phenylcarbamoyl, sulfamoyl, N-(l - 4C) alkylsulfonyl, N,N-di (1-4C)alkylsulfonyl, N - phenylsulfonyl, (1-6C)alkanesulphonic, benzosulfimide, ureido, 3-(1-6C)alkaluria, 3 phenylurea, touraid, 3-(1 - 6C)allylthiourea, 3 phenylthioureido, the five-membered heterocycle containing 1, 2, 3 or 4 heteroatoms which are independently selected from nitrogen, oxygen and sulfur, six-membered heterocycle containing 1, 2 or 3 heteroatoms that are independently selected from nitrogen, oxygen and sulfur, and the group-NRaRbin which Raand Rbindependently selected from hydrogen, (1-6C)alkyl, phenyl (1 - 4C)alkyl and (1-6C)alkyl bearing carboxy, (1-6C)alkoxycarbonyl, carbarnoyl, (1-6C)allylcarbamate or di(1-6C)allylcarbamate, or the group-NRaRbin General, forms a cycle 1-pyrrolidinyl, 2-oxo-1 - pyrrolidinyl, 1 - piperidinyl, 2-oxo-1-piperidinyl, morpholino or thiomorpholine;

IN1denotes optional substituents on the carbon atom of the group AND1AND2rd W, X, Y and Z and bearing the substituent R1choose from:

(a) cycle, in which W represents nitrogen; X represents CH; Y represents nitrogen and Z represents CRyin which Rydenotes hydrogen, halogen, (1-4C)alkyl, (1-4C)alkoxy or triptoreline; and the substituent R1denotes hydrogen, halogen, (1-4C)alkyl, methoxy, ethoxy, trifluoromethyl or ethinyl;

(b) cycle, in which W denotes CRzin which Rzdenotes hydrogen, halogen, (1-4C)alkyl, (1 - 4C)alkoxy or triptoreline; X is nitrogen; Y represents nitrogen and Z represents CH; and the substituent R1denotes halogen, (1 - 4C)alkyl, methoxy, ethoxy, trifluoromethyl or ethinyl and

(C) cycle, in which W and X both represent nitrogen; Y represents CH and Z represents CRxin which Rxdenotes hydrogen, halogen, (1-4C)alkyl, (1 - 4C)alkoxy or triptoreline, and the substituent R1denotes halogen, (1 - 4C)alkyl, methoxy, ethoxy, trifluoromethyl or ethinyl; and where any of the said phenyl, benzene or heterocyclic fragments radical Ar may be unsubstituted or bear one or two substituent which is independently selected from the group consisting of (1-4C)alkyl, (1 - 4C)alkoxy, halogen, cyano, carboxy or trifluoromethyl; or an N-oxide, or supplied with the crystals I or its N-oxide, or its pharmaceutically acceptable salt, defined as above, with the exception of the compounds, their N-oxides and pharmaceutically acceptable salts, in which Ar shall be: (1-6C)alkylcarboxylic (1-6C)alkyl, N-(1-6C) allylcarbamate (1-6C)alkyl, hydroxy (1-6C)alkoxy, (2-6C)-alkenylamine (1-6C)alkyl, (1-6C)alkoxycarbonyl (1-6C)-alkoxy- (1-6C)alkyl, carboxy (1-6C)alkoxy (1-6C)alkyl, hydroxy (1 - 6C)alkoxy (1-6C)alkyl, pyridyl-(1-6C) alkoxy (1-6C)alkyl, substituted or unsubstituted five-membered a heterocycle containing 1, 2, 3 or 4 heteroatoms which are independently selected from nitrogen, oxygen and sulfur, substituted or unsubstituted six-membered heterocycle containing 1, 2 or 3 heteroatoms that are independently selected from nitrogen, oxygen and sulfur, or the cycle of morpholino or thiomorpholine; and with the exception of the compounds and their N - oxides and pharmaceutically acceptable salts, in which the phenyl or benzyl substituent on Ar is carboxypropyl.

You should take into account that depending on the nature of the substituents, some of the compounds of formula I can possess one or more chiral centers and can be allocated in one or more racemic or optically active forms. You should also understand that this izobretenie properties, and it is well known how to obtain the optically active forms, for example, by the synthesis of suitable chiral intermediates or by separation, and how to determine their pharmacological properties, for example, using the following tests.

You should also take into account that the compound of the formula I may exhibit polymorphism, the compound of formula I may form the MES and the compound of the formula I can exist in more than one tautomerism form. It should also be understood that the invention applies to any polymorphic form, any tautomer or any MES, or any mixture thereof, which has antagonistic activity against endothelioma receptors.

Moreover, it should be considered that the compound of formula I may be chemically modified so that in vivo it can turn into a connection, the source for the compounds of formula I (for example, hydrolytic, oxidative or enzymatic cleavage). Such chemically modified compounds are commonly referred to as prodrugs can, for example, be metabolically unstable (labile) derivatives of esters or amides of starting compound having a group which auxillou group). It is clear that this invention concerns such proletarienne forms, including metabolically unstable derivatives of esters or amides of compounds of formula I.

It should further be understood that such terms as "alkyl" options include linear or branched chains where allows the number of carbon atoms.

However, when given an individual radical such as "propyl", it corresponds to the variant of a linear chain; when we have in mind the options branched chain, they are specifically referred to as "isopropyl". The same notation adopted for other radicals.

In addition, it should be understood that the loop containing AND1AND2AND3and4indicates the cycle pyridyl, optionally substituted by 1, 2 or 3 substituents IN1defined above. In those compounds where there is more than one IN1Deputy (i.e., when m is 2 or 3), the values for each IN1may be the same or different. Also, when the substituents on Ar denotes a heterocyclic group, it joins the loop containing A1, A2, A3and A4through a cyclic carbon heterocyclic group.

Specific C is isopropyl, isobutyl, tert-butyl and sec-butyl;

for amino (1-6C)alkyl: amino (1-4C)alkyl, such as aminomethyl and 2-amino-ethyl;

for hydroxy (1-6C)alkyl: hydroxy (1 - 4C)alkyl, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxy-2-methylpropyl (otherwise known as 2-(hydroxymethyl) propyl) and 1-hydroxy-2-methylpropyl; for N-[(1-4C)alkyl] amino (1 - 6C)alkyl: N-[(1-20-alkylamino (1-4C)alkyl, such as methylaminomethyl and 2-(methylamino) ethyl;< / BR>
for N, N-[di (1-4C)alkyl] amino (1-6C)alkyl: N,N-[di(1-2C)alkyl] amino (1-4C)alkyl, such as dimethylaminoethyl and 2-(dimethylamino)ethyl;

for carboxy (1 - 6C)alkyl: carboxy (1-4C)alkyl, such as carboxymethyl, 1 - carboxyethyl, 2-carboxyethyl, 2-carboxypropyl and 2-carboxy-2 - methylpropyl;

for (1-6C)alkoxycarbonyl (1-6C)alkyl: (1-4C) alkoxycarbonyl (1-4C)alkyl, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(methoxycarbonyl) ethyl, 2-(methoxycarbonyl) ethyl, 1-(etoxycarbonyl) ethyl, 2-(etoxycarbonyl) ethyl, 2- (methoxycarbonyl) propyl, 2- (etoxycarbonyl) propyl, 2-methoxycarbonyl-2-methylpropyl and 2-propoxycarbonyl-2-methylpropyl;

for (1-6C)alkylcarboxylic(1 - 6C)alkyl: (1-4C)-alkylcarboxylic(1-4C)alkyl, such as acetoxymethyl, propylbromoacetate, pivaloyloxymethyl, 3 - acetoxy - 2-methylprop and, 1 carboxymethoxy, 2-carboxymethoxy and 2 carboxypropyl;

for carboxy(1-6C)alkylthio: carboxy(1-4C) alkylthio, such as carboxymethylthio, 1 carboxymethylthio, 2 - carboxymethylthio and 2 carboxypropyl;

for (1 - 6C)alkoxycarbonyl(1-6C)alkoxy: (1-4C) alkoxycarbonyl (1-4C) alkoxy, such as ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, 1- (methoxycarbonyl) ethoxy, 1- (etoxycarbonyl) ethoxy, 2-(methoxycarbonyl) ethoxy, 2- (etoxycarbonyl) ethoxy, 2-(methoxycarbonyl) propoxy and 2- (etoxycarbonyl) propoxy;

for (1-6C)alkoxycarbonyl(1-6C) alkylthio: (1-4C) alkoxycarbonyl (1-4C) alkylthio, such as (methoxycarbonyl) methylthio, ethoxycarbonylmethyl, 1- (methoxycarbonyl) ethylthio, 1- (etoxycarbonyl) ethylthio, 2- (methoxycarbonyl) ethylthio, 2-(etoxycarbonyl) ethylthio, 2- (methoxycarbonyl) propylthio and 2-(etoxycarbonyl)-propylthio;

for (2-6C)alkenyl: (2-4C)alkenyl, such as vinyl, allyl, 1-propenyl and 2-butenyl;

for carbarnoyl(1-6C)alkyl: carbarnoyl(1-4C)alkyl, such as carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 2-carbamoylethyl,

for (1-6C)allylcarbamate(1 - 6C)alkyl: (1-4C) allylcarbamate(1-4C)alkyl, such as (N - methylcarbamoyl) methyl, (N-ethylcarbamate) methyl, 1- (N - methylcarbamoyl)-ethyl, 2-(N-methylcarbamoyl)ethyl, 1-(N - difficult economic conditions)allylcarbamate(1-6C)alkyl: di(1-4C) allylcarbamate(1 - 4C)alkyl, such as (N, N-dimethylcarbamoyl)methyl, (N, N - diethylcarbamoyl)methyl, 1-(N,N - dimethylcarbamoyl)ethyl, 2-(N,N - dimethylcarbamoyl)ethyl, 1-(N, N-diethylcarbamoyl)ethyl, 2- (N,N - diethylcarbamoyl)-ethyl, 2- (N,N-dimethylcarbamoyl) propyl and 2- (N,N-diethylcarbamoyl)propyl;

for N-(1-6C)allylcarbamate(1 - 6C)alkyl: N-(1-4C)-allylcarbamate(1-4C)alkyl, such as N - methylcarbamoylmethyl, N-ethylcarbodiimide, N-propyl - carbamoyloxymethyl, N-butylcarbamoyl, 2-methyl-N - ethylcarboxylate, 2-methyl-N-propylboronic, 2 - methyl-N-BUTYLCARBAMATE, 2-methyl-3- (N-propylgallate) propyl and 2-methyl-3-(N-butylcarbamoyl) propyl;

for carbarnoyl(1-6C)alkoxy: carbarnoyl(1-4C) alkoxy, such as carbamoylmethyl, 1 carbamoylethyl, 2 - carbamoylethyl and 2 carbamoylphenoxy;

for (1 - 6C)allylcarbamate(1-6C)alkoxy: (1-4C)allylcarbamate(1 - 4C)alkoxy, such as (N-methyl-carbarnoyl)-methoxy, N - ethylcarbamate)methoxy, 1-(N-methyl - carbarnoyl)ethoxy, 2- (N - methylcarbamoyl)ethoxy, 1- (N - ethylcarbazole)ethoxy, 2-(N - ethylcarbazole)ethoxy, 2-(N - methylcarbamoyl)propoxy and 2-(N - ethylcarbazole)propoxy;

for di(1-6C)allylcarbamate(1-6C)alkoxy: di(1-4C)allylcarbamate(1-4C)alkoxy, such as (N,N - dimethylcarbamoyl)methoxy, (N, N-diethylcarbamoyl)methoxy) ethoxy, 2-(N,N-dimethylcarbamoyl)-propoxy and 2-(N,N - diethylcarbamoyl) propoxy;

for carbarnoyl(1-6C)alkylthio: carbarnoyl(1-4C)alkylthio, such as carbamoylmethyl, 1 carbamoylethyl, 2 - carbamoylethyl and 2 carbamoylphosphate;

for (1-6C)allylcarbamate(1-6C)alkylthio: (1-4C)allylcarbamate(1-4C) alkylthio, such as (N-methylcarbamoyl)methylthio, (N - ethylcarbamate)methylthio, (N-ethylcarbamate)methylthio, 1-(N - methylcarbamoyl)ethylthio, 2-(N-methylcarbamoyl)ethylthio, 1-(N - ethylcarbazole)ethylthio, 2- (N-ethylcarbazole)ethylthio, 2-(N - methylcarbamoyl)-propylthio and 2-(N-ethylcarbazole)propylthio;

for di (1-6C)allylcarbamate(1-6C)alkylthio: di(1-4C) allylcarbamate(1-4C)alkylthio, such as (N,N-dimethylcarbamoyl)methylthio, (N,N-diethylcarbamoyl)methylthio, 1-(N, N-dimethylcarbamoyl)ethylthio, 2- (N, N-dimethylcarbamoyl)ethylthio, 1-(N,N-diethylcarbamoyl)ethylthio, 2-(N,N - diethylcarbamoyl)ethylthio, 2- (N,N-dimethylcarbamoyl)-propylthio and 2- (N,N-diethylcarbamoyl)propylthio;

for carboxy(2-6C)alkenyl: carboxy(2-4C)alkenyl, such as 2-carboxyethyl, 3-carboxy-1-propenyl and 4 - carboxy-2 - butenyl;

for carboxy(2-6C)quinil: carboxy(2-4C)quinil, such as carboxyethyl, 3-carboxy-1-PROPYNYL and 4 - carboxy-2 - butenyl;

for (2-6C)quinil: (2-4C)quinil, such as ethinyl, 1 - PROPYNYL, 2-PROPYNYL and the l, deformity, 2,2,2-triptorelin and pentafluoroethyl;

for (1-6C)alkoxy: (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy;

for hydroxy(1-6C)alkoxy: hydroxy(1 - 4C)alkoxy, such as hydroxyethoxy, 1 hydroxyethoxy, 2 - hydroxyethoxy, 2-hydroxy-2-methylpropoxy and 2 - hydroxy-1,1 - dimethylamine;

for di - or triploid (1-6C)alkoxy: di - or triploid(1-4C)alkoxy, such as deformedarse, triptoreline, 2,2,2-triptoreline, 3,3,3-cryptochromes and pen - tartarate;

for di - or triploid(1-3C)alkoxy: deformedarse, triptoreline and 2,2,2-triptoreline;

for (2-6C)alkenylamine(1 - 6C)alkyl: (2-4C)alkenylamine(1-4C)alkyl, such as allyloxymethyl, (2-methyl-2-propenyloxy)methyl and (3-methyl-3 - butenyloxy)methyl;

for (2-6C)alkenylacyl: (2-4C)alkenylamine, such as vinyloxy, allyloxy, 1 propenyloxy and 2 butenyloxy;

for (1-4C)alkoxy(1-6C)alkyl: (1-2C)alkoxy (1-4C)-alkyl, such as methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2 - ethoxyethyl and 3-methoxypropyl;

for (1-6C)alkoxycarbonyl(1 - 6C)alkoxy(1-6C)alkyl: (1 - 4C)alkoxycarbonyl(1-4C)alkoxy(1 - 4C)alkyl, such as (1-methoxycarbonyl-1-methyl)ethoxymethyl, (1 - etoxycarbonyl-1-methyl)ethoxymethyl, ethoxycarbonylmethoxy, ethoxycarbonylmethyl the sludge: carboxy (1 - 4C)alkoxy(1-4C)alkyl, such as carboxymethoxy, (1-carboxy-1-methyl)ethoxymethyl and (1 carboxymethoxy)-methyl;

for hydroxy(1-6C)alkoxy(1-6C)alkyl: hydroxy(1-4C)alkoxy(1-4C)alkyl, such as (1-methyl-2 - hydroxyethoxy)methyl, (1,1-dimethyl-2-hydroxyethoxy) methyl and (2-hydroxyethoxy)methyl;

for (1-4C)alkylthio(1 - 6C)alkyl: (1-2C)alkylthio(1-4 C)alkyl, such as methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 2-metaltype-2-yl, ethylthiomethyl, 1-ethylthioethyl, 2-ethylthioethyl and 2-utilipro-2-yl;

for (1 - 4C)alkylsulfonyl(1-6C)alkyl: (1-2C)alkylsulfonyl(1-4C)alkyl, such as methylsulfonylmethyl, 1-methylsulfinylbutyl, 2- (methylsulfinyl)ethyl, 2-(methylsulfanyl)prop-2-yl, ethylsulfonyl, 1-(ethylsulfinyl)ethyl, 2-(ethylsulfinyl)ethyl and 2-(ethylsulfinyl)prop-2-yl;

for (1-4C)alkylsulfonyl(1 - 6C)alkyl: (1-2C)alkylsulfonyl(1-4C)alkyl, such as methylsulfonylmethyl, 1-(methylsulphonyl)ethyl, 2- (methylsulphonyl) ethyl, 2-(methylsulphonyl)prop-2-yl, ethylsulfonyl, 1-(ethyl - sulfonyl)ethyl, 2-(ethylsulfonyl)ethyl and 2-(ethylsulfonyl)prop-2 - yl;

for (1-4C)alkylenedioxy: methylenedioxy, Ethylenedioxy, isopropylidenedioxy;

for (3-6C)cycloalkyl: cyclopropyl, cyclobutyl and cyclopentyl;

for (3-8C)cycloalkyl(1-6C)alkyl: (3-5C)cycloalkyl(1-2C) alkyl, such as qi(1-6C)alkyl: phenyl (1-4C)alkyl, such as benzyl, 1-phenylethyl and 2-phenylethyl;

for phenyl (1-6C)alkoxy: phenyl (1-4C)alkoxy, such as benzyloxy, 1-phenylethane, 2 - phenylethane, 2 - phenylpropoxy and 3 phenylpropoxy;

for phenyl (1-3C) alkoxy: benzyloxy, 1-phenylethane and 2 venlafaxi;

for pyridyl(1-6C)alkoxy (1-6C)alkyl: pyridyl(1 - 4C)alkoxy (1-4C) alkyl, such as pyridylmethyl, (2- (pyridyl)ethoxy)methyl and 2- (pyridyloxy)ethyl;

for halogen: fluorine, chlorine, bromine and iodine;

for (1-6C)alkoxycarbonyl: (1-4C)alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl and propoxycarbonyl;

for (2 - 6C)alkenylcarbazoles: allyloxycarbonyl, 2 - methyl-2 - propenylboronic and 3-methyl-3-butyloxycarbonyl;

for phenyl (1-6C)alkoxycarbonyl: phenyl (1-4C)alkoxycarbonyl, such as benzyloxycarbonyl, 1 - fenilalaninammonii and 2 - fenilalaninammonii;

for (1-6C)alkanoyl: (1-4C)alkanoyl, such as formyl, acetyl, propionyl, butyryl and isobutyryl;

for (1-6C)alkylthio: (1-4C)alkylthio, such as methylthio, ethylthio;

for (1 - 6C)alkylsulphonyl: (1-4C)alkylsulfonyl, such as methylsulfonyl and ethylsulfonyl;

for (1-6C)alkylsulphonyl: (1-4C) alkylsulfonyl, such as methylsulphonyl and ethylsulfonyl;

for (1-6C)alkanolamine: (1-4C)alkanoate and N-ethyltryptamine;

for N-[(1 - 4C)alkyl]benzamide: N-methylbenzamide and N - ethylbenzamide;

for (1-4C)allylcarbamate: N-methylcarbamoyl and N-ethylcarbamate;

for di (1-4C)allylcarbamate: N,N-dimethylcarbamoyl and N,To-diethylcarbamoyl;

for N-(1-4C)alkylsulphonyl: N-methylcarbamoyl and N - ethylsulfonyl;

for N, N-di(1-4C)alkylsulphonyl: N,N-dimethylsulphamoyl and N,N-diethylcarbamoyl;

for (1-6C)alkanesulphonic: (1-4C)alkanesulfonyl, such as methanesulfonamido, acanalonia;

3-(1-6C)alkaluria: 3-(1-4C)alkaluria, such as 3-methylurea, 3 amiloride and 3 propylurea;

3-(1-6C)allylthiourea: 3-(1-4C)allylthiourea, such as 3 - methylthiourea, 3 ethylthiourea and 3 propylthiourea;

for five-membered heterocycle containing 1, 2, 3 or 4 heteroatoms which are independently selected from nitrogen, oxygen and sulfur: pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furutani, 1,2,4 - thiadiazolyl, 1,3,4-thiadiazolyl and tetrazolyl and six-membered heterocycle containing 1, 2, or 3 heteroatoms which are independently selected from nitrogen, oxygen and sulfur: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tan (1-6C)alkyl: (1-4C)alkyl, such as methyl, ethyl, propyl and isopropyl;

for (1-6C)alkyl bearing carboxy, (1-6C)alkoxycarbonyl, carbarnoyl, (1-6C)allylcarbamate or di(1 - 6C)allylcarbamate, (1-4C)alkyl bearing carboxy, (1-4C)alkoxycarbonyl, carbarnoyl, (1-4C)allylcarbamate or di(1-4C)allylcarbamate, such as carboxymethyl, 1-(carboxy)ethyl, 2-(carboxy)ethyl, 2-(carboxy)propyl, methoxycarbonylmethyl, 1-(methoxycarbonyl)ethyl, 2- (methoxycarbonyl)ethyl, 1- (etoxycarbonyl)ethyl, 2-(etoxycarbonyl)ethyl, 2- (methoxycarbonyl)propyl, 2-(etoxycarbonyl)propyl, carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl, 2-carbamoylethyl, (N-methylcarbamoyl)methyl, (N-ethylcarbamate)methyl, 1-(N - methylcarbamoyl)ethyl, 2-(N-methylcarbamoyl)ethyl, 1-(N - ethylcarbazole)ethyl, 2- (N-ethylcarbazole)ethyl, 2-(N - methylcarbamoyl)propyl, 2-(N-ethylcarbazole)propyl, (N, N - dimethylcarbamoyl)methyl, (N,N-diethylcarbamoyl)methyl, 1-(N, N-dimethylcarbamoyl), 2-(N,N-dimethylcarbamoyl)ethyl, 1-(N,N - diethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoyl)ethyl, 2-(N, N-dimethylcarbamoyl)propyl and 2-(N,N-diethylcarbamoyl)propyl and

for phenyl (1-4C)alkyl: benzyl, 1-phenylethyl and 2-phenylethyl.

Specific values of Rx, Ryand Rzinclude, for example,

for halogen: fluorine, chlorine, bromine and iodine;

for (1-4C)alkyl: methyl, R1include, for example, chlorine, bromine, iodine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and ethinyl.

Specific values IN1or a substituent on the phenyl, benzene or heterocyclic group Deputy Ar include, as an example, for (1-4C)alkyl: methyl and ethyl;

for (1-4C)alkoxy: methoxy, ethoxy and

for halogen: fluorine, chlorine, bromine and iodine.

Specific values of R1include, for example, methyl and halogen (in particular chlorine or bromine), particularly preferably the presence of bromide.

Specific values of Rx, Ryand Rzinclude, for example, methoxy.

Group specific values for Ar includes, for example, unsubstituted phenyl or phenyl carrying 1, 2 or 3 substituent which is independently selected from the group including: (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1 - 6C)alkylsulfonyl, (1-6C)alkylsulfonyl, halogen, amino, N-(1 - 4C)alkylamino, N, N-di(1-4)alkylamino, carboxy(1-6C)alkyl, (2 - 6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy(1-6C)alkyl, (1 - 6C)alkylthio (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoromethyl, triptoreline, carbarnoyl, (1-4C)allylcarbamate, di(1-4C) allylcarbamate and (1-6C)alkoxycarbonyl. A separate subset of values of the group Ar includes, for example, unsubstituted phenyl or phenyl, ness-4C)alkylamino, N,N-di(1-4C)alkylamino, carboxy(1 - 4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C) alkylthio (1-4C)alkyl and (1-4C)alkoxycarbonyl.

A separate subgroup of compounds according to the invention includes, for example, compounds in which m is zero, 1 or 2, especially zero or 1. Preferably, m is equal to zero.

Another particular subgroup of compounds according to this invention includes, for example, compounds in which the group Ar denotes unsubstituted phenyl or phenyl carrying one or two substituent which is independently selected from any of the values shown above for the substituent on Ar, in particular phenyl, which carries a pair of Vice.

A preferred group of compounds according to this invention includes, for example, compounds in which the group Ar represents phenyl substituted in the para-position of Deputy chosen from the above values and, in particular, from the group including: (1-4C)alkyl (especially isobutyl), (1-4C)alkoxy (especially isopropoxy), (1-4C)alkylthio (especially methylthio), N,N - di(1-4C)alkylamino (especially dimethylamino), carboxy(1-4C)alkyl (especially 2-carboxypropyl), carboxy(1-4C)alkoxy (particularly 1 - carboxymethoxy), halogen (especially chlorine), (2-4C) alkenyl (especially vinyl or allyl), hydroxy (1-4C)alkyl (especially), (2-4C)alkanoyl (especially acetyl), N-(1-4C)alkylamino (especially isopropylamino), (1 - 4C)alkoxycarbonyl (especially methoxycarbonyl), (1-4C)alkoxy (1 - 4C)alkyl (especially methoxymethyl or isopropoxyphenyl). In this group, particularly preferred compounds in which m is equal to zero (i.e., unsubstituted cycle pyridyl), as well as compounds in which a pair of Vice is 2-hydroxy-2-methylpropyl and 2 - carboxy-2-methylpropyl.

Another preferred group of compounds according to this invention includes, for example, compounds in which the group Ar represents phenyl substituted in the para-position of Deputy chosen from the group consisting of: pyridyl (especially 2-pyridyl or 3-pyridyl), pyrimidinyl (especially 2 - pyrimidinyl), oxadiazolyl (especially 1,3,4-oxadiazol-2-yl and 1,2,4-oxadiazol-3-yl), 3-methylisoxazol-5-yl, 3-methyl-1,2,4 - oxadiazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl, pyridyl (1 - 4C)alkoxy(1-4C)alkyl (particularly (3 pyridyloxy) methyl), (2 - 4C)alkenylamine(1-4C)alkyl, (1-4C)alkoxycarbonyl (1-4C) alkoxy (1-2C)alkyl, carboxy (1-4C) alkoxy(1-2C)alkyl, hydroxy(1 - 4C)alkoxy(1-2C) alkyl, phenyl (1-4C) alkoxy, carboxy (1-4C) alkyl, carboxy(2-4C)alkenyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylcarboxylic (1-4C)alkyl, N-(1-4C)allylcarbamate (1-4C)Alki connection in which Ar denotes phenyl, substituted 1,2,4-oxadiazol-3-yl and 1,3,4-oxadiazol-2-yl, and m is equal to zero.

Other independent subgroups of compounds of this invention include, for example, compounds of formula I in which:

(1) AND1denotes the nitrogen and2AND3AND4represent CH;

(2) AND2denotes the nitrogen and1AND3AND4represent CH;

(3) AND3denotes the nitrogen and1AND2AND3represent CH and

(4) AND4denotes the nitrogen and1AND2AND3represent CH;

and where in each of the subgroups (1) to(4)1, m, Ar, W, X, Y, Z, and R1take any of the above values (including the particular and preferred values and groups of values), their N-oxides and pharmaceutically acceptable salts. Within these subgroups, additional subgroup includes compounds in which:

(i) the loop containing W, X, Y, and Z and bearing R1indicates the cycle pyrazine bearing Ryand R1defined above, and

(ii) the loop containing W, X, Y, and Z and bearing R1indicates the cycle pyridazine bearing Rxand R1that defined above.

In subgroups(1), (2), (3) and (4) are preferred compounds in which the loop containing the nitrogen and Z represents CRywhere Ryis hydrogen, halogen, (1-4C)alkyl or (1 - 4C)alkoxy, and R1denotes hydrogen, halogen, (1-4C)alkyl, methoxy, ethoxy, trifluoromethyl, triptoreline or ethinyl. Especially preferred group of compounds includes, for example, compounds in which Rydenotes methoxy, and R1denotes methyl or halogen, especially methyl.

Another preferred group of compounds includes, for example, the compounds of formula II, where1, m, Ar, W, X, Y, Z, and R1have the above values (including the particular and preferred values), their N-oxides or their pharmaceutically acceptable salts. In this group, particularly preferred compounds include, for example, compounds in which the loop containing W, X, Y, Z and bearing Deputy1indicates the cycle in which W represents nitrogen; X represents CH; Y represents nitrogen and Z represents CRywhere Ryis hydrogen, halogen, (1-4C)alkyl, (1-4C)alkoxy or triptoreline; and R1denotes hydrogen, halogen, (1-4C)alkyl, methoxy, ethoxy, trifluoromethyl, or ethinyl. In this group, particularly preferred compounds include, for example, compounds in which Rydenotes methoxy, and R1denotes methyl or garyh m is equal to zero.

Especially preferred group of compounds according to this invention includes, for example, the compounds of formula II in which m is zero, Ar denotes a phenyl group bearing a pair of Vice, which is selected from (1-6C)alkyl, carboxy(1-6C)alkoxy, (2-6C)alkenyl, hydroxy(1-6C)alkyl, (2-6C)alkanoyl and group-NRaRbin which Raand Rbindependently selected from hydrogen and (1-6C)alkyl; loop containing W, X, Y, and Z and bearing R1chosen from:

(a) cycle, in which W represents nitrogen, X represents CH; Y represents nitrogen and Z represents CRy, where Ry is methoxy

(b) cycle, in which W denotes CRzwhere Rzdenotes methoxy; X is nitrogen; Y represents nitrogen and Z represents CH;

and the substituent R1(as in (a) and (b)) denotes methyl, chlorine or bromine. Of these particularly preferred compounds include, for example, those compounds in which two substituents on Ar are selected from the group comprising: carboxy(1 - 4C)alkoxy (such as 1-carboxymethoxy), (1-4C) alkyl (such as methyl, ethyl, propyl, isopropyl, isobutyl or tert-butyl), (1 - 4C)alkylamino (such as isopropylamino), di(1-4C) alkylamino (such as dimethylamino or diethylamino), (2-4C)alkanoyl (such as acetyl), (2-4C)alkenyl (so is l) and (1-4C)alkoxycarbonyl (such as methoxycarbonyl), and those compounds in which the cycle, carrying W, X, Y, and Z and R1has above in (a).

Another especially preferred group of compounds according to this invention includes, for example, the compounds of formula II in which m is zero, Ar denotes a phenyl group bearing a pair of Vice, which is chosen from the group including: (1-4C) alkyl (such as ethyl or isobutyl), hydroxy(1-4C) alkyl (such as 3 - hydroxy-2-methylpropyl, 1-hydroxyethyl or 2-hydroxy-2 - methylpropyl), (2-6C) alkenyl (such as allyl), 3-pyridyl, 2 - pyrimidinyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, hydroxy(1 - 4C)alkoxy(1-2C) alkyl (such as (2-hydroxyethoxy)methyl), hydroxy(1-4C)alkoxy (such as 2-hydroxyethoxy), (1 - 4C)alkylcarboxylic(1-4C) alkyl (such as 3-acetoxy-2 - methylpropyl), carboxy(1-4C) alkyl (such as 2-carboxypropyl or (2-carboxy-2-methyl)propyl), (2 - 4C)alkanoyl (such as isopropanol), (3-6C)cycloalkyl(1-2C)alkyl (such as cyclopropylmethyl) and (1-4C)alkoxycarbonyl(1-4C)alkyl (such as (2-propoxycarbonyl-2-methyl)propyl), and the cycle bearing W, X, Y, and Z and R1indicates the cycle in which W represents nitrogen, X represents CH; Y represents nitrogen and Z represents CRyin which Rydenotes methoxy, and the substituent R1indicates the teres, include, for example, the specific embodiment that is given below in the accompanying examples. Of these compounds of the formula I, disclosed in the examples 1, 5, 8, 12, 13, 19, 21, 22, 23, 26, 33, 35, 36, 39, 41, 48, 52, 57, 58, 63, 64, 66, 67 isomer b and 69, is particularly interesting and these compounds or their pharmaceutically acceptable salts are considered as another characteristic of the present invention.

Examples of metabolically unstable ester derivatives carboxypropyl are esters derived from alcohols such as (1-6C)alkanols, e.g. methanol, ethanol, propanol and isopropanol; indanol; adamanta; (1 - 6C)alkanoyloxy(1-4C)alkanols, such as pivaloyloxymethyl; glycolamide; (S-methyl-2-oxo-1,3-dioxol-4-yl)methyl alcohol and (1-4C)allyloxycarbonyl(1-4C)alkanols.

Examples of metabolically unstable amide derivatives carboxypropyl include amides derived from ammonia and amines, such as (1-4C)alkylamine, for example, methylamine, di(1-4C)alkylamines followed, (1-4C)alkoxy(1 - 4C)alkylamines followed such as methoxyethylamine, phenyl (1-2C) bonds alkylamines, such as benzylamine; and amino acids such as glycine or its ester.

It should be understood that when the mentioned subgroup of compounds according to the invention or individual, or preferred grouprt of these compounds, such as metabolically unstable esters or amides.

Suitable pharmaceutically acceptable salts include, for example, salts with alkali metals (such as sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium), ammonium salts and salts with organic bases, which give physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine or morpholine. In addition to the compounds with sufficient basic properties, suitable pharmaceutically acceptable salts include pharmaceutically acceptable acid salt of joining with kaleidotrope, sulfuric acid, phosphoric acid and organic acids such as citric acid, maleic acid, methanesulfonate and p-toluensulfonate. Or the compounds of formula I can exist in the form of zwitter ions.

The compounds of formula I can be obtained by standard techniques of organic chemistry well known in the relevant field to obtain structural analogs of compounds. Such methods constitute an additional feature of the present invention and include, by way of example, the following methods ="ptx2">

(a) Removing protection from the compounds of formula III in which P represents a protective group.

Suitable protective group P includes, for example, (1 - 6C)alkoxycarbonyl (such as methoxycarbonyl, etoxycarbonyl, or isobutoxide), benzyloxycarbonyl (in which benzo - cycle can be optionally substituted, for example, he may be halide, (1-4C)alkyl or (1-4C)alkoxy Deputy), 2 - methoxyethoxymethyl and three(1-4C)alkylsalicylate (such as 2-(trimethylsilyl)ethoxymethyl). The protective group P can be removed from the compounds of formula III by treatment one or more agents for removing the protective group. Note that the agent or agents for removing the protective group will depend on the specific values of R. the Appropriate agents for removing the protective group used for this methods well known in the relevant field. For example, alkoxycarbonyl group can be easily removed in an alkaline environment, such as sodium hydroxide or alcoholate, for example, methylate, in a suitable solvent, such as methanol; 2-methoxyethoxymethyl group can be removed using acidic environment, such as hydrochloric acid in a suitable solvent, such as ethanol; and three(1 - 4C)alkylcyclopentanes triperoxonane acid or a mixture of hydrochloric acid in a suitable solvent, such as ethanol.

The compound of formula III can be obtained by the coupling of compounds of formula IV where T denotes bromine, iodine, tripterocalyx or, if A1or AND3denote nitrogen, chlorine, optionally substituted phenylboric acid of formula ArB(OH)2(or its anhydride, or a complex ester) in the presence of a suitable base and in the presence of a catalyst: palladium (0), palladium (II), Nickel (0) or Nickel (II).

Suitable catalysts include, for example, tetrakis (triphenylphosphine) Nickel (0), bis (triphenylphosphine) Nickel (II)chloride, Nickel (II) chloride, bis(triphenylphosphine)palladium (II)chloride, tetrakis (triphenylphosphine)palladium (0) and palladium (II) chloride.

Suitable for use in the reaction is, for example, an alcoholate of an alkali metal such as sodium methylate or sodium ethylate, alkali metal hydroxide, such as sodium hydroxide or potassium, and carbonate of an alkali metal such as sodium carbonate or potassium, or an organic base such as tri (1 - 6C)alkylamino, for example, triethylamine.

Joining is usually performed in the presence of a suitable solvent or diluent, for example, hydrocarbons, such as Tolu is whether butanol, water or their mixtures (for example, a mixture of toluene, ethanol and water).

The reaction is usually carried out at a temperature, for example, 50-150oC and, as a rule, at (or near) the boiling point of the solvent or of the mixture of the used solvents.

Alternatively, the interaction of the compounds of formula IV with AGV(OH)2(or the corresponding anhydride, or a complex ester) can be performed by using a source of fluoride ions in the aqueous environment, for example, using potassium fluoride in a mixture of toluene and water when heated to the boiling point.

The compounds of formula IV can be obtained, for example, by the reaction of galodamadruga sulfonic acids of the formula V, where Hal denotes a halogen group such as chlorine, bromine or iodine), with appropriately protected amine of formula VI, where P denotes a protective group, for example, in an alkaline medium using sodium hydride in N,N - dimethylformamide (DMF). Or otherwise, galoyanized sulfonic acids of formula V can react with the amine of formula VII, giving the compound of formula VIII, which then protects, receiving compound of formula IV. The protective group P is chosen so that it is possible to obtain the compound of formula III in the specified conditions. Suitable protective is whether the compounds of formula VIII can be carried out using standard techniques of organic chemistry. For example, the amine of formula VII can be protected alkoxycarbonyl group or benzyloxycarbonyl group by reaction with an appropriate alkylchlorosilanes or benzylchloride in the presence of a base such as tertiary amine (e.g. pyridine or triethylamine) in the presence of a solvent, such as dichloromethane. The compound of formula VIII can be protected on the nitrogen sulfonamidnuyu group 2-methoxyethoxymethyl group or triamterenetriamterene group using the reaction with 2-methoxyethoxymethyl or dialkyldimethylammonium, respectively, in the presence of a base, such as diisopropylethylamine or sodium hydride and in a suitable solvent such as DMF. Galodamadruga sulfonic acids of the formula V are known in the relevant field or can be obtained, for example, by analogy with the methods described in European patent applications, publications 558288 and 569193. A convenient way of obtaining golodnikov sulfonic acids of the formula V from the corresponding amine of formula IX is illustrated below by examples, or may be similar. Amines of the formula IX are commercially available or well known and described in standard methods g is th chemistry.

Note that the method (a) can be modified, for example, so that the interconversion of functional groups and removing the protective group P can be performed in one stage or gradually and emitting or without isolation of intermediate products, such as illustrated, for example, in the examples 8, 26, 28, 29, 36, 39, 40, 42, 43, 44, 47, 55 and 56.

(b) amine of formula VII (or its salt with an alkaline metal) reacts with halogenerator sulfonic acids of the formula XI, in which Hal represents halide group (for example, chlorine, bromine or iodine) or a sulfonate of the formula Ha, where Re denotes an electron-deficient phenyl group such as 4-nitrophenyl, in a suitable solvent.

When used as a compound of formula XI, the suitable solvent includes, for example, pyridine. Can be added to the catalyst, such as 4-dimethylaminopyridine or 4 - pyrrolidinedione promoting the reactions proceed. The reaction is usually conducted in the temperature range of 0-120oC and more 20-120oC. Or solvent such as dichloromethane, chloroform, dimethoxyethane, tetrahydrofuran, dioxane or DMF can be used in the presence of a suitable inorganic bases such as sodium carbonate or potassium (the a, such as pyridine or triethylamine. When using salt and alkali metal amine of the formula VII, it can be obtained in situ (in place) before adding galodamadruga sulfonic acids, for example, using a suitable base, such as diisopropylamide lithium, for example, at a temperature of about -60oC, or lithium hydride at ambient temperature. It should be noted that the reaction of galodamadruga sulfonic acids with the amine to form sulfonamida (and typical solvents and conditions used therein are well known in the respective field.

If used as a compound of the formula XIa, preferably to obtain a salt of an alkali metal amine of formula VII in place, as mentioned above, using, for example, DMF as solvent before adding the compounds of formula XIa. After that, the reaction can be conducted at (or near) ambient temperature.

The compound of the formula Chi can be obtained by using a method similar to that described above for obtaining the compounds of formula III, but using the compound of the formula X instead of the compounds of formula IV. The compound of formula X can be obtained by the reaction of galodamadruga sulfonic acids of the formula V with the corresponding phenol by politowaniem DMF as solvent in the presence of a tertiary amine, such as N,N - diisopropylethylamine at a temperature of, for example, in the range of 20-100oC.

Then the compound of the formula I can be converted into another compound of formula I, standard mutual transformation of functional groups, for example, as illustrated in the examples 22, 33, 34, 37, 38, 45, 46, 57, 59, 60, 65, 68 and 69.

Note that in addition to the protective group P, as referred to above, it may be convenient or necessary to protect one or more functional groups suitable protective groups before performing the above method (a) or (b), or before carrying out mutual conversion of functional groups and subsequently to remove the protective group (for example, as shown in examples 19, 48, 49 and 52). Suitable protective groups and methods for their use, together with ways of removing the protective groups are well known in the field of organic chemistry and described, for example, in "Protective Groups in Organic Syntheses" by Theodora Greene (John Wiley and Sons Inc., 1981). Then, if you want pharmaceutically acceptable salt of the compounds of formula I, can be obtained for example by reaction with an appropriate base, giving a physiologically acceptable cation, or with a suitable acid, producing a physiologically acceptable anion, or any dregeno in the prodrug (e.g., in metabolically unstable ester or amide) is well known in the relevant field methods. For example, pharmaceutically acceptable metabolically unstable ester or amide can be obtained, respectively, by the esterification of compounds of formula I containing a carboxylic acid group (or a hydroxyl group) or an interaction carboxylato group (or its reactive derivative) with the appropriate amine using conventional methods.

Further, if you want optically active form of compounds of formula I, one of the above methods can be performed using optically active starting compound. Or racemic form the compounds of formula I may be separated, for example, by reaction with optically active form of a suitable organic base, for example, ephedrine, hydroxide, N,N,N-trimethyl(1-phenylethyl) ammonium or 1 - phenethylamine, followed by standard separation diastereoisomeric mixture thus obtained salts, for example, fractionated kristallizatsiei of a suitable solvent, for example, (1-4C) alkanol, after which the optically active form of the compounds of formula I can be you the coy as dilute hydrochloric acid. Or a racemic compound may be separated into individual isomers by chromatography using chiral media, for example as shown in example 67.

Some intermediate products described or shown here as examples, are new, for example, the compounds of formula III and IV, and are another sign of this invention.

As indicated above, the compounds of formula I possess favorable pharmacological effects in warm-blooded animals (including humans) diseases and conditions in which elevated or abnormal levels of endothelin play a significant causal role. (References to studies confirming the involvement of endothelin to the emergence of various diseases or medical conditions, see, for example, in international patent applications, publication numbers WO 93/21219 and WO 94/02474.) Compounds according to the invention are thus useful in the treatment of diseases and conditions requiring treatment, such as hypertension, pulmonary hypertension, congestive heart failure, disorders caused by hyperlipidemia, atherosclerosis, restenosis, acute and chronic renal failure, ish is th limb, asthma and organic disorders after General surgery or transplantation. They can also be useful in the treatment of pre-eclampsia, premature birth, myocardial infarction, angina, arrhythmias, cardiogenic and endotoxic shock, diabetes, disease, Raynaud's disease, scleroderma, Buerger's disease, systemic sclerosis, bronchitis, acute respiratory failure, cirrhosis, Crohn's disease, ulcerative colitis, mucous colitis, urinary incontinence, migraine, glaucoma, arthritis and some cancers.

Endothelin-receptor antagonistic activity of the compounds according to the invention can be examined by using one or several of the following ways:

Test:

Endothelin-receptor antagonistic activity of the compounds of formula I can be studied in vitro for their ability to inhibit the binding of [125I] -endothelin-1 with its receptors.

Human EMAor NOBreceptors (subclasses of receptor endothelin) Express in erythroleukemic cells of mice (MEL cells) using standard molecular techniques (e.g. as described in Sambrook J., Fritsch e F &Maniatis T. (1989) Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Press, USA). The DNA sequence is 1), Biochem. Biophys. Res. Comm., 178, 656-663) subcloning in pBluescript vector and subsequent inclusion in the vector pEV MEL-cell expression, as described in Needham et a1. (1992), Nuc. Acids Res., 20, 997-1003. The resulting expression vector transfection in MEL cells by electroporation using techniques described in Shelton et a1., (1993), Receptors and Channels, 1, 25-37.

MEL cells expressing recombinant human ETAor NOBthe receptor are grown in an environment Duibecco''s modified Eagle's (DMEM) with 10% serum fetal cow (FCS), 1% glutamine, 1% penicillin/streptomycin and 2 mg/ml, Gibco Geneticin (G-418) sulfate. After induction for 3-6 days with 1% M, N-dimethylsulfoxide MEL cells harvested for the preparation of membranes. Freshly prepared precipitates after centrifugation MEL cells (3109cells) homogenized in 30 ml of buffer containing 50 mm hydrochloride 2-amino-2-(hydroxymethyl)-1,3-propane diol (Tris-HCl), 0,19 M sucrose, 5 μg/ml of inhibitor soybean trypsin, 100 μg/ml bacitracin, 1 mm benzamidine and 1 mm phenanthroline, a pH of 7.4 with a 5oC. Intact cells and nuclei are precipitated by centrifugation of the homogenate at 1000 rpm for 15 minutes with 5oC. the Precipitate after centrifugation membranes resuspended in the buffer and stored in liquid nitrogen until use.

m 50 mm Tris-HCl, 1 mm CaCl2, 0.05% monolaurate of polyoxyethylenesorbitan, 0.1% bovine serum albumin (BSA), 0.02% of sodium azide, pH of 7.4 at 30oC after 180 minutes of incubation. Suspension of membranes (equivalent to 1.5 μg and 0.5 μg protein/ tube OAand NOBreceptor, respectively) are added to incubate containing the test compound and 30 RM [125I] -endothelin-1 in a total volume of 225 μl. Nonspecific binding measured in the presence of its 100 nm endothelin-1. Incubation torn collecting incubate with 50 mm Tris pH 7,4 on GF/B filter collector cells Brandel'a.

Plate filter beat and cheated on gamma-counter. Connection experience within the concentration range, making three samples at each concentration, and calculate the values of the IC50(or pIC50).

Basically, the compounds of formula I, as defined above, show inhibition in the test And when pIC50equal to 6 or more.

Test:

Endothelin-receptor antagonistic activity of the compounds of formula I can be studied in vitro in selected tissues by their ability to inhibit reluctantly response to endothelin-1 in selected intestinal heavy (taenia coli) Guinea pigs.

Guinea pigs of both sexes and weighing >250 g which indicate the intestinal heavy and strips approximately 4 cm in length is placed for isotonic registration in 20 ml bath for organs containing oxygenated solution Krebsa when the 32oC. After 90-120-minute period of equilibration, allowing tissue to spontaneously develop increased tension, build a cumulative curve of the concentration-response (relaxation) on endothelin-1 (0.3 to 10 nm). Then the fabric is washed for at least 90 minutes before building the second curve of the concentration-response to endothelin-1 in the presence of the test compound. The test compound added to the bath for bodies (with an initial concentration of 20 μm) of not less than 30 minutes to build the second curve of the concentration-response to endothelin-1. The ratio of concentrations of endothelin-1 for each experiment is determined by comparing the most parallel parts of the curves of the concentration-response for control and treated drug tissue. From these data calculate RA2: RA2= - log [molar concentration of the medicinal product] + log [concentration ratio-1].

Test WITH:

This in vivo test involves measuring the antagonistic effects of the test compounds on the Pressor response caused by intravenous proendothelin-1 in the drug rats, crammed with puncturing the spinal cord.

Male rats (280-330 g) Kai needle with a diameter of 2 mm through the eye cavity through the foramen magnum (the hole capitate bone) and lower in the spinal canal. Isolate the left femoral vein and right carotid artery and implanted catheter filled with heparinized isotonic, for introducing connections, and blood pressure measurement, respectively. The temperature of the body support at the 38oC (measured rectally) using the heated pillow. Exclude rats with an initial level of mean arterial pressure less than 55 mm Hg or above 70 mm Hg. Blood pressure is allowed to stabilize for approximately 10 minutes before removing the zero level. Two initiating provocative tests proendothelin-1 (0.3 and 1.0 nmol/kg-1) injected cumulative way and record the response pressure. Then aged 55-minute period and excluded rats whose blood pressure cannot return to the value within 20% from the zero line. The test compound is administered intravenously at doses of 1.0 ml per kg of body weight, and after 5 minutes introduce additional provocative tests proendothelin-1. Proendothelin-1 is administered in cumulative increasing doses (ranging from 0.3 nmol/kg-1) until Pressor response. Endothelin-receptor antagonism determine quantitatively by calculating the shift of the ratio of the impact of the test compounds on the Pressor response, caused by intravenous proendothelin-1 in the product in the minds of rats.

Male rats (260-290 g) anastasiou using Saffan'a, injected into the tail vein. Isolate the right jugular vein and carotid artery and implanted catheter filled with heparin. Take them to the back of the neck, using a metal trocar, and the cervical incision is closed by autoclips. Rats are placed individually, providing free access to food and water for the recovery period. After a day of clean food and rats leave overnight with free access to water. The next day, rats are placed in restrictive tube, drain arterial catheter and connected to a pressure sensor for measuring mean arterial pressure. After a ten-minute period of stabilization impose cumulative proendothelin-1 (usually 0.3-1.0 nmol/kg-1) to achieve Pressor response in 30 mm Hg. Then the animals are returned to their cages and allowed to recover for 2 hours. Compound administered orally (by feeding through a stomach tube) at some point of time during the recovery period. Then remove the curve dose of feedback on proendothelin-1 in a fixed IOM is damelin-receptor antagonism determine quantitatively calculating the shift in the ratio of doses at 30 mm Hg level changes.

As an illustration of endothelin-antagonistic properties of the compounds of formula I: compound of example 3 gives the value pIC508.6 and oral dosing of rats 3 mg/kg, and when using the test Protocol D, leads to an average shift in the ratio of doses = 2,93 (n=5) in the Pressor response to proendothelin-1 defined through one hour after administration of the test compounds.

The compounds of formula I is usually administered in therapeutic or prophylactic uses warm-blooded animals (including man) in need of such treatment, in the form of a pharmaceutical composition, which is well known in the field of pharmacy. Accordingly, the following characteristic of the invention is to provide pharmaceutical compositions comprising a compound of formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier. Such compositions are usually in a form suitable for oral administration (e.g. tablets, capsules, solution, suspension or emulsion) or parenteral administration (for example, in the form of aqueous or oily solution for injection or emulsions for the ü therapeutic or prophylactic purposes together with other pharmacological means, known in General pharmacy, what is of value in treating one or more diseases or conditions requiring treatment, such as beta-adrenergic blocker (eg, atenolol), calcium channel blockers (such as nifedipine), an inhibitor of angiotensin converting enzyme (ACE) (eg, lisinopril), diuretic (for example, furosemide or hydrochlorothiazide), an inhibitor of endothelin converting enzyme (ECE) (for example, phosphoramidon), neutral inhibitor endopeptidase (NEP), an inhibitor of HMGCoA-reductase, a donor of nitric oxide, antioxidant, vasodilator, a dopamine agonist, a neuroprotective agent, a steroid, beta-agonist or thrombolytic agent. Note that this combination of therapeutic agents is another aspect of the invention.

Basically, the compound of formula I (or appropriate its pharmaceutically acceptable salt is administered to a person thus, for example, it is generally accepted that a daily oral dose of 50 mg/kg body weight (and preferably 10 mg/kg) or daily parenteral dose of 5 mg/kg body weight (and preferably 1 mg/kg), injected, if necessary, separate doses, according to well known principles of treatment, the exact number of input connections (or t specific disease or condition requiring treatment.

In addition to the above application in human therapy, the compound of formula I is also useful for veterinary treatment of similar diseases that affect the securities industry warm-blooded animals, such as dogs, cats, horses and cattle. Mainly for this treatment, the compounds of formula I can be put in the same amount and the same method described above for the introduction of man. The compounds of formula I are also valuable pharmacological tools in the development and standardisation of test systems for evaluating the effects of endothelin on laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the ongoing research in the field of new and improved therapeutics.

The invention is illustrated by the following non-limiting examples in which, unless otherwise stated:

(i) the concentration and evaporation carried out on a rotary evaporator in a vacuum;

(ii) operations are performed at room temperature, i.e., in the range of 18-26oC;

(iii) chromatography and flash column chromatography performed on Merck Kieseigel 60 (Art. no. 9385) and thin-layer chromatography" (left Honey Bond Elut column, this means (unless otherwise noted) column containing 10 g of silicon dioxide with a particle size of 40 microns, the silicon dioxide contained in a 60 ml disposable syringe and as the carrier is used porous plate supplied by Varian, Harbor City, California, USA, under the name "Honey Bond Elut SI";

(v) outputs, if given, then only for the purpose of easier reading, and do not mean the maximum yield obtained by careful development of the way, and

(vi)1H NMR spectrum usually shoot at 250 MHz in d6-DMSO or CDCl3using tetramethylsilane (TMS) as internal standard and expressed as chemical shifts (Delta values) in ppm relative to TMS using conventional symbols for the major peaks: s, singlet; m, multiplet; t, triplet; OSiR., enlarged; d, doublet; DD, double doublet.

Example 1

1 M sodium hydroxide solution (11.2 ml) are added to a solution of N-(isobutoxide)-2-(4-isobutylphenyl)-N-(3-methoxy - 5-methylpyrazine-2-yl)pyridine-3-sulfonamida (2.6 g) in methanol (50 ml) and the mixture is stirred and heated to boiling point under reflux for 30 minutes.

Add water (100 ml) and the mixture podkalyvayut to pH 3 with 2 M hydrochloric acid. This mixture is extracted with uh the). Volatile product is removed by evaporation and the residue is purified column of silica gel Mega Bond Elut, using gradient-elution 0-15% ethyl acetate/hexane, and pound subsequently with diethyl ether, obtaining 2-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide (720 mg) as a solid substance, so pl. 128-129oC;

1H NMR (CDCl3):

of 0.95(d, 6H), and 1.9(m, 1H), 2,3 (s, 3H), by 2.55(d, 2H), and 3.8(s, 3H), and 6.6(s, 1H), 7,1-7,3(m, 4H), 7,35(s, 1H), and 7.5(DD, 1H), and 8.7(DD, 1H), 8,8(DD, 1H);

mass spectrum (positive elektrorazpredelenie (+ve ESP)): 413(M+N)+.

The original N- (isobutoxide)-2-(4-isobutylphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) a Solution of sodium nitrite (6.5 g) in water (15 ml) is added gradually to a solution of 3-amino-2-chloropyridine (10 g) in acetic acid (100 ml) and concentrated hydrochloric acid (37 ml) at 0-5oC. This cooled solution is added then portions to a stirred and cooled (5oC) a mixture of copper chloride (I) (2,33 g) in acetic acid (160 ml), saturated with sulfur dioxide, maintaining the temperature below 10oC. After complete addition, remove the cooling bath and the mixture is stirred an additional 90 minutes at ambient temperature, leucanthemum and the solid is dissolved in diethyl ether (500 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), water (200 ml) and saturated aqueous sodium chloride and then dried (MgSO4). Volatile compound is removed by evaporation, receiving 2 - chloropyridin-3-sulphonylchloride (12.1 g) in the form of oil, which solidified upon cooling and is used without further purification;

H1NMR (CDCl3):

to 7.5(DD, 1H), 8,5(DD, 1H), and 8.7(DD, 1H).

(ii) sodium Hydride (60% dispersion in oil; 0.083 g) is added to a stirred solution of isobutyl-N-(3-methoxy-5-methylpyridin-1 - yl)carbamate (0,451 g) in dry N,N-dimethylformamide (DMF); 8 ml) at 4oC. the Mixture is stirred while warming to ambient temperature for 1 h, re-cooled to 4oC and added in portions over 2 minutes 2-chloropyridin-3 - sulphonylchloride (0.40 g). Mixture is allowed to warm to ambient temperature and additionally stirred for 30 minutes. Add water (40 ml), then podkalyvayut 1 M hydrochloric acid. The mixture is extracted with ethyl acetate (4 x 15 ml) and the organic extracts washed with water (10 ml) and saturated sodium chloride solution (10 ml) and then dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified Mega Bond Elut column of silica gel, using a gradient elution 0-35% ethyl acetate/hexane and triturated sulfonamide (0.34 g) in the form of a solid connection, so pl. 99-101oC;

H1NMR (CDCl3): of 0.7(d, 6H), 1,7(m, 1H), 2,5 (s, 3H), and 3.8(d, 2H), 4,0 (s, 3H), 7,45(DD, 1H), and 7.9 (s, 1H), and 8.6(DD, 1H), and 8.7(DD, 1H);

mass spectrum (+ve ESP): 415(M+N)+.

(iii) a Solution of 2-chloro-N-isobutoxide-N-(3-methoxy - 5 - methylpyrazine-2-yl)pyridine-3-sulfonamida (4.0 g), 4 - isobutylacetophenone acid (obtained as described in European patent application, publication N 0569193) (1,72 g) and tetrakis(triphenylphosphine) palladium (0) (0,334 g) in toluene (80 ml) and ethanol (40 ml) obeskislorozhennuju, vacuuming and filling with argon (4 cycles). Then add 2 M sodium carbonate solution (25 ml). The mixture is stirred and heated to boiling point under reflux for 16 hours. Add water (100 ml) and the mixture extracted with ethyl acetate (4 x 40 ml). The organic extracts washed with water (50 ml) and saturated sodium chloride solution (50 ml) and then dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified on 20 g - silikagelevye Mega Bond Elut column, using a gradient elution 0-20% ethyl acetate/hexane, obtaining N- (isobutoxide)-2-(4-isobutylphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)-pyridine-3-sulfonamide (3.1 g) in the form of a solid connection, so pl. 133-137oC;

H1NMR (CDCl3): of 0.7(d, 6H), and 0.9 (d, 6H), 1,7(m, 1 CLASS="ptx2">

Isobutyl-N-(3-methoxy-5 - methylpyrazine-2-yl)-carbamate used in stage (ii), was obtained as follows:

(a) a Solution of bromine (of 0.11 ml) in chloroform (20 ml) is added dropwise over 20 minutes to a solution of 2 - amino-5-methylpyrazine (0,218 g) in chloroform (30 ml), protected from light. After complete addition, the reaction mixture is stirred for 90 minutes and then washed with water (50 ml). The organic phase is dried (MgSO4) and volatile compounds are removed by evaporation, receiving a yellow oil. The oil is purified silikagelevye Mega Bond Elut column using elution dichloromethane, receiving 2-amino-3-bromo-5-methylpyrazine (0,286 g) in the form of a solid product, so pl. 51-52oC;

mass spectrum (+ve CI): 188 (M+N)+.

(b) 2-Amino-3-bromo-5-methylpyrazine (0,374 g) added to their solution of sodium methylate in methanol (obtained by adding sodium (0,115 g) to methanol (6 ml). The reaction mixture is heated to boiling point under reflux for 18 hours, cooled to ambient temperature and the solvent is removed by evaporation. To the residue water is added (5 ml) and the mixture extracted with dichloromethane (3 x 20 ml). The combined organic extracts dried (MgSO4) and the solvent is removed by evaporation. The remainder of the clean gas chromatography is itallow (0,208 g, 75%), so pl. 67-69;

mass spectrum (+ve CI): 140 (M+N)+.

(C) Isobutylparaben (4,79 ml) is added to a stirred solution of 2-amino-3-methoxy-5 - methylpyrazine (5 g) and pyridine (2,91 ml) in dichloromethane (10 ml) at ambient temperature. After 90 minutes the reaction mixture was diluted with dichloromethane (10 ml) and washed with 2 M hydrochloric acid (3 x 20 ml), water (20 ml) and saturated sodium chloride solution (20 ml) and then dried (MgSO4). Volatile compounds are removed by evaporation, giving a solid product, which is recrystallized from hexane, obtaining N-(3-methoxy-5 - methylpyrazine-2-yl)carbamate (6.5 g);

1H NMR (CDCl3): 1,0(d, 6N), 2.0 (m, 1H), and 2.4 (s, 3H), 4,0(d, 2H), was 4.02(s, 3H), and 7.3(s, 1H), and 7.8(s, 1H);

mass spectrum (positive chemical ionization (+ve CI): 240 (M+N)+.

Examples 2-3. Using a method similar to that described in example 1 given the following compounds of formula I with the release of 10-37%:

(Example 2)

N-(3-methoxy-5-methylpyrazine-2-yl)-2 - phenylpyridine-3-sulfonamide;

1H NMR (d6-DMSO): 2,2 (s, 3H), 3,6 (s, 3H), 7.3 to at 7.55(m, 6H), and 7.6(DD, 1H), and 8.4(DD, 1H); 8,8(DD, 1H), 10,5 (user. s, 1H);

mass spectrum (bombing quick positive atoms (+ve FAB, methanol/m-nitrobenzyl alcohol (NBA)): 357 (M+N)+;

proceeding from N-(and the d, 6H), and 1.7(m, 1H), to 2.55(s, 3H), and 3.7 (d, 2H), 3,9 (s, 3H), 7,4-of 7.55(m, 5H), and 7.8(DD, 1H), 8,9(DD, 1H), 8,95(DD, 1H);

mass spectrum (+ve CI): 457 (M+H)+;

obtained by the method similar to that described in example 1, part (iii), but using phenylboronic acid.

(Example 3)

2-(4-isopropoxyphenyl)-N-(3-methoxy-5 - methylpyrazine-2 - yl) pyridine-3-sulfonamide

H1NMR (CDCl3): of 1.40(d, 6H), 2,3 (s, 3H), and 3.8 (s, 3H), 4,6(m, 1H), 6,7(user. s, 1H), 6,9(d, 2H), 7,2-7,35(m, 3H), and 7.5(DD, 1H), and 8.7(DD, 1H), 8,8(DD, 1H);

mass spectrum (+ve ESP): 415 (M+N)+;

on the basis of N - isobutoxide-2-(4-isopropoxyphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamida;

H1NMR (CDCl3): 0,7(d, 6N), of 1.40(d, 6H), 1,7(m, 1H), 2,5 (s, 3H), and 3.8(d, 3H), 4,0(s, 3H), 4,6(m, 1H), 6,9(d, 2H), 7,45(DD, 1H), and 7.6(d, 2H), and 7.9(s, 1H), 8,8(DD, 1H), 8,95(DD, 1H);

mass spectrum (+ve ESP): 515 (M+N)+; 2 obtained by the method similar to that described in example 1, part (iii), but with the addition of potassium iodide (1 molar equivalent) and using 4-isopropoxyaniline acid, obtained as described in European patent application N publication 569193.

Example 4

Tetrabutylammonium (0.7 ml of a 1.1 M solution in THF) are added to a solution of N-(3-methoxy-5-methylpyrazine-2-yl)-2- (4-methylthiophenyl)-N-[2-trimethylsilyl)ethoxymethyl] pyridine-3 - Sul solution of tetrabutylammonium-fluoride (0.35 ml) and continue heating for 5 hours. Add an additional aliquot of a solution of tetrabutylammonium (optional overall 2.5 ml) until the completion of the reaction, which is established by thin-layer chromatography (elution ethyl acetate/hexane (1:1 in volume ratio)). Volatile products are removed by evaporation, the residue diluted with water and extracted three times with ethyl acetate. The organic extracts washed with water and saturated sodium chloride solution and then dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified Mega Bond Elut column of silica gel, using a gradient elution 0-40% ethyl acetate/hexane, obtaining N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-methylthiophenyl)-pyridine-3 - sulfonamide (0,201 g) as a foam.

1H NMR (CDCl3): 2,3 (s, 3H), of 2.5 (s, 3H), and 3.8 (s, 3H), 7,15-7,35(m, 4H), 7.5(m, 1H), and 8.7(DD, 1H), 8,8(DD, 1H);

mass spectrum (+ve ESP): 403(M+N)+.

The source connection of the N-(3-methoxy-5-methylpyrazine-2 - yl)-2-(4-methylthiophenyl)-N-[2-trimethylsilyl)ethoxymethyl] pyridine-3-sulfonamide was obtained as follows:

(i) 4-Dimethylaminopyridine (0.1 g) are added to a solution of 2-chloropyridin-3-sulphonylchloride (1.06 g), 2-amino-3-methoxy-5 - methylpyrazine (0,695 g) and pyridine (0,424 ml) in dichloromethane (5 ml) and the mixture is stirred at a temperature of okruzhyon gives 2-chloro-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide (0,47 g) in the form of butter;

1H NMR (d6-DMSO): 2,3(s, 3H), at 3.9(s, 3H), and 7.5(s, 1H), 7,65(DD, 1H), 8,45(DD, 1H); to 8.7(DD, 1H);

mass spectrum (+ve Cl): 315 (M+N)+.

(ii) 2-(Trimethylsilyl)ethoxymethylene (0,315 ml) is added dropwise to a stirred solution of 2-chloro-N- (3-methoxy-5 - methylpyrazine-2-yl) pyridine-3-sulfonamida (0,47 g) and N,N-diisopropylethylamine (0,347 ml) in dry DMF (7 ml) at -15oC. After complete addition, stirring is continued at the same temperature for 40 minutes. Add ethyl acetate (40 ml) and the mixture washed with water (3 x 15 ml) and saturated sodium chloride solution and then dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified Mega Bond Elut column of silica gel, using a gradient elution of 0-30% ethyl acetate/hexane, obtaining 2-chloro - N-(3-methoxy-5-methylpyrazine-2-yl)-N-[2-(trimethylsilyl) ethoxymethyl]pyridine-3-sulfonamide (0,462 g) in the form of butter;

1H NMR (CDCl3): 0,0 (s, 9H), of 0.85 (t, 2H), and 2.5 (s, 3H), of 3.75(t, 2H), and 3.8(s, 3H), 5,3(s, 2H), and 7.3(DD, 1H), and 7.8 (s, 1H), and 8.4(DD, 1H), 8,5(DD, 1H);

mass spectrum (+ve ESP): 403 (M+H)+.

(iii) Tetrakis(triphenylphosphine) palladium (0) (0,022 g) is added to the mixture, devoid of oxygen of 2-chloro-N-(3-methoxy-5-methylpyrazine-2 - yl)-N-[2-(trimethylsilyl)-ethoxymethyl] pyridine-3-sulfonamida (0,405 g), 4-methyldiphenylamine to the and sodium carbonate (7 ml) and the mixture is stirred and heated to boiling point under reflux for 18 hours. Water is added and the mixture extracted three times with ethyl acetate. The organic extracts are combined, washed with saturated sodium chloride solution and then dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified silikagelevye Mega Bond Elut column, using a gradient elution 0-35% ethyl acetate/hexane, obtaining N-(3-methoxy - 5-methylpyrazine-2-yl)-2-(4-methylthiophenyl)-N-[2-(trimethylsilyl) ethoxymethyl]pyridine-3-sulfonamide (0, 415 g) in the form of butter;

1H NMR (CDCl3): 0,0 (s, 9H), 0.8 a (t, 2H), and 2.5 (s, 3H), by 2.55 (s, 3H), 3,6(t, 2H), 3,9(s, 3H), and 4.8(s, 2H), 7.3 to 7.5 (m, 3H), of 7.6 to 7.7(m, 2H), and 7.8 (s, 1H), and 8.7(DD, 1H), 8,8(DD, 1H); mass spectrum (+ve ESP): 533 (M+N)+< / BR>
Example 5

Sodium hydride (60% dispersion in oil; 0,098 g) was washed with hexane (2 x 3 ml) in an argon atmosphere. Add with stirring dry DMF (1.5 ml) and the resulting suspension is cooled to 5oC and add a solution of 2-amino-5-chloro-3-methoxypyrazine (0,178 g) in dry DMF (3 ml), after the termination of allocation of gas bubbles is added dropwise over 5 minutes a solution of 4-nitrophenyl-2-(4 - isobutylphenyl) pyridine-3-sulfonate (0,459 g) in dry DMF (3 ml). Remove the cooling bath and the reaction mixture is stirred for 40 minutes, then poured into 2 M hydrochloric acid (100 ml) and the product extracted with ethyl acetate (2 x 200 ml). Extractuse connection is removed by evaporation and the residue is purified Mega Bond Elut column of 20 g of silica gel, using elution methanol/dichloromethane (1:99 in volume ratio) to give N-(5-chloro-3-methoxypyrazine-2-yl)-2- (4-isobutylphenyl)-pyridine-3-sulfonamide (0,339 g) in the form of a solid connection, so pl. 156-157oC,

1H NMR (d6-DMSO): of 0.9(d, 6H), and 1.9 (m, 1H), 2,55(d, 2H), 3,85(s, 3H), and 7.1(d, 2H), and 7.3(d, 2H), and 7.6(DD, 1H), and 7.7(s, 1H), and 8.4(DD, 1H), 8,8(DD, 1H), 10,9(user. s, 1H);

mass spectrum (+ve ESP): 433 (M+N)+.

The original connection 4-nitrophenyl-2-(4-isobutyl-phenyl)pyridine-3 - sulfonate was obtained as follows:

(i) N,N-Diisopropylethylamine (0.45 ml) are added to a solution of 2-chloropyridin-3-sulphonylchloride (0,53 g) and 4-NITROPHENOL (0.35 g) in DMF (5 ml). The mixture was stirred at ambient temperature for 30 minutes and diluted with ethyl acetate (25 ml), washed with water (2 x 25 ml), saturated sodium carbonate solution (3 x 20 ml), water (20 ml) and saturated aqueous sodium chloride. Water layers again extracted with ethyl acetate (25 ml) and the organic layers combined and dried (MgSO4). Volatile product is removed by evaporation, receiving 4-nitrophenyl-2-chloropyridin-3-sulfonate (0.52 g) in the form of a solid connection, so pl. 127-128oC;

1H NMR (d6-DMSO): 7.5(d, 2H), and 7.7(DD, 1H), 8.3(l, 2H), and 8.4(DD, 1H), 8,8(DD, 1H);

mass spectrum (+ve FAB, NBA/DMSO): 315 (M+N)+.

(ii) Nata (0,69 g), 4-isobutyl-phenylboronic acid (0,47 g), potassium fluoride (0,38 g), toluene (15 ml) and water (2.5 ml) and the mixture is stirred and heated to boiling point under reflux for 24 hours. Add water (50 ml) and the mixture extracted with ethyl acetate (2 x 80 ml). The organic extracts washed with sodium chloride solution and then combined and dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified silikagelevye Mega Bond Elut column, using a gradient elution dichloromethane/hexane (1:1 to 1:0, volume ratio), then dichloromethane/hexane/ ethyl acetate (10:9:1 in volume ratio), followed by recrystallization from ethyl acetate/hexane, receiving 4-nitrophenyl-2-(4-isobutylphenyl) pyridine-3-sulfonate (0.50 g), so pl. 123-124oC;

1H NMR (d6-DMSO): of 0.9(d, 6H), and 1.9(m, 1H), 2,55(d, 2H), 7,2-7,3(m, 4H), 7.5(d, 2H), and 7.7(DD, 1H), and 8.2(d, 2H), and 8.4(DD, 1H), and 9.0(DD, 1H);

mass spectrum (+ve FAB, NBA/DMSO): 413 (M+N)+.

The original connection 2-amino-5-chloro-3-methoxypyrazine receive the following way:

(a) Methyl 2-aminopyrazine-3-carboxylate (5.4 g) is suspended in acetic acid (40 ml) and add water (140 ml). The mixture is heated to 40oC and bubbled chlorine gas through it. The obtained clear solution is then cooled to 0

The resulting precipitate is collected by filtration and through the filtrate bubbled chlorine for 10 minutes, after which the weight of the filtrate increases even 2.2, the Second precipitate is collected by filtration and combined solids are mixed with a solution of sodium bisulfite (9 g) in water (60 ml) for 1.5 hours. The solid product is collected by filtration, washed with water ice (2 x 100 ml) and dried in vacuum, obtaining methyl 2-amino-5-chloropyrazine-3-carboxylate (4.3 g);

1H NMR (d6-DMSO): a 3.87 (s, 3H), 7,5(user. s, 2H), of 8.37 (s, 1H);

mass spectrum (+ve Cl): 188 (M+N)+.

(b) Methyl 2-amino-5-chloropyrazine-3-carboxylate (3.75 g) are added to a solution of sodium hydroxide (2.0 g) in water (20 ml) and the solution heated to boiling point under reflux for 1.5 hours. The reaction mixture was cooled to 0oC and the resulting precipitate collected by filtration. The solid product is re-dissolved in water (60 ml) under heating and the solution is filtered. Then the filtrate podkalyvayut to pH 2 with 2 M hydrochloric acid; the precipitate is collected by filtration and washed with water ice (2 x 20 ml) and dried in vacuum. The solid product is suspended in diphenyl ether (15 ml) and heated to boiling point under reflux in an atmosphere of argon is, which precipitate is collected by filtration and washed with hexane (3 x 25 ml), getting 2-amino-5-chloropyrazine (1.78 g);

1H NMR (d6-DMSO): 6,55(user. s, 2H), to 7.67(d, 1H), 7,95(d, 1H);

mass spectrum (+ve Cl): 130(M+N)+.

(C) 2-Amino-5-chloropyrazine (1.7 g) dissolved in chloroform (190 ml) and added dropwise pyridine (1.3 ml) in an argon atmosphere. The flask and contents protect from light and add a solution of bromine (0.7 ml) in chloroform (85 ml) for 1 hour. After stirring for 2 hours add an additional amount of bromine (0,07 ml) in chloroform (8.5 ml). After stirring for 30 minutes, add pyridine (0.2 ml). The reaction mixture is stirred for 30 minutes, then washed with water (50 ml) and separate the organic phase. Volatile products are removed by evaporation and the residue is cleaned by chromatography through a layer of silica (90 g), elwira hexane (200 ml) and then dichloromethane. Containing the product fractions dichloromethane evaporated, obtaining 2-amino-3-bromo-5-chloropyrazine (1.68 g);

1H NMR (de-DMSO): 6,94(user. s, 2H), of 8.09(s, 1H);

mass spectrum (+ve Cl): 208(M+N)+.

(d) Sodium (2,82 g) dissolved in dry methanol (50 ml) in an argon atmosphere and added in small portions with stirring, 2-amino-3-bromo-5-chloropyrazine (1.68 g). Stir the solution is heated to boiling point under reflux in the product is removed by evaporation and to the residue water is added (10 ml). The mixture is extracted with dichloromethane (3 x 50 ml) and the combined extracts dried (MgSO4) and evaporated, obtaining 2-amino-5-chloro-3-methoxypyrazine (1.28 g), so pl. 102-103oC;

1H NMR (d6-DMSO): 3,90 (s, 3H), 7,53 (s, 1H);

mass spectrum (+ve Cl): 160(M+H)+.

Example 6

Using a method similar to that described in example 5, get (23% yield) of N-(5-chloro-3-methoxypyrazine-2-yl)-2- [4-(N,N-dimethylamino)phenyl]pyridine-3-sulfonamide;

1H NMR (d6-DMSO): 3,0 (s, 6H), and 3.8 (s, 3H), 6,7(d, 2H), and 7.4(d, 2H), and 7.5(DD, 1H), and 7.7(s, 1H), and 8.4(DD, 1H), 8,8(DD, 1H);

mass spectrum (+ve ESP): 420 (M+N)+;

on the basis of 4-nitrophenyl-2-[4-(N,N-dimethylamino)phenyl]pyridine - 3-sulfonate;

1H NMR (d6-DMSO): 3,0(s, 6H), 6,8(d, 2H), and 7.3(d, 2H), 7,6(m, 3H), and 8.2(d, 2H), and 8.4(DD, 1H), and 9.0(DD, 1H);

mass spectrum (+ve ESP): 400 (M+N)+;

obtained by the method similar to that described in example 5, part (ii) but using 4-(N,N-dimethylamino)phenylboronic acid (obtained by the method described in Annalen der Chemie, 1971, 753, 80).

Example 7

Tetrabutylammonium (0,45 ml of 1.0 M solution in THF) are added to a solution of 4-(4-isobutylphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)-N-[2-(trimethylsilyl)-ethoxymethyl) pyridine - 3-sulfonamida (0,205 g) in dry THF (2 ml) and the solution heated to campmany-fluoride (0.95 ml) and continue heating for 2 hours. The reaction mixture was diluted with water (15 ml) and extracted with diethyl ether (2 x 30 ml). The organic extracts washed with water and saturated sodium chloride solution and then dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified silikagelevye Honey Bond Elut column, using a gradient elution of 40-50% ethyl acetate/hexane, followed by recrystallization from ethyl acetate/hexane, obtaining 4-(4-isobutylphenyl)-N-(3-methoxy - 5-methyl-pyrazin-2-yl)pyridine-3-sulfonamide (0,014 g), so pl. 232-233oC;

1H NMR (d6-DMSO): of 0.9(d, 6H), 1,8(user. m, 1H), 2.1 to 2.5(user. m, 5H), and 3.8(s, 3H), 7,1-7,3(m, 4H), 7,35(d, 1H), and 7.5(s, 1H), up 8.75(d, 1H), and 9.1(s, 1H), 10,4(s, 1H);

mass spectrum (+ve ESP): 413 (M+N)+.

The original compound, 4-(4-isobutylphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)-N-[2-(trimethylsilyl)-ethoxymethyl] -pyridine-3 - sulfonamide, was obtained as follows:

(i) 2-Amino-3-methoxy-5-methylpyrazine (0,346 g) are added to a suspension of sodium hydride (60% dispersion in oil; 0.25 g) in DMF (10 ml). After 30 minutes add 4-chloropyridin-3-sulphonylchloride (0,58 g) (obtained according to the method described by C. Ann. Pharm. Fr., 1973, 31, 467) in the form of a solid connection, washed with DMF (1 ml). The mixture is stirred an additional 2 hours at ambient temperature and then agree with water (2 x 100 ml) and a saturated solution of sodium chloride, then combined and dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified silikagelevye Mega Bond Elut column, using a gradient elution of 30-50% ethyl acetate/hexane, followed by recrystallization from ethyl acetate/hexane, receiving 4-chloro-N-(3-methoxy-5-methylpyrazine - 2-yl) pyridine-3-sulfonamide (0,117 g), which decomposes without melting 130oC;

1H NMR (d6-DMSO): 2,3(d, 3H), 4,0(s, 3H), and 8.2(d, 1H), and 8.5(d, 1H), and 9.0(d, 1H), and 9.2(s, 1H);

mass spectrum (+ve ESP): 315 (M+N)+.

(ii) 2-(Trimethylsilyl) ethoxymethylene (0,22 ml) is added dropwise over 5 minutes to a stirred solution of 4-chloro - N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine-3-sulfonamida (0,306 g) and N,N-aminobutiramida-ethylamine (of 0.21 ml) in dry DMF (1 ml) at -15oC. the resulting solution was allowed to warm to -5oC for 40 minutes, then add ethyl acetate (30 ml) and the mixture was washed with 2 M hydrochloric acid (30 ml), water (30 ml) and saturated sodium chloride solution and then dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified silikagelevye Mega Bond Elut column, using a gradient elution of 30-50% ethyl acetate/hexane, receiving 4-chloro-N-(3-methoxy-5-methylpyrazine - 2-yl)-N-[2-(trimethylsilyl)ethoxymethyl] -pyridine-3-Sul is 1H), to 8.0(s, 1H), and 8.8(d, 1H), and 9.1(s, 1H);

mass spectrum (+ve FAB, DMSO/glycerol): 445(M+N)+.

(iii) Tetrakis(triphenylphosphine) palladium (0) (0,018 g) is added to the mixture, devoid of oxygen 4-chloro-N-(3-methoxy-5-methylpyrazine-2-yl) -N-[2-(trimethylsilyl)-ethoxymethyl] pyridine-3-sulfonamida (0,225 g), 4-isobutylacetophenone acid (0,109 g), toluene (4 ml), ethanol (2 ml) and 2M sodium carbonate solution (6 ml) and the mixture is stirred and heated to boiling point under reflux for 18 hours. Add diethyl ether (25 ml) and the mixture washed with water (2 x 25 ml) and a saturated solution of sodium chloride. The aqueous layers are re-extracted with diethyl ether (25 ml). The organic extracts are combined and dried (MgSO4). Volatile compounds are removed by evaporation and the residue is purified silikagelevye Mega Bond Elut column, using a gradient elution of 25-50% ethyl acetate/hexane, obtaining 4-(4-isobutylphenyl)-N-(3-methoxy - 5-methylpyrazine-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl] pyridine-3-sulfonamide (0,213 g) in the form of butter;

1H NMR (d6-DMSO): -0,1(s, 9H), 0,7(t, 2H), and 0.9(d, 6H), and 1.9(m, 1H), of 2.45(s, 3H), 2,5(d, 2H), 3,5(t, 2H), and 3.8(s, 3H), 4,7(s, 2H), 7,2(d, 2H), and 7.3(d, 2H), and 7.4(d, 1H), and 8.0(s, 1H), and 8.8(d, 1H), and 9.2(s, 1H);

mass spectrum (+ve ESP): 543(M+N)+.

Example 8

2 M sodium hydroxide solution (1) - Rev. yl)pyridine-3 - sulfonamida (0,302 g) in methanol (5 ml) and dimethoxyethane (5 ml) and the solution stirred for 3 days. Volatile products are removed by evaporation and the residue is dissolved in water (15 ml). The solution is washed with ethyl acetate (2 x 15 ml) and podkalyvayut to pH 3 with 6 M hydrochloric acid. The mixture is extracted with ethyl acetate (2 x 10 ml) and the extracts are re-extracted with saturated sodium bicarbonate solution (2 x 10 ml). The aqueous layer was podkalyvayut 2 M hydrochloric acid and extracted with ethyl acetate. (2 x 10 ml). The extracts washed with water (10 ml) and dried (MgSO4). Volatile compounds are removed by evaporation and the residue is recrystallized from ethyl acetate, obtaining 2-[4-(1 - carboxymethoxy)phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide (0,098 g), so pl. 149-151oC;

microanalysis found: C, up 53.6; H, a 4.9; N, 11.7 per cent;

for C18H18N4O6S 0,2 C4H8O2,

theoretically, C, of 54.1; H, 4,7; N, 12.1 per cent.

The original N-(isobutoxide)-2-[4-(1-methoxycarbonyl) ethoxyphenyl]-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) a Solution of 4-bromophenol (86,5 g), 3,4-dihydro-2H-Piran (46.2 g) and p-toluensulfonate pyridinium (1.25 g) in dichloromethane (500 ml) is stirred in an argon atmosphere for 24 hours. The solution was washed with 2 M sodium hydroxide solution (200 ml) and water (2 x 200 ml) and then dried (MgSO4). Volatile SOA.sq. 51-53oC.

(ii) Tert-butyl lithium in pentane (1.7 M, 200 ml) is added over 20 minutes to a solution of 2-(4-bromophenoxy)-2H-tetrahydropyran (38,6 g) in dry tetrahydrofuran (450 ml) at -90oC in argon atmosphere. The solution was stirred at -90oC for 30 minutes and then added dropwise within 15 minutes, the solution trimethylborane (30 ml) in dry tetrahydrofuran (50 ml). The solution was stirred at -90oC for 30 minutes and then allowed to warm to -30oC. Add a saturated solution of ammonium chloride (100 ml) and the mixture allowed to warm to room temperature. Add water (100 ml) and the mixture extracted with diethyl ether (2 x 250 ml). The extracts washed with water (2 x 200 ml) and dried (MgSO4). Volatile compounds are removed by evaporation and the residue is recrystallized from a mixture of diethyl ether and hexane, obtaining 4-(2H-tetrahydropyran-2-yloxy)phenylboronic acid (23,4 g), so pl. 140-142oC.

(iii) a Solution of potassium fluoride (6.5 g) in water (100 ml) are added to a solution of 2-chloro-N-isobutoxide-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamida (7,8 g), 4-(2-(2H) - tetrahydropyranyloxy) phenylboronic acid (10.0 g), tri-o - tolylphosphino (0.73 g) and palladium acetate (0.25 g) in toluene (100 ml) and the mixture is heated to boiling point with the inverse holodilny the solution of sodium hydroxide (100 ml) and water (250 ml) and then dried (MgSO4). Volatile compounds are removed by evaporation and the residue clean flash chromatography, elwira 25-50% ethyl acetate/hexane. The residue is recrystallized from ethyl acetate/hexane, obtaining N-(isobutoxide)-2[4-(2H)- tetrahydropyran-2-yloxy)phenyl] -N-(3-methoxy-5-methylpyrazine - 2-yl)pyridine-3-sulfonamide (4.0 g), so pl. 142-144oC.

(iv) a Solution of N-(isobutoxide)-2[4-(2H)-tetrahydropyran - 2-yloxy)phenyl-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamida (5.9 g) and p-toluensulfonate pyridinium (0.27 g) in ethanol (150 ml) is heated at 60oC 3 hours. Volatile compounds are removed by evaporation and the residue clean flash chromatography, elwira ethyl acetate/hexane (2:3 in volume ratio). The residue is triturated with ethyl acetate/hexane (1:9, volume ratio) to give 2-(4 - hydroxyphenyl)-N-(isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide (4.7g), so pl. 144-146oC.

(v) a Mixture of 2-(4-hydroxyphenyl)-N-(isobutoxide)-N-(3-methoxy - 5-methylpyrazine-2-yl)pyridine-3-sulfonamida (0,472 g), methyl-2-bromopropionate (217 mg) and potassium carbonate (166 mg) in acetone (20 ml) is heated to the boiling temperature under reflux for 15 hours. Volatile compounds are removed by evaporation and to the residue is added water (25 ml). The mixture Ekor dried (MgSO4) and the solvent is removed by evaporation. The remainder of the clean flash chromatography, elwira ethyl acetate/hexane (1:1 in volume ratio) to give N-(isobutoxide)-2-(4-[1-(methoxycarbonyl) ethoxy] phenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (0.32 g);

1H NMR (d6-DMSO): 0,6(d, 6H), of 1.5-1.7(m, 4H), of 2.5(s, 3H), and 3.7(s, 3H), and 3.8(d, 2H), 4,0(s, 3H), 5,1(kV, 1H), 6,95(d, 2H), 7.5(d, 2H), 7,7-7,8(m, 1H), and 8.2(s, 1H), cent to 8.85(d, 1H), 8,9(d, 1H).

Example 9

The sodium methylate (0,115 g) are added to a solution of 2-[4- (N,N-dimethylamino)phenyl]-N-(isobutoxide)-N-(3-methoxy - 5-methylpyrazine-2-yl)pyridine-3-sulfonamida (0,212 g) in methanol (10 ml) and the mixture is stirred and heated to boiling point under reflux for 90 minutes. The reaction mixture is cooled, poured into saturated aqueous solution of ammonium chloride (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic extracts are combined and dried (MgSO4). Volatile products are removed by evaporation and the residue triturated with diethyl ether, obtaining 2-[4-(N,N-dimethylamino)phenyl] -N- (3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (104 mg) as a solid substance, so pl. 183-184,5oC;

1H NMR (d6-DMSO): 2,2 (s, 3H), 2.95 and (s, 6H), and 3.8 (s, 3H), 6,7(user. s, 2H), 7.3 to 7.5(m, 4H), of 8.37(DD, 1H), and 8.7(DD, 1H), 10,1(user. s, 1H);

mass spectrum (bonil)-N-3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide are obtained from 51% yield, using a method similar to that described in example 8, part (iii) but using 4-(N,N - dimethylamino)-phenylboronic acid;

1H NMR (d6-DMSO): 0,6(d, 6H), 1,6(m, 1H), to 2.55 (s, 3H), 3.0 a(s, 3H), and 3.8(d, 2H), 4,0(s, 3H), 6,7(d, 2H), 7,45(d, 2H), and 7.6(DD, 1H), and 8.2 (s, 1H), cent to 8.85(m, 2H);

mass spectrum (+ve FAB, DMSO/NBA): 500 (M+N)+.

Example 10

Using a method similar to that described in example 1, get (32% yield) of 2-(4-chlorophenyl)-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide

1H NMR (CDCl3): 2,3(s, 3H), 3,85(s, 3H), 6,7(s, 1H), 7,25 was 7.45(m, 5H), and 7.5(DD, 1H), 8,65(d, 1H), and 8.8(d, 1H);

mass spectrum (+ve ESP): 391(M+H)+; based on 2-(4-chlorophenyl) -N-isobutoxide-N-(3-methoxy-5-methyl-pyrazin-2-yl) pyridine-3-sulfonamida;

1H NMR (CDCl3): 0,65(d, 6H), 1,7(m, 1H), 2,5(s, 3H), and 3.8(d, 2H), 4,0(s, 3H), 7,35 and 7.6(m, 5H), and 7.9(s,1H), cent to 8.85(DD, 1H), 8,95(DD, 1H);

mass spectrum (+ve ESP): 491(M+N)+; obtained by the method similar to that described in example 1, part (iii) but using 4-Chlorfenvinphos acid.

Example 11

2 M sodium hydroxide Solution (1 ml) are added to a solution of N-(isobutoxide)-2-(4-propylphenyl)-N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida (0.7 g) in methanol (2 ml) and the reaction mixture stirred for 17 hours at ambient temperature. Menenia organic extracts dried (MgSO4) and then the solvent is removed by evaporation. The oil obtained is purified silikagelevye Mega Bond Elut column, elwira 30% ethyl acetate/isohexane, and subsequently triturated with isohexane/diethyl ether, obtaining 2-(4 - propylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide (0.4 g) in the form of a solid connection, so pl. 70-72oC; mass spectrum (+ve ESP): 399(M+N)+.

The source connection of the N-(isobutoxide)-2-(4-propylphenyl) -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) n-Utility (34 ml, 1.6 M solution in hexane) is added dropwise to a stirred solution of 1-bromo-4-propylbenzene (9,96 g) in dry THF (30 ml) at -70oC in argon atmosphere. The reaction mixture is stirred for 1 hour at -70oC before adding triisopropylsilane (12,7 ml) and then further stirred for 90 minutes at -70oC before adding saturated aqueous solution of ammonium chloride (30 ml). The reaction mixture was stirred at -70oC for 10 minutes, add water (100 ml) and the reaction mixture allowed to warm to ambient temperature. The reaction mixture was extracted with diethyl ether (3 x 50 ml), the combined organic layers are dried (MgSO4and then the solution is th acid in the form of a white solid, 6.7 g;

mass spectrum (negative elektrorazpredelenie (-ve ESP): 163 (M-H)-.

(ii) Tetrakis(triphenylphosphine) palladium (0) (60 mg) are added to obeskislorozhennaja solution of sodium carbonate (212 mg), 4 - propylpentanoic acid (328 mg) and 2-chloro-N-(isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamida (828 mg) in a mixture of water (5 ml), ethanol (8 ml) and toluene (16 ml). The mixture is stirred and heated in an argon atmosphere at 80oC 17 hours and then cooled to ambient temperature. Add ice water (25 g) and the reaction mixture is extracted with ethyl acetate (3 x 50 ml). The combined organic layers are dried (MgSO4) and evaporated, getting amber oil, cleaned chromatography on silikagelevye Mega Bond Bint column, elwira 20% ethyl acetate/isohexane, receiving N-(isobutoxide)-2-(4-propylphenyl)-N-(3-methoxy-5-methylpyrazine - 2-yl)pyridine-3-sulfonamide (760 mg) in the form of solid compounds;

mass spectrum (+ve ESP): 499(M+N)+.

Example 12

Using a method similar to that described in example 11, receive (72% yield) of 2-(4-ethylphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide in the form of a crystalline solid connection, so pl. 73-75oC;

1H NMR (d6-DMSO): 1,C N-(isobutoxide)-2-(4 - ethylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamida.

The source connection of the N-(isobutoxide)-2-(4-ethylphenyl) -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 11, part (i), but using 1-bromo-4-ethylbenzene as a starting compound, receive (93% yield) of 4-ethylvinylbenzene acid as a white solid; mass spectrum (-ve ESP); 149 (M-H)-.

(ii) Using a method similar to that described in example 11, part (ii) but using 4-ethylvinylbenzene acid, receive (36% yield) N-(isobutoxide)-2-(4-ethylphenyl)-N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide as a white crystalline compound; mass spectrum (+ve ESP): 485(M+N)+.

Example 13

Using a method similar to that described in example 11, receive (48% yield) of 2-(4-tert-butylphenyl)-N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide as a white crystalline substance, so pl. 150-151oC;

1H NMR (d6-DMSO): 1,3(s, 9H), of 2.25(s, 3H), and 3.8(s, 3H), of 7.4(m, 4H), and 7.6(DD, 1H), and 8.4(d, 1H), and 8.8(d, 1H);

mass spectrum (+ve ESP): 413(M+N)+; proceeding from N-(isobutoxide) -2-(4-tert-butylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamida.

The source connection of the N-(ISM:

(i) Using a method similar to that described in example 11, part (i), but using 1-bromo-4-tert-butylbenzoyl as the parent compound, receive (81% yield) of 4-tert - butylphenylmethyl acid (81%) as a white solid, mass spectrum (-ve ESP): 177 (M-H)-.

(ii) Using a method similar to that described in example 11, part (ii), but on the basis of 4-tert-butylaniline acid, receive (33% yield) of N-(ISO-butoxycarbonyl)-2-(4-tert - butylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide as a white crystalline substance, mass spectrum (+ve ESP): 513 (M+N)+.

Example 14

Using a method similar to that described in example 11, get (42% yield) of 2-(4-isopropylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide as a white crystalline substance, so pl. 74-75oC; mass spectrum (+ve ESP): 399(M+N)+; proceeding from N-(isobutoxide)-2-(4-isopropylphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamida.

The source connection of the N-(isobutoxide)-2-(4-isopropylphenyl) -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 11, part (i), but using 1-bromo-in the form of a white solid, mass spectrum (-ve ESP): 163 (M-H)-.

(ii) Using a method similar to that described in example 11, part (ii), but on the basis of 4-isopropylaniline acid, receive (45% yield) N-(isobutoxide)-2-(4 - isopropylphenyl)-N-(3-methoxy-5-methyl-pyrazin-2-yl)pyridine-3-C of the sulfonamide as a white crystalline substance, mass spectrum (+ve ESP): 499 (M+N)+.

Example 15

Using a method similar to that described in example 11, receive (33% yield) of 2-(4-vinylbenzyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide as a white crystalline substance, so pl. 110-112oC; mass spectrum (+ve ESP): 383(M+H)+; proceeding from N-(isobutoxide) -2-(4-vinylbenzyl)-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamida.

The source connection of the N-(isobutoxide) -2-(4-vinylbenzyl)-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 11, part (i), but using 1-bromo-4-vinylbenzyl as the parent compound, receive (82% yield) of 4-vinylferrocene acid as a white solid, mass spectrum (-ve ESP): 149 (M-H)-.

(ii) Using a method similar to that described in example 11, part (ii), but based on Alperin-2-yl)pyridine-3-sulfonamide as a white crystalline substance, mass spectrum (+ve ESP): 483 (M+N)+.

Example 16

Using a method similar to that described in example 11, receive (30% yield) of 2-(4-N, N-diethylamino)phenyl)-N-(3 - methoxy-5-methylpyrazine-2-yl)- pyridine-3-sulfonamide as a white crystalline substance, so pl. 115-117oC;

mass spectrum (+ve ESP): 428(M+N)+; proceeding from N-(isobutoxide)-2-(4-(N,N-diethylamino)phenyl) -N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamida.

The source connection of the N-(isobutoxide)-2-(4- (N, N-diethylamino)phenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine - 3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 11, part (i), but using 4-bromo-N, N-diethylaniline as the parent compound, receive (76% yield) of 4-(N, N - diethylamino)phenylboronic acid as a white solid, mass spectrum (-ve ESP): 192 (M-H)-.

(ii) Using a method similar to that described in example 11, part (ii), but on the basis of 4-(N,N-diethylamino)phenylboronic acid, receive (31% yield) N-(isobutoxide)-2-(4-(N, N-diethylamino)phenyl)-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide as a white crystalline compound; mass spectrum (+ve ESP): 528(M+N)+.

Example XI-5-methylpyrazine-2-yl)pyridine-3-sulfonamide as a white crystalline substance, so pl. 134-135oC; mass spectrum (+ve ESP): 415(M+N)+; proceeding from N-(isobutoxide)-2-(4-propoxyphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamida.

The source connection of the N-(isobutoxide)-2-(4 - propoxyphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine-3 - sulfonamide was obtained as follows:

(i) a Mixture of 4-bromophenol (8.65 g), potassium iodide (83 mg), potassium carbonate (6.9 g) and propyl bromide (6,15 g) is heated to the boiling point under reflux in acetone (100 ml) for 48 hours. The reaction mixture is cooled to room temperature, filtered and removed in vacuo acetone, receiving an amber oil. The oil is purified silikagelevye Mega Bond Elut column, using gradient elution with 20% ethyl acetate/isohexane, which gives 1-bromo-4-propoxy-benzene (9.4 g) as a clear oil;

mass spectrum (+ve Cl): 214 (M+N)+.

(ii) Using a method similar to that described in example 11, part (i), but on the basis of 1-bromo-4-propoxybenzene receive (95% yield) of 4-propositionally acid as a white solid;

mass spectrum (-ve ESP): 179 (M-H)-.

(iii) Using a method similar to that described in example 11, part (ii), but on the basis of 4-propositionally acid, receive (de white crystalline substance;

mass spectrum (+ve ESP): 515(M+N)+.

Example 18

Using a method similar to that described in example 11, get (46% yield) of 2-(4-ethoxyphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide as a white crystalline substance, so pl. 162-163oC; mass spectrum (+ve ESP): 401(M+N)+; proceeding from N-(isobutoxide) -2-(4-ethoxyphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida.

The source connection of the N-(isobutoxide)-2-(4-ethoxyphenyl) -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 17, part (i), but using ethylbromide as the parent compound, receive (76% yield) of 1-bromo-4-ethoxybenzoyl in the form of a clear oil, mass spectrum (+ve Cl): 200 (M+N)+.

(ii) Using a method similar to that described in example 11, part (i), but on the basis of 1-bromo-4-ethoxybenzene receive (96% yield) of 4-ethoxyphenylurea acid as a white solid, mass spectrum (-ve ESP): 165 (M-H)-.

(iii) Using a method similar to that described in example 11, part (ii), but on the basis of 4-ethoxyphenylacetic acid, receive (36% yield) N-(isobutoxide)-2-(4-ethoxyphenyl)-N- (3): 501 (M+N)+.

Example 19

Tetrabutylammonium (0.4 ml of 1.0 M solution in THF) are added to a solution 2-[4-(2-((tert-butyldimethylsiloxy) methyl)propyl)phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine - 3-sulfonamida (118 mg) in THF (5 ml) at ambient temperature. Additional solution of tetrabutylammonium (0.4 ml), added over 0.25 hour, 0.75 hour (1.0 ml), and finally, after 1.5 hours (0.2 ml). The reaction mixture is stirred an additional 0.5 hour, diluted with water (10 ml) and extracted with dichloromethane (4 x 10 ml).

The combined organic extracts dried over MgSO4and evaporated, receiving an amber oil. The oil is purified silikagelevye Mega Bond Elut column, using a gradient elution 0-50% methanol/dichloromethane, receiving 2-[4-(3-hydroxy-2-methylpropyl " phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide (75 mg) as a white crystalline substance, so pl. 118-119oC;

1H NMR (d6-DMSO): of 0.95(d, 3H), of 1.35(m, 1H), 2.0(m, 1H), 2,3(s, 3H), 2,5(m, 1H), 2,9(m, 1H), 3,5(m, 2H), and 3.8(s, 3H), of 6.65(s, 1H), 7,2(m, 4H), 7,35(s, 1H), 7.5(m, 1H), and 8.7(d, 1H), 8,8(DD, 1H); mass spectrum (+ve ESP): 429(M+N)+.

Source 2-[4-(2-((tert-butyldimethylsiloxy)-methyl)propyl) phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide receive follow is to promote 5oC and add 2 minutes diethyl-2-methylmalonate (68,8 ml). The resulting mixture was stirred at 5oC for 20 minutes and then add 20 minutes 4-bromobenzylamine (97,0 g). Then the reaction mixture is heated to boiling point under reflux for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth and evaporated.

The residue is partitioned between water (500 ml) and diethyl ether (1000 ml). Diethyl ether was separated and the aqueous layer was extracted with diethyl ether (2 x 500 ml). The combined organic layers are dried (MgSO4) and evaporated, receiving an amber oil. The oil is cleaned by vacuum distillation, obtaining diethyl-2-(4-bromobenzyl)-2 - methylmalonate (84,4 g), so pl. 122-125oC/0.1-0.2 mm Hg; mass spectrum (+ve Cl): 343 (M+N)+.

(ii) a Solution of sodium hydroxide (34,0 g) in water (155 ml) was added to a solution of diethyl-2-(4-bromobenzyl)-2-methylmalonate (29,2 g) in ethanol (165 ml) and then heated to the boiling temperature under reflux for 9 hours. The reaction mixture is cooled, the solvent evaporated and the residue is dissolved in water (150 ml). Add the sodium hydroxide tablets (25.4 g) and the reaction mixture is heated to boiling point under reflux for 2 cha is of solid product. The reaction mixture was extracted with diethyl ether (3 x 150 ml), the combined organic layers are dried (MgSO4) and then evaporated the solvent, obtaining a white solid connection. This solid product is heated at 205oC for 20 minutes, cooled to ambient temperature, dissolved in 1.0 M solution of sodium hydroxide (150 ml), triturated with activated charcoal and then filtered through diatomaceous earth. The obtained clear solution again podkalyvayut and then extracted with diethyl ether (3 x 150 ml). The combined organic layers are dried (MgSO4) and evaporated, getting the oil crystallized upon storage, which gives 2-methyl-3-(4-bromophenyl)propanoic acid as a white solid (18.2 g), so pl. 69-70oC; mass spectrum (+ve Cl): 243 (M+N)+.

(iii) DIBORANE (192 ml of 1.0 M solution in THF) is added dropwise over 25 minutes to a solution of 2-methyl-3-(4-bromophenyl)propanoic acid (38,9 g) in THF (240 ml) at 0oC. the Reaction mixture is stirred for 45 minutes at 0oC and then allowed to warm to ambient temperature for 2 hours. Add water (120 ml), and then solid potassium carbonate (144 g) and then water (80 ml). The reaction mixture was extracted with diethyl ether (3 x 250 ml). United organizes time (37.4 g), mass spectrum (+ve Cl): 248 (M+NH4)+.

(iv) a Solution of imidazole (27,2 g) in DMF (100 ml) is added to a stirred solution of 2-methyl-3-(4-bromophenyl)propanol (37,4 g) and tert-butyl - dimethylsilicone (28,9 g) in dry DMF (100 ml) at 0oC. the Reaction mixture is allowed to warm with stirring to room temperature for 21 hours and then poured on ice (500 g). The reaction mixture was extracted with diethyl ether (3 x 500 ml), the combined organic layers are dried (MgSO4) and the solvent evaporated, obtaining 1-(tert-butyldimethylsiloxy)-2-methyl-3- (4-bromophenyl) propane as a yellow oil (53,3 g); mass spectrum (+ve Cl): 343 (M+N)+.

(v) Using a method similar to that described in example 11, part (i), but on the basis of 1-(tert - butyldimethylsiloxy)-2-methyl-3-(4-bromophenyl)propane, get (93% yield) of 4-[2-((tert-butyl-dimethylsiloxy)methyl)propyl]phenylboronic acid as a white solid;

mass spectrum (-ve ESP): 149 (M-H)-.

(vi) Using a method similar to that described in example 11, part (ii), but on the basis of 4-[2-((tert-butyldimethylsiloxy)methyl) propylpentanoic acid, receive (36% yield) N-(isobutoxide)-2-[4-(2-((tert-butyldimethylsiloxy)methyl) propyl)phenyl] -N-(3-methoxy-5-methylpyran>.

(vii) Using a method similar to that described in example 11, but proceeding from N-(isobutoxide)-2- [4-(2-((tert-butyldimethylsiloxy) methyl)propyl)phenyl] -N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida receive (output 55%) 2-[4-(2-((tert-butyldimethylsiloxy)methyl)propyl) phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide as a clear oil;

1H NMR (d6-DMSO): 0,0(s, 6H), 0,60(d, 6H), and 0.8(d, 3H), and 0.9(s, 9H), 1,6(m, 1H), and 1.9(m, 1H), 2,4-2,6(m, 4H), to 2.75(m, 1H), 3,4(DD, 2H), and 3.8(d, 2H), 3,95(s, 3H), 7,2(d, 2H), and 7.4(d, 2H), of 7.8(s, 1H), 8,15(s, 1H), 8,8-8,9(m, 2H);

mass spectrum (+ve ESP): 643(M+N)+.

Example 20

Using a method similar to that described in example 9, get (52% yield) of 2-(4-acetamidophenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide in the form of a solid connection, so pl. 208-209oC;

1H NMR (d6-DMSO): 2,1(s, 3H), 2,2(s, 3H), and 3.8 (s, 3H), and 7.4(d, 2H), 7,4-7,6(m, 4H), and 8.4(d, 1H), and 8.8(d, 1H), 10.0 g(user. s, 1H), 10,4(user. s, 1H);

mass spectrum (+ve ESP): 414(M+N)+; based on 2-(4-acetamidophenyl)-N-isobutoxide-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamida;

1H NMR (d6-DMSO): 0,6(d, 6H), 1,6(m, 1H), 2,1(s, 3H), and 2.6(S, 3H), and 3.8(d, 2H), 4,0(s, 3H), and 7.4(d, 2H), and 7.6(d, 2H), and 7.8(DD, 1H), 8,15(s, 1H), cent to 8.85(DD, 1H), 8,9(DD, 1H), 10.0 g (s, 1H); mass spectrum (+ve ESP): 544(M+H)+; R>1H NMR (d6-DMSO): 2,1(s, 3H), 7.5(d, 2H), 7.7(d, 2H), and 7.8(s, 2H), 9,9(user. s, 1H).

4-Acetaminophenydrocodone acid is obtained by using a method similar to that described in example 11, part (i), except that the use of 4'-bromoacetanilide, one equivalent of sodium hydride added before cooling to -78oC and for extraction of the product using ethyl acetate.

Example 21

Using a method similar to that described in example 1, get (45% yield) of 2-(4-acetylphenyl)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide;

1H NMR (CDCl3): 2,3(s, N) to 2.65(s, 3H), and 3.8(s, 3H), 6,7(s, 1H), 7,35(s, 1H), and 7.4(d, 2H), and 7.5(DD, 1H), 7,95(d, 2H), and 8.7(d, 1H), and 8.8(d, 1H); mass spectrum (+ve ESP): 399(M+N)+; based on 2-(4-acetylphenyl)-N-isobutoxide-N- (3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida;

1H NMR (CDCl3): 0,7 (d, 6N), and 1.7(m, 1H), 2,5(s, 3H), 2,65(s, 3H), 3,85(d, 2H), 4,0(s, 3H), and 7.5(DD, 1H), 7.7(d, 2H), and 7.9(s, 1H), 8.0 a(d, 2H), cent to 8.85(DD, 1H), 8,95(DD, 1H); mass spectrum (+ve ESP): 499(M+H)+; obtained by the method similar to that described in example 1, part (iii), but on the basis of 4-acetylphenylalanine acid (obtained as described in patent application great Britain, N publishing 2276160).

Example 22

Tetrahydroborate sodium (0,051 g) added in portions over 5 El stirred for 45 minutes at ambient temperature and then poured into water (20 ml) and podkalyvayut to pH 3 with 2 M hydrochloric acid. The mixture is extracted with ethyl acetate (3 x 20 ml). The extracts are combined, washed with water and saturated sodium chloride solution and dried (MgSO4). Volatile products are removed by evaporation and the residue is purified silikagelevye Mega Bond Elut column, using a gradient elution of 10 to 70% ethyl acetate/hexane, obtaining 2-[4-(1-hydroxyethyl)phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (0,096 g) as a foam;

1H NMR (CDCl3+ CD3COOD): 1.55V(d, 3H), 2,3(s, 3H), 3,85(s, 3H), of 4.95(q, 1H), 7,25(s, 1H), and 7.3(d, 2H), 7,35(d, 2H), 7,55(DD, 1H), and 8.7(d, 1H), cent to 8.85(d, 1H); mass spectrum (+ve ESP): 401(M+N)+.

Example 23

Using a method similar to that described in example 1, except that the dissolved reagents add dimethoxyethan receive (69% yield) of 2-(4-allylphenol)-N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

1H NMR (CDCl3): of 2.25(s, 3H), 3,5(d, 2H), and 3.8(s, 3H), 5,15(m, 2H), 6,0(m, 1H), 6,65(s, 1H), 7,15-to 7.3(m, 4H), 7,35(s, 1H), 7,45(DD, 1H), 8,65(DD, 1H), 8,8(DD, 1H); mass spectrum (+ve ESP): 397(M+N)+; based on 2-(4-allylphenol)-N-isobutoxide-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamida.

The original 2-(4-allylphenol)-N-isobutoxide-N-(3-methoxy-5-methylpyrazine - 2-yl) pyridine-3-sulfonamide was obtained as follows:

(i) Using SP1H NMR (CDCl3): 3,38-of 3.53(m, 2H), 5,03-by 5.18 (m, 2H), 5,88-6,10(m, 1H), 7,34(d, 2H), 8,15(d, 2H); mass spectrum (-ve ESP): 161 (M-H)-; on the basis of 4-allyl-1-bromine benzol (obtained as described in J. Orq. Chem., 1970, 35, 1777).

(ii) Using a method similar to that described in example 11, part (ii), but on the basis of 4-allylanisole acid, receive (48% yield) of 2-(4-allylphenol)-N-isobutoxide-N-(3-methoxy - 5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

1H NMR (CDCl3): of 0.7(d, 6H), 1,7(m, 1H), 2,5 (s, 3H), of 3.45(d, 2H), and 3.8(d, 2H), 4,0(s, 3H), 5,1(m, 2H), 6,0(m, 1H), 7.23 percent (d, 2H), and 7.5 (DD, 1H), 7,55(d, 2H), and 7.9(s, 1H), cent to 8.85 (DD, 1H), and 9.0(DD, 1H); mass spectrum (+ve ESP): 497 (M+N)+.

Example 24

Using a method similar to that described in example 9, get (79% yield) of N-(3-methoxy-5-methylpyrazine-2-yl)-2- [4-(isopropylamino)phenyl]pyridine-3-sulfonamide in the form of a solid connection, so pl. 105-107oC;

1H NMR (d6-DMSO): 1,2(d, 6N), and 2.3(s, 3H), and 3.8(s, 3H), 3,6(m, 1H), 6,6(user. s, 2H), 7,35(d, 2H), and 7.4(user. s, 1H), 7,45(DD, 1H), and 8.4(DD, 1H), and 8.7(DD, 1H), 10,1(user. s, 1H); mass spectrum (+ve ESP): 414 (M+N)+; based on N-isobutoxide-N-(3-methoxy-5-methylpyrazine-2-yl)-2-[4- (isopropylamino)phenyl]pyridine-3-sulfonamida.

The original N-isobutoxide-N-(3-methoxy-5 - methylpyrazine-2-yl)-2-[4-(isopropylamino)phenyl]pyridine-3 - sulfonamide A double the excess 4-aminophenylarsonic acid as a source of reagent, receive (50% yield) of 2-(4-AMINOPHENYL)-N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine - 2-yl)pyridine-3-sulfonamide in the form of solids;

1H NMR (d6-DMSO): 0,6(d, 6H), 1,6(m, 1H), to 2.55(s, 3H), and 3.8(d, 2H), 4,0(s, 3H), of 5.45(user. s, 2H), 6,5(d, 2H), and 7.3(d, 2H), and 7.6(DD, 1H), and 8.2(s, 1H), 8,8(m, 2H); mass spectrum (+ve ESP): 472(M+N)+.

(ii) a Solution of 2-(4-AMINOPHENYL)-N-(isobutoxide)-N- (3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida (0.17 g) in acetone (3 ml) and water (3 ml) podkalyvayut to pH 4 using glacial acetic acid. Add centralimediat sodium (0,045 g) and the mixture was stirred at ambient temperature for 16 hours. The mixture is then poured into 2 M hydrochloric acid (10 ml) and extracted with ethyl acetate (2 x 25 ml). The aqueous layer was alkalinized to pH 10 with 2 M of sodium hydroxide and re-extracted with ethyl acetate (2 x 25 ml). All organic extracts are combined, washed with salt solution and dried (MgSO4). Volatile products are removed by evaporation and the residue is purified silikagelevye Mega Bond Elut column, using a gradient elution of 35-50% ethyl acetate/hexane, obtaining N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)-2- [4-(isopropylamino)phenyl]pyridine-3-sulfonamide (0.11 g) in the form of resin;

1H NMR (d6-DMSO): 0,6(d, 6H), 1,2(d, 6H),ptx2">

Example 25

Using a method similar to that described in example 5, get (29% yield) of N-(5-chloro-3-methoxypyrazine - 2-yl)-2-(4-ethoxycarbonylphenyl)pyridine-3-sulfonamide;

1H NMR (CDCl3): of 3.8(s, 3H), 4,0(s, 3H), 6,7(user. s, 1H), and 7.4(d, 2H), 7,55(s, 1H), EUR 7.57(DD, 1H) and 8.1(d, 2H), and 8.7(DD, 1H), 8,65(DD, 1H); mass spectrum (+ve FAB, DMSO/NBA): 435(M+N)+; based on 4 - nitrophenyl-2-(4-ethoxycarbonylphenyl)pyridine-3-sulfonate;

1H NMR (d6-DMSO): 3,8(s, 3H), and 7.3(d, 2H), 7.7(d, 2H), of 7.75(DD, 1H), with 8.05(d, 2H), of 8.25(d, 2H), 8,45(DD, 1H), 9,05(DD, 1H), mass spectrum (+ve ESP): 414(M+N)+; obtained by the method similar to that described in example 5, part (ii) but using 4-(methoxycarbonyl)phenylboronic acid.

Example 26

Limitedregenerative of 20.5 ml of 1 M solution in diethyl ether) is added over 10 minutes to a solution of 2-[4-(2,3 - epoxy-2-methylpropyl " phenyl]-N-(isobutoxide)-N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida (1.8 g) in anhydrous THF at 0oC. After 30 minutes the reaction mixture was poured into a saturated aqueous solution of ammonium chloride (50 ml) and extracted with ethyl acetate (4 x 50 ml). The extracts are washed with salt solution and dried (MgSO4). Volatile products are removed by evaporation and the residue is purified silikagelevye Mega Bond Elut column, using hail the Zin-2-yl)-pyridine-3 - sulfonamida (0,115 g) as a foam;

1H NMR (CDCl3+ CD3COOD): 1,3 (s, 6H), 2,3 (s, 3H), and 2.8 (s, 2H), and 3.8(s, 3H), 7,2-7,3(m, 5H), 7,55(DD, 1H), and 8.7(DD, 1H), cent to 8.85(DL, 1H); mass spectrum (+ve ES): 429 (M+N)+.

The original 2-[4-(2,3-epoxy-2-methylpropyl " phenyl] -N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine - 3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 11, part (i), but using 1-bromo-4-(2-methylprop-2-enyl)benzene (obtained as described in Chemische Berichte, 1962, 95, 1921) and purification on silikagelevye Mega Bond Elut column using a gradient elution of 0-70% ethyl acetate/hexane, get (32% yield) of 4-(2 - methylprop-2-enyl)phenylboronic acid;

1H NMR (CDCl3): 1,7(s, 3H), 3,4(s, 2H), and 4.8(d, 2H), 7,35(d, 2H), 8,15(d, 2H);

mass spectrum (-ve ESP): 175(M-H)-.

(ii) Using a method similar to that described in example 11, part (ii), but on the basis of 4-(2-methylprop-2-enyl)phenylboronic acid, receive (61% yield) N-isobutoxide-N- (3-methoxy-5-methylpyrazine-2-yl)-2[4-(2-methylprop-2-enyl)phenyl] pyridine-3-sulfonamide;

1H NMR (CDCl3): of 0.7(d, 6H), 1,7(s, 3H), of 1.75(m, 1H), 2,5(s, 3H), at 3.35(s, 3H), and 3.8(d, 2H), 4,0(s, 3H), and 4.8(d, 2H), 7,25(d, 2H), and 7.5(DD, 1H), and 7.6(d, 2H), and 7.9(s, 1H), cent to 8.85(DD, 1H), 8,95(DD, 1H); mass spectrum (+ve ESP): 511 (M+N)+.

(iii) 3-Chloroperoxybenzoic-2-enyl)phenyl] pyridine-3 - sulfonamida (1.8 g) in 75 ml of dichloromethane at 0oC. the Reaction mixture is allowed to warm to ambient temperature and stirred for further 1 hour. The mixture was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water and saturated sodium chloride solution, then dried (MgSO4). Volatile products are removed by evaporation and the residue clean flash chromatography with suction and then passed through silicagel Mega Bond Elut column, using a gradient elution 0-40% ethyl acetate/hexane, obtaining 2-[4-(2,3-epoxy-2-methylpropyl " phenyl]-N-(isobutoxide) -N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine-3-sulfonamide (0.16 g) in the form of solid compounds;

1H NMR (CDCl3): 0,65(d, 6H), 1,3(s, 3H), 1,7(m, 1H), 2,5(s, 3H), 2,65(DD, 2H), 2,9(kV, 2H), 3,85(d, 2H), 4,0(s, 3H), and 7.3(d, 2H), and 7.5(DD, 1H), and 7.6(d, 2H), 7,95 (s, 1H), cent to 8.85(DD, 1H), 8,95(DD, 1H); mass spectrum (+ve ESP): 527(M+H)+.

Example 27

Using a method similar to that described in example 1, but proceeding from N-(isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)-2(4-were)pyridine-3-sulfonamida receive (35% yield) of N-(3-methoxy-5-methylpyrazine-2-yl)-2(4 - were)pyridine-3-sulfonamide, so pl. 184-185oC; microanalysis

found: C, 58,0; H, a 4.9; N, 14.9 per cent; for C18H18N4O3S

the].: C, FOR 58.4; H, A 4.9; N, 15.1 PER CENT.

The source of N-(from the Ute with 72% yield, using a method similar to that described in example 1, part (iii), but on the basis of 4-methylphenylacetic acid.

Example 28

Nesadurai oil sodium hydride (240 mg) is added with stirring to methanol (20 ml). After cessation of hydrogen is added 2-(4-bromomethylphenyl)-N-(isobutoxide) -N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine-3-sulfonamide (549 mg) and the mixture is stirred for 2 hours. Volatile products are removed by evaporation and to the residue is added a saturated solution of ammonium chloride (10 ml). The mixture is extracted with ethyl acetate (3 x 20 ml) and the extracts dried (MgSO4). Volatile products are removed by evaporation and the residue clean flash chromatography, elwira ethyl acetate/hexane (13:7, volume ratio) to give 2-(4-methoxymethyl)-N-(3-methoxy-5-methylpyrazine-2-yl) - pyridine-3-sulfonamide (170 mg), so pl. 129-130oC (after trituration with diethyl ether; microanalysis

found: C, accounted for 56.9; H, a 4.9; N, 13.9 percent; for C19H20N4O4S

the].: C TO 57.0; H, 5,0; N, 14.0 PERCENT.

The original 2-(4-bromomethylphenyl)-N-(isobutoxide)-N-(3 - methoxy-5-methylpyrazine-2-yl)-pyridine-3 - sulfonamide was obtained as follows:

N-Bromosuccinimide (2,99 g) and azobisisobutyronitrile (275 mg) are added to a solution of N-(isobutoxide (150 ml) and the mixture is heated to boiling point under reflux for 4 hours. Insoluble compounds are removed by filtration and the filtrate is concentrated by evaporation. The residue is dissolved in ethyl acetate (200 ml) and the solution washed with water (100 ml) and saturated sodium chloride solution (100 ml). The solution is dried (MgSO4) and the solvent is removed by evaporation. The residue is triturated with ethyl acetate/hexane (3: 7 volume ratio, 80 ml) to give 2-(4-bromomethylphenyl)-N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine - 2-yl)-pyridine-3-sulfonamide (6.5 g), so pl. 125-128oC.

Example 29

Using a method similar to that described in example 28, but using isopropanol as solvent, receive (39% yield) of 2-(4-isopropoxyphenyl)-N-(3-methoxy-5-methylpyrazine - 2-yl) pyridine-3-sulfonamide, so pl. 123-124oC;

1H NMR (DMSO-d6): 1,2(d, 6H), of 2.25(s, 3H), 3,65 of 3.75(m, 1H), 3,85(s, 3H), and 4.5(s, 2H), of 7.25-7.5(m, 5H), and 7.6(DD, 1H), 8,45(DD, 1H), 8,8(DD, 1H).

Example 30

A solution of N-(isobutoxide)-2-(4-ethoxycarbonylphenyl) -N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine-3-sulfonamida (830 mg) and sodium methylate (433 mg) in methanol (25 ml) is heated to the boiling temperature under reflux for 1 hour. Volatile products are removed by evaporation and to the residue is added a saturated solution of ammonium chloride (20 ml). The mixture is extracted with et is the STATCOM clean flash chromatography, elwira 25-50% ethyl acetate/hexane, and get 2-(4-methoxy-carbonitrile)-N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine-3-sulfonamide (190 mg), so pl. 144-146oC; microanalysis

found: C, to 55.2; H, a 4.3; N, 13.3 percent; for C23H24BrN4O4S

the].: C, WITH 55.1; H, 4,4; N, 13.5 PER CENT.

The original N-(isobutoxide)-2-(4-ethoxycarbonylphenyl) -N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine-3-sulfonamide was obtained as follows:

(i) a Solution of 4-carboxybenzeneboronic acid (25 g) and concentrated sulfuric acid (1 ml) in methanol (250 ml) is heated to the boiling temperature under reflux for 36 hours. Volatile compounds are removed by evaporation and the residue is dissolved in ethyl acetate (200 ml). Add water (100 ml) and the mixture is stirred for 1 hour. Separate the organic phase and washed with saturated sodium bicarbonate solution (50 ml), water (100 ml) and saturated sodium chloride solution (50 ml). The solution is dried (MgSO4) and the solvent is removed by evaporation, receiving 4-methoxycarbonylpropionyl acid (27 g), so pl. 227-229oC.

(ii) a Solution of potassium fluoride (7.0 g) in water (150 ml) are added to a solution of 2-chloro-N-isobutoxide-N-(3-methoxy-5-methyl pyrazin-2-yl)-pyridine-3-sulfonamida (8,3 g), 4-methoxycarbonylpropionyl the deposits under reflux in an argon atmosphere for 18 hours, add ethyl acetate (150 ml) and the organic phase is separated. The solution was washed with 2 M sodium hydroxide solution (100 ml) and water (250 ml) and then dried (MgSO4). Volatile products are removed by evaporation and the residue triturated with ethyl acetate/hexane (1:3 in volume ratio) to give N-(isobutoxide)-2-(4-ethoxycarbonylphenyl)-N-(3-methoxy - 5-methylpyrazine-2-yl)pyridine-3-sulfonamide (8.5 g), so pl. 134-136oC.

Examples 31-32

By analogy with the method described in example 5, but using the appropriate aminoheterocycles formula VII, the following compounds are obtained from the output 23-27%:

(Example 31):

N-(5-bromo-3-methoxypyrazine-2-yl)-2(4-isobutylphenyl) - pyridine-3-sulfonamide; microanalysis

found: C, 50,0; H, 4,4; N, 11.5 percent; for C20H21BrN4O3S

the].: C AND 50.3; H, 4,4; N, 11.7 PER CENT.

1H NMR (CDCl3): of 0.95(d, 6H), and 1.9(m, 1H), 2,5(d, 2H), 3,5(s, 3H), 6,65(user. s, 1H), 7,2(d, 2H), and 7.3(d, 2H), and 7.5(DD, 1H), and 7.6(s, 1H), and 8.6(DD, 1H), 8,8(DD, 1H); from 2-amino-5-bromo-3-methoxypyrazine (obtained as described in Gazz. Chem. Ital. 1960, 90, 1807).

(Example 32):

N-(2-chloro-4-methoxypyridine-5-yl)-2(4-isobutylphenyl) - pyridine-3-sulfonamide;

1H NMR (CDCl3): of 0.95(d, 6H), and 1.9(m, 1H), 2,5(d, 2H), and 3.8(s, 3H), x 6.15(s, 1H), 7,25(d, 2H), and 7.4-7.5(m, 3H), and 8.1(s, 1H), 8,5(DD, 1H), cent to 8.85(DD the way:

A mixture of 5-amino-2,4-dichloropyrimidine (0.32 g) (obtained as described in Chem. Pharm. Bull., (JAPAN), 1958, 6, 343-346) and a solution of sodium methylate in methanol (from sodium (0.05 g) and methanol (25 ml) is heated to the boiling temperature under reflux for 15 minutes and leave to cool. Volatiles are removed by evaporation and add a small amount of water. The mixture is twice extracted with diethyl ether, the combined extracts dried (MgSO4) and evaporated, obtaining 5-amino-2-chloro-4-methoxypyridine (0.2 g) as oil;

1H NMR (d6-DMSO-): to 3.92 (s, 3H), of 5.25(s, 2H), 7,72 (s, 1H); mass spectrum (+ve Cl): 160 (M+N)+.

Example 33

Tetrakis (triphenylphosphine) palladium (0) (25 mg) are added to a solution of sodium carbonate (223 mg) without oxygen, dimethoxy-(3-pyridyl)borane (116 mg) and 2-(4-itfeel)-N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida (828 mg) in a mixture of water (1.8 ml), ethanol (3 ml) and toluene (6 ml). The mixture is stirred and heated in an argon atmosphere at 85oC 17 hours, then allowed to cool to ambient temperature. Water is added and the reaction mixture is washed three times with ethyl acetate. Water layers podkalyvayut to pH 7 with 2 M hydrochloric acid and extracted six times with ethyl acetate. These extracts are combined, washed natok cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 0-8% methanol/dichloromethane, receiving N-(3-methoxy-5 - methylpyrazine-2-yl)-2-(4-[3-pyridyl]phenyl)pyridine-3 - sulfonamide (123 mg) in the form of solid compounds;

1H NMR (CDCl3): 2,3(s, 3H), and 3.7(s, 3H), of 7.3 to 7.7(m, 7H), 7,92(m, 1H), 8,55 is 8.75(m, 2H), 8,8(DD, 1H), 8,9(d, 1H); mass spectrum (+ve ESP): 434 (M+H)+.

The original 2-(4-itfeel)-N-(3-methoxy-5-methylpyrazine-2 - yl)pyridine-3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 11, part (i), but using 1-bromo-4-(trimethylsilyl)benzene (obtained as described in J. Am.Chem. Soc. , 1994, 116, 11723) as starting compound, receive (58% yield) of 4-trimethylsilylimidazole acid in the form of a solid; mass spectrum (-ve ESP): 193 (M-H)-.

(ii) Using a method similar to that described in example 11, part (ii), with the exception that as the starting compound used is 4-trimethylsilylimidazole acid and the crude product is clean, rubbing with 20% ethyl acetate/isohexane receive (81% yield) N-(isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)-2-(4-trimethylsilylethynyl)pyridine-3-sulfonamide as a solid substance, so pl. 132-134oC; mass spectrum (+ve ESP): 529 (M+N)+.

(iii) N-Iodosuccinimide (0.84 g) are added to a solution of N-(isobut is (15 ml) and the reaction mixture was stirred and heated at 65oC 17 hours. Add an additional portion of N-iodosuccinimide (50 mg)and heating continued for 24 hours, then add another N-iodosuccinimide (100 mg) and heating continued for 24 hours. The mixture is cooled and the volatile products are removed by evaporation. The residue is cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 0-25% ethyl acetate/hexane, then triturated with hexane (2 x 25 ml) to give 2-(4-itfeel)-N-isobutoxide-N-(3-methoxy-5 - methylpyrazine-2-yl)-pyridine-3-sulfonamide in the form of solid compounds; so pl. 156-158oC;

1H NMR (CDCl3): of 0.7(d, 6H), 1,7(m, 1H), 2,5 (s, 3H), and 3.8(d, 2H), 4,0 (s, 3H), and 7.4(d, 2H), and 7.5(DD, 1H), 7.7(d, 2H), and 7.9(s, 1H), 8,8(DD, 1H), 8,9(DD, 1H); mass spectrum (+ve ESP): 583 (M+N)+.

(iv) Using a method similar to that described in example 9, except that as the starting compound using 2-(4-itfeel)-N-isobutoxy - carbonyl-N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine-3 - sulfonamide and the crude product is clean, triturating with ethyl acetate, get (72% yield) of 2-(4-itfeel)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide as a solid substance, so pl. 180-183oC;

1H NMR (CDCl3): 2,3(s, 3H), at 3.9(s, 3H), 6,7(user. s, 1H), and 7.1(d, 2H), 7,3(user. s, 1H), and 7.5(DD, 1H), 7,7(user. d, 2H), 8,7 (user. d, 1H), and 8.8(d, 1H).

Dimethoxy-(3-p is UEMOA to a solution of 3-bromopyridine (4.8 ml) and trimethylborane (6.2 ml) in dry THF (100 ml) at such a speed, to ensure that the temperature did not exceed -65oC. the Mixture is allowed to warm to ambient temperature for 16 hours and filtered. The solid product is washed with diethyl ether, combined with the extension of the solid compound obtained from the filtrate, and repeatedly washed with diethyl ether, receiving dimethoxy-(3-pyridyl)borane (3.5 g) as a solid;

1H NMR (CH3OD): 3,4(s, 6H), 7,2(m, 1H), 7,9(m, 1H), and 8.2(DD, 1H), and 8.6 (s, 1H); mass spectrum (+ve Cl): 152 (M+H)+.

Example 34

Using a method similar to that described in example 33, but using dimethoxy-(4-pyridyl)borane as a source of connection, get (28% yield) of N-(3-methoxy-5 - methylpyrazine-Il)-2-(4-[4-pyridyl]phenyl)-pyridine-3 - sulfonamide as a solid substance, so pl. 218-220oC (Razlog.);

1H NMR (DMSO-d6): 2,1(s, 3H), 3.0 a(s, 3H), 7,3(user. s, 1H), and 7.5 to 7.7(m, 4H), of 7.7 to 7.9(m, 4H), to 8.45(DD, 1H), and 8.7(d, 2H), 8,8(DD, 1H); mass spectrum (+ve ESP): 434 (M+N)+.

Source dimethoxy-(4-pyridyl)borane was obtained as follows:

Anhydrous potassium carbonate (7.6 g) are added to a solution of 4-bromopyridin-hydrochloride (9,73 g) in water (50 ml). The mixture is extracted with diethyl ether (100 ml) and dried (MgSO4). Volatiles are removed by evaporation and the residue re-dissolved in betw plan n-utility (31,3 ml of 1.6 M solution in hexane), keeping the temperature below -90oC. Add trimethylboron (6.2 ml) and the mixture is stirred for 16 hours, until it is heated to -40oC. the precipitate is collected, washed with diethyl ether containing a few drops of ethereal hydrochloric acid, and dried in vacuum, obtaining dimethoxy- (4-pyridyl)borane in the form of a solid (6.2 g); mass spectrum (+ve Cl): 152 (M+N)+.

Example 35

Using a method similar to that described in example 9, except that as the starting compound used is N-isobutoxide-N-(3-methoxy-5-methylpyrazine-2 - yl)-2-(4-[2-pyridyl] phenyl)pyridine-3-sulfonamide and the product cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 0-10% methanol/dichloromethane, receive (76% yield) of N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[2-pyridyl] phenyl) pyridine-3-sulfonamide in the form of solids;

1H NMR (CDCl3): 2,3(user. s, 3H), 3,6(user. s, 3H), 6,7(user. s, 1H), 7,2-7,6(m, 4H), and 7.7(DD, 1H), 7.5(d, 2H), with 8.05(m, 2H), 8.6 out of 8,9(m, 2H), 8,8(user. d, 1H); mass spectrum (+ve ESP): 434 (M+N)+.

The original N-isobutoxide-N-(3-methoxy-5-methylpyrazine-2-yl) -2-(4-[2-pyridyl]phenyl)pyridine-3-sulfonamide was obtained as follows:

Tetrakis(triphenylphosphine) palladium (0) (45 mg) are added to a solution of (2-pyrid is)pyridine-3-sulfonamida (465 mg) in xylene (15 ml). The mixture is stirred and heated in an argon atmosphere at 125oC 17 hours, then allowed to cool to ambient temperature. Water is added and the mixture extracted with ethyl acetate. The organic layers are combined, washed with saturated sodium chloride solution and dried (MgSO4). Volatiles are removed by evaporation and the residue is cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 0-65% ethyl acetate/hexane, giving N-isobutoxide-N-(3 - methoxy-5-methylpyrazine-2-yl)-2-(4-[2-pyridyl]phenyl)pyridine - 3-sulfonamide (135 mg) as a foam;

1H NMR (CDCl3): of 0.7(d, 6H), 1,7(m, 1H), 2,5(s, 3H), and 3.8(d, 2H), 4,0(s, 3H), and 7.5(DD, 2H), 7,6-7,8(m, 4H), and 7.9(s, 1H), 8,1(DD, 2H), and 8.7(DD, 1H), 3,9(DD, 1H) 9,0(DD, 1H); mass spectrum (+ve ESP): 534 (M+N)+.

Example 36

Hydrazinehydrate (1.2 ml) are added to a solution of N-(isobutoxide)-2-(4-ethoxycarbonylphenyl)-N-(3-methoxy - 5-methylpyrazine-2-yl) pyridine-3-sulfonamida (1.54 g) in methanol (15 ml) and the mixture is heated with stirring to the boiling temperature for 24 hours, then cooled. The solid product is collected and dried under reduced pressure, getting free sulfonamidophenylhydrazine (0,857 g);

1H NMR (d6-DMSO): 2,2 (s, 3H), and 3.7 (s, 3H), 6,7(user. s, 2H), and 7.3(s, 1H), 7.5(m, 3H), and 7.8(d, 2H), and 8.4(d, 1H), up 8.75(DD, 1H), 9,8(user. s, 1H).

what Hladilnika 17 hours and then cooled. The obtained solid product is collected and cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 0-10% methanol/dichloromethane, receiving N-(3-methoxy-5-methylpyrazine-2-yl) -2-(4-[1,3,4-oxidiazol-2-yl] phenyl)pyridine-3-sulfonamide (3 mg) in the form of solid compounds;

1H NMR (DMSO-d6): 2,2(user. s, 3H), and 3.8 (s, 3H), 7,4(user. s, 1H), 7,6-7,8(m, 3H), 8,0(m, 2H), 8,5(DD, 1H), 8,9(DD, 1H), and 9.4 (s, 1H); mass spectrum (+ve S): 425 (M+N)+.

Example 37

n-Utility (1,63 ml of 1.6 M solution in pentane) is added to a mixed solution of acetone oxime (95 mg) in dry THF (5 ml) at 0oC. After 1 hour, add a solution of 2-(4-ethoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamida (414 mg) in THF (5 ml). The solution is kept heated for 17 hours. The mixture is then poured into stirred solution of concentrated sulfuric acid (0.6 g) in THF (2.8 ml) and water (0.7 ml) and heated to boiling point under reflux for 1 hour. The cooled solution is treated with a saturated solution of sodium carbonate to pH 5 and then extracted three times with ethyl acetate. The organic extracts washed with water and saturated sodium chloride solution and dried (MgSO4). Volatile products are removed by evaporation and the residue is purified silikagelevye Mega Bond Elut is l) pyridine-3-sulfonamide (37 mg) as a solid;

1H NMR (DMSO-d6when C): 2,2(s, 3H), 2,3(s, 3H), and 3.8(s, 3H), 6,7(s, 1H), and 7.4(user. s, 1H), and 7.5 to 7.7(m, 4H), and 7.8(d, 2H), 8,5(DD, 1H), 8,8(DD, 1H); mass spectrum (+ve ESP): 438 (M+N)+< / BR>
Example 38

Sodium hydride (60% dispersion in oil; 132 mg) was washed with hexane and suspended and dry THF (5 ml). Add molecular sieves 4A (250 mg) and then the oxime hydrochloride ndimethylacetamide (133 mg), the mixture is stirred and heated at 60oC for 1 hour. Add a solution of 2-(4-ethoxycarbonylphenyl)-N-(3-methoxy - 5-methylpyrazine-2-yl)pyridine-3-sulfonamida (414 mg) in dry THF (2 ml) and heating continued for another 2 hours. The resulting mixture is cooled, filtered and concentrated by evaporation. The residue is triturated with water and extracted three times with ethyl acetate. The organic extracts washed with water and saturated sodium chloride solution and then dried (MgSO4). Volatile products are removed by evaporation and the residue is cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 0-35% ethyl acetate/hexane, and get N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[3-methyl - 1,2,4-oxadiazol-5-yl]phenyl)pyridine-3-sulfonamide (115 mg) as a solid;

1H NMR (CDCl3): 2,3(user. s, 3H), of 2.5 (s, 3H), and 3.8(s, 3H), 6,7(user. s, 1H), and 7.4(user. s, 1H), and 7.4 to 7.7(m, 3H), 8,2(user. d, 2H), 8,7(user. d, 1H), 8,8(DL, 1H); mass spectrum (+ve ESP): 439 (M+N)
1H NMR (CDCl3): 2,3(s, 3H), and 3.8(s, 3H), 4,9(user. s, 2H), 7,2(user. s, 1H), and 7.4(DD, 2H), 7,45-to 7.6(m, 2H), and 7.6(d, 2H), and 8.7(DD, 1H), 8,8(DD, 1H); mass spectrum (+ve ESP): 415(M+N)+.

A mixture of hydroxyamide (1.3 g) and triethylorthoformate (20 ml) is stirred under heating up to the boiling temperature under reflux for 7 hours and then cooled. Volatile products are removed by evaporation and the residue is cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 0-50% ethyl acetate/dichloromethane, to obtain N-(3 - methoxy-5-methylpyridin-3-yl)-2-(4-[1,2,4-oxidiazol-3-yl] phenyl)pyridine-3-sulfonamide (405 mg) as a solid substance; so pl. 179-180,5oC;

1H NMR (CDCl3): 2,3(s, 3H), and 3.7(s, 3H), 6,7(user. s, 1H; exchange with CO3COOD), 7,4(user. s, 1H), 7,45 to 7.7(m, 3H), 8,2(user. d, 2H), 8,7(user. d, 1H), 8,8(m, 2H); mass spectrum (+ve ESP): 425 (M+N)+.

The source is Ohm:

Stir a mixture of 1,1'-bis(diphenylphosphino)-ferrocene (0,532 g) and palladium (II) acetate (rate £ 0.162 g) in obeskislorozhennuju toluene (95 ml) is heated at 50oC in argon atmosphere for 30 minutes and then cooled to ambient temperature. Add 2-chloro-N- (isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide (10 g), 4-cyanoaniline acid (of 8.47 g), potassium fluoride (8, 37 g) and water (95 ml), the mixture is stirred while heating to the boiling temperature under reflux for 8 hours, then cooled. Add water (100 ml) and the mixture extracted with ethyl acetate (100 ml), then filtered through diatomaceous earth. The aqueous layer was separated and additionally extracted with ethyl acetate (2 x 100 ml). The organic extracts are combined washed with aqueous sodium carbonate (100 ml, 2 M solution) and water (100 ml), then treated with activated charcoal and dried (MgSO4). Volatile products are removed by evaporation and the residue is cleaned by recrystallization from diethyl ether/isohexane, receiving 2-(4-cyanophenyl-N-isobutoxide-N-(3-methoxy-5 - methylpyrazine-2-yl)-pyridine-3-sulfonamide (9,58 g) in the form of solids;

1H NMR (DMSO-d6): or 0.6(d, 6H), 1,6(m, 1H), and 2.6(s, 3H), and 3.8(d, 2H), 4,0(s, 3H), 7.7(d, 2H), 7,9(m, 3H), and 8.2 (s, 1H), 8,9(d, 1H), and 9.0(d, what destfolder example (173 mg, obtained from 2-(4-cyanophenyl)- N-isobutoxide-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamida (288 mg) in pyridine (2 ml) is treated with acetylchloride (0,034 ml) and heated at 60oC 3 hours. The mixture is cooled, diluted with water and extracted three times with ethyl acetate.

The organic extracts washed with water and saturated sodium chloride solution, then dried (MgSO4). Volatile products are removed by evaporation and the residue is cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 0-10% methanol/dichloromethane, yielding a resin (104 g); mass spectrum (+ve ESP): 457 (M+N)+. This resin (95 mg), and again dissolved in pyridine (3 ml) and heated to boiling point under reflux in an argon atmosphere for 4 hours. The mixture is cooled, diluted with water and extracted three times with ethyl acetate. Volatile products are removed by evaporation and the residue is cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 0-60% ethyl acetate/hexane, to obtain N-(3-methoxy-5-methylpyrazine-2 - yl)-2-(4-[5-methyl-1,2,4-oxadiazol-3-yl] phenyl)pyridine-3 - sulfonamide (56 mg) as a solid;

1H NMR (CDCl3): 2,3(s, 3H), and 2.7(s, 3H), and 3.7(s, 3H), 6,7(user. s, 1H), and 7.3 and 7.6(m, 4H), 8,1(user. d, 2H), 8,7(user. d, 1H), 8,8(user. d, 1H);

mass spectrum (+ve ESP): 439 (M+N)+the amount of starting compound using N-isobutoxide-N-(3-methoxy-5-methylpyrazine-2 - yl)-2-(4-[pyrimidine-2 - yl] phenyl)pyridine-3-sulfonamide, get (40% yield) of N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[pyrimidine-2-yl]phenyl) pyridine-3-sulfonamide in the form of solids;

1H NMR (DMSO-d6): 2,2(user. s, 3H), and 3.8 (s, 3H), and 7.4(t, 1H), 7.5 to 7.6 for(user. m, 3H), of 7.65(DD, 1H), 8.4V(user. s, 2H), 8,5(DD, 1H), 8,8(DD, 1H), 8,9(d, 2H), 10,5(user. s, 1H); mass spectrum (+ve ESP): 435 (M+N)+.

The original N-isobutoxide-N-(3-methoxy-5 - methylpyrazine-2-yl)-2-(4-[pyrimidine-2-yl]phenyl)pyridine-3 - sulfonamide was obtained as follows:

Tetrakis(triphenylphosphine)palladium (0) (60 mg) are added to a solution of sodium carbonate (233 mg), deprived of oxygen, 1,4-benzodiacepinas acid (165 mg), 2-chloropyrimidine (114,5 mg) and 2-chloro-N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl) -pyridine-3-sulfonamida (414 mg) in a mixture of water (1.6 ml), ethanol (4 ml) and toluene (8 ml). The mixture is stirred and heated in an argon atmosphere at the boiling point under reflux for 16 hours, then allowed to cool to ambient temperature. Add water (15 ml) and the mixture extracted with ethyl acetate (2 x 20 ml). The combined organic layers are washed with saturated sodium chloride solution and dried (MgSO4). Volatiles are removed by evaporation and the residue is cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira 25-100% of this is in-3-sulfonamide (95 mg) as a solid; mass spectrum (+ve ESP): 535 (M+N)+.

Example 42

Nesadurai oil sodium hydride (240 mg) is added to a stirred solution of 3-pyridylcarbinol (1,09 g) in dry THF. After cessation of hydrogen is added 2-(4-bromomethylphenyl)-N-(isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide (549 mg) and the mixture is stirred for 2 hours. Volatile products are removed by evaporation and to the residue is added a saturated solution of ammonium chloride (10 ml). The mixture is extracted with ethyl acetate (3 x 20 ml) and the extracts dried (MgSO4). Volatile products are removed by evaporation and the residue clean flash chromatography, elwira methanol/ethyl acetate (1:19 volumes), after trituration with diethyl ether to obtain N-(3-methoxy-5-methylpyrazine-2-yl)-2-{ 4-[(3-pyridyl) methoxymethyl]phenyl}pyridine-3-sulfonamide (187 mg), so pl. 183-185oC; microanalysis

found: C, 60,9; H, a 4.9; N, 14.2 percent; for C24H23N5O4S

in theory: C, 60,4; H, is 4.85; N, 14.7 per cent.

Example 43

Using a method similar to that described in example 42, but using allyl alcohol as the source of the connection, receive (38% yield) 2-[4-(allyloxymethyl)phenyl] -N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide, so pl. 72-76oC; micro,1%.

Example 44

Using a method similar to that described in example 42, but using methyl 2-hydroxy-2-methylpropionate as the parent compound, receive (30% output) 2-[4-([(1-methoxycarbonyl-1-methyl)ethoxy]methyl)phenyl]-N- (3-methoxy-5-methylpyrazine-2-yl)-pyridine-3-sulfonamide, so pl. 125-127oC; microanalysis

found: C, with 56.8; H, 5,6; N, 11.4 percent; for C23H26N4O6S

in theory: C, with 56.8; H, 5,4; N, 11.5 per cent.

Example 45

A solution of lithium hydroxide (150 mg) in water (2 ml) are added to a solution 2-[4-([(1-methoxycarbonyl-1-methyl)ethoxy] methyl)phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamida (340 mg) in THF (8 ml) and methanol (2 ml) and the solution stirred for 20 hours. Volatiles are removed by evaporation and the residue is dissolved in water (25 ml).

The solution is washed with ethyl acetate (2 x 25 ml) and the extracts are re-extracted with saturated sodium bicarbonate solution (2 x 10 ml). An aqueous solution podkalyvayut 20% aqueous citric acid and extracted with ethyl acetate (2 x 25 ml). The extracts washed with water (10 ml) and saturated sodium chloride solution (50 ml) and dried (MgSO4). Volatile products are removed by evaporation and the residue triturated with diethyl ether, receiving 2-[4-([(1-carboxy-1-methyl)ethoxy] methyl)phenyl] -N-(3 - IU the with, 2H), 7,2-7,5(m, 5H), and 7.6(d, 1H), and 8.4(d, 1H), and 8.8(d, 1H), 10,4(s, 1H), 12,45(user. s, 1H); mass spectrum (+ve ESP): 473 (M+N)+.

Example 46

1.0 M solution of DIBORANE in tetrahydrofuran (5.6 ml) is added over 10 minutes to a solution of 2-[4-([(1-methoxycarbonyl-1 - methyl)ethoxy]methyl)phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamida (500 mg) in THF (10 ml) at 0oC. the Mixture is allowed to warm to room temperature and stirred for 20 hours. Add a saturated solution of ammonium chloride (15 ml) and the solution podkalyvayut to pH 3 with 2 M hydrochloric acid. The mixture is extracted with diethyl ether (2 x 20 ml) and the extracts dried (MgSO4) and concentrate. The residue is cleaned by chromatography on silikagelevye Mega Bond Elut column, elwira with ethyl acetate and then precrystallization of diethyl ether, which gives 2-[4-([(1-hydroxy-1,1-dimethyl)ethoxy] methyl)phenyl] - N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (60 mg), so pl. 72-73oC; microanalysis

found: C, to 57.1; H, 6,1; N, 11.9 percent; for C22H26N4O5S

in theory: C, to 57.1; H, 5,7; N, 12.2 per cent.

Example 47

Using a method similar to that described in example 45, but from N-(isobutoxide-2-{4-[(4-ethoxycarbonylphenyl) methoxy]phenyl}-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida, floor square 204-205oC;

1H NMR (DMSO-d6): of 2.25(s, 3H), and 3.8(s, 3H), and 4.5(s, 2H), 7,0(d, 1H), 7.5(d, 2H), 7.5 to at 7.55(m, 1H), and 7.6(d, 2H), and 8.0(d, 2H), and 8.4(d, 2H), and 8.8(d, 2H), 10,4(s, 1H), 12,9(user. s, 1H).

The original N-(isobutoxide-2-{ 4-[(4-ethoxycarbonylphenyl) methoxy] phenyl} -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide get by using a method similar to that described in example 8, part (v), with 68% yield, so pl. 134-135oC, using methyl-4-bromeilles instead methyl-2-bromopropionate.

Example 48

Using a method similar to that described in example 19, but on the basis of 2-[4-[2-(tert-butyldiphenylsilyl)- ethoxymethyl)phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamida, get (42% yield) 2-[4-[(2-hydroxyethoxy) methyl]phenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide, so pl. 106-108oC; microanalysis

found: C, at 55.3; H, 5,1; N, 12.7 per cent; for C20H22N4O5S

theoretically: C and 55.8; H, 5,15; N, 13,0%.

The original 2-{ 4-[2-(tert-butyldiphenylsilyl)- ethoxymethyl]phenyl}-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide get by using a method similar to that described in example 42, 46% yield;

1H NMR (d6-DMSO): 1,0(s, 9H), of 2.25(s, 3H), up 3.6-3.7(m, 2H), 3.75 to a 3.9(m, 5H), and 4.6(s, 2H), 7.3 to 7.5(m, 10H), of 7.6 to 7.7(m, 6H), to 8.45(DD, 1H), 8J.Org.Chem. (1992), 57, 1707) instead of 3-pyridylcarbinol.

Example 49

A solution of 2-{ 4-[(2-tert-butoxy-1 methylethoxy)- methyl]phenyl}-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamida (248 mg) in triperoxonane acid (1 ml) and left to stand for 30 minutes. Add a saturated solution of ammonium chloride (20 ml) and the mixture extracted with ethyl acetate (2 x 20 ml). The extracts are dried (MgSO4) and concentrated and the residue is dissolved in dichloromethane (10 ml). The solution was washed with water (2 x 10 ml) and dried (MgSO4). Volatiles are removed by evaporation and the residue clean flash chromatography, elwira methanol/ethyl acetate (1: 24 volumes), and get 2-[4- ([2-hydroxy-1-methyl)ethoxy)methyl)phenyl]-N-(3-methoxy-5-methylpyrazine - 2-yl)pyridine-3-sulfonamide (82 mg);

1H NMR (d6-DMSO): 1,15(s, 3H), of 2.25(s, 3H), 3,3-3,7(s, 3H), and 3.8(s, 3H), 4,6(s, 2H), 7.3 to at 7.55(m, 5H), and 7.6(DD, 1H), 8,45(DD, 1H), 8,8 (DD, 1H), 10,35-10,45(user. s, 1H); mass spectrum (+ve ESP): 445 (M+N)+.

Source 2-{4-[1-(2-tert-butoxy-1 methylethoxy)-methyl]phenyl} -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide get by using a method similar to that described in example 42, 57% yield;

1H NMR (d6-DMSO): 1,2(d+s, 12H), 2,3 (s, 3H), 3,3 (DD, 1H), of 3.45(DD, 1H), 3,55-the 3.65(m, 1H), and 3.8(s, 3H), 4,6(user. s, 2H), 7.3 to 7.5(m, 5H), and 7.6 (DD, 1H), and 8.4 to 8.5(m, 1H), 8,8-8,9(m, analogichny described in example 11, but proceeding from N-(isobutoxide)-N-(3 - methoxy-5-methylpyrazine-2-yl)-2-[4-morpholinyl] pyridine-3 - sulfonamida receive (55% yield) of N-(3-methoxy-5 - methylpyrazine-2-yl)-2-[4-morpholinyl]pyridine-3-sulfonamide, so pl. 197-198oC; microanalysis

found: C, at 56.6; H, 5,3; N, 15.5 percent; for C21H23N5O4S

in theory: C, to 57.1; H, a 5.25; N, 15.9 per cent.

The original N-(isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)-2-[4-morpholinyl]pyridine-3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 11, part (i), get (90% yield) of 4-morpholinobutyrophenone acid;

1H NMR (CDCl3): 3,2-3,3(m, 4H), 4,8-4,9(m, 4H), to 7.0(d, 2H) and 8.1(d, 2H); from 4-(4-bromophenyl)of the research (obtained as described in J. Chem.Soc. (), (1971), 132).

(ii) Using a method similar to that described in example 11, part (ii) but using 4-morpholinobutyrophenone acid, receive (56% yield) N-(isobutoxide) -N-(3-methoxy-5-methylpyrazine-2-yl)-2-[4-morpholinyl] pyridine-3-sulfonamide;

1H NMR (CDCl3): of 0.7(d, 6H), of 1.5-1.7(m, 1H), 2,5(s, 3H), 3,2-3,3(m, 4H), 3,8-3,9(m, 4H), 4,0(s, 3H), 6,95(d, 2H), and 7.4(DD, 1H), and 7.6(d, 2H), 7,95(s, 1H), 8,8(DD, 1H), 8,95(DD, 1H).

Example 51

Using a method similar to that described in example 11, but recognize the(56% yield) of 2-(4-neopentylene)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide, so pl. 159-160oC; microanalysis

found: C, 62,0; H, 6,3, N, 13,0%; for C22H26N4O3S

in theory: C, 62,0; H, 6,1; N, 13.1 per cent.

The original 2-(4-neopentylene)-N-(isobutoxide)-N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 11, part (i), get (92% yield) of 4-neopentylenephosphorus acid;

1H NMR (CDCl3): of 0.9 (s, 9H), and 2.6(s, 2H), and 7.3(d, 2H), 8,15(d, 2H); from 1-bromo-4-neopentylene (obtained as described in J. C. S Perkin I, (1982), 181).

(ii) Using a method similar to that described in example 11 part (ii) but using 4-neopentylenephosphorus acid, receive (59% yield) of 2-(4-neopentylene)-N- (isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine - 3-sulfonamide;

1H NMR (CDCl3): of 0.7(d, 6H), of 0.95 (s, 9H), of 1.6-1.8(m, 1H), 2,5(s, 3H), 3,85(d, 2H), 4,0(s, 3H), 7,2(d, 2H), and 7.5(DD, 1H), 7,55(d, 2H), 7,95(s, 1H), cent to 8.85(DD, 1H), and 9.0 (DD, 1H).

Example 52

Using a method similar to that described in example 8, part (iv), but proceeding from N-(3-methoxy-5-methylpyrazine-2-yl)-2- { 4-[2H-tetrahydropyran-2-yloxy)ethoxy)phenyl} pyridine-3 - sulfonamida receive (65% yield) of 2-(4-(2-hydroxyethoxy) phenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-su is>< / BR>
in theory: C, of 54.8; H, 4,8; N, 13.5 per cent.

The source of N-(3-methoxy-5-methylpyrazine-2-yl)-2-{4-[2-[2H - tetrahydropyran-2-yloxy)ethoxy)phenyl}pyridine-3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 8, part (i), receive (95% yield) 2-[2-(4-bromophenoxy) ethoxy)-2H-tetrahydropyran;

1H NMR (d6-DMSO): 1,4-1,8(m, 6H), 3,4-3,5(m, 1H), 3,65-of 3.85(m, 2H), 3,9-4,0(m, 1H), 4,1(t, 2H) and 4.65(t, 1H), 6,9(d, 2H), and 7.4 (d, 2H), starting from 2-(4-bromophenoxy) ethanol.

(ii) Using a method similar to that described in example 8, part (ii), but using 2-[2-(4-bromophenoxy)ethoxy]-2H - tetrahydropyran receive (51% yield) of 4-[2-(2H - tetrahydropyran-2-yloxy)ethoxy]phenylboronic acid;

1H NMR (d6-DMSO): 1,4-1,8(m, 6H), 3,4-3,5(m, 1H), 3,65-of 3.85(m, 2H), 3,9-4,0(m, 1H), 4,2(t, 2H) and 4.65(t, 1H), 6,9(d, 2H), of 7.75 (d, 2H), and 7.8(s, 2H).

(iii) Using a method similar to that described in example 11, part (ii) but using 4-[2-(2H-tetrahydropyran-2-yloxy) ethoxy) phenylboronic acid, receive (42% yield) N-(isobutoxide)-N-(3-methoxy-5-methyl-pyrazin-2-yl)-2-{ 4- [2-(2H-tetrahydropyran-2-yloxy)ethoxy]phenyl}pyridine-3 - sulfonamide;

1H NMR (d6-DMSO): 0,6 (d, 6H), 1,4-1,8(m, 7H), and 2.5 (s, 3H), 3,4-3,5(m, 1H), of 3.7-3.8(m, 2H), 3,85 (d, 2H), 3,9-4,0(m, 1H), of 4.05(s, 3H), 4,2(t, 2H), 4,7(t, 1H), 7,0(d, 2 but using N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine-2 - yl)-2-{4-[2-(2H-tetrahydropyran-2-yloxy)ethoxy] phenyl} pyridine - 3-sulfonamide, get (39% yield) of N-(3-methoxy-5 - methylpyrazine-2-yl)-2-{4[2-(2H-tetrahydropyran-2-yloxy)ethoxy] phenyl}pyridine-3-sulfonamide;

1H NMR (d6-DMSO): 1,4-1,8(m, 6H), 2,3(s, 3H), 3,4-3,5(m, 1H), 3,65-of 3.85(m, 5H), 3,9-4,0(m, 1H), 4,15(s, 2H), 4,7(s, 1H), 6,9(d, 2H), and 7.4(d, 2H), 7,55 and 7.6(m, 2H), and 8.4(d, 1H), and 8.8(d, 1H), to 10.3(s, 1H).

Example 53

Using a method similar to that described in example 45, but from 2-[4-(2-hydroxy-2-methylpropoxy)phenyl] -N- (isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamida receive (49% yield) 2-[4-(2-hydroxy-2 - methylpropoxy)phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl) pyridine - 3-sulfonamide, so pl. 156-157oC; microanalysis

found: C, 56.7 g; H, 5,6; N, 12.7 per cent; for C21H24N4O5S

in theory: C, 56.7 g; H; 5,4; N, 12.6 per cent.

The original 2-[4-(2-hydroxy-2-methylpropoxy)phenyl]-N- (isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide was obtained as follows:

(i) 3.0 M of methylmagnesium in diethyl ether (14,0 ml) is added dropwise over 10 minutes to a solution of ethyl-4-bromperoxidase (5,2 g) in diethyl ether (50 ml) at 0oC in argon atmosphere. The solution was stirred at 0oC for 1 hour and then added a saturated solution of ammonium chloride (50 ml). The mixture is stirred for 10 minutes, OTDELENIE extracts. The extracts washed with water (50 ml), saturated sodium chloride solution (50 ml) and dried (MgSO4). Volatile product is removed by evaporation, obtaining 1-(4-bromophenoxy)-2 - methylpropan-2-ol (4.7 g) in the form of butter;

1H NMR (d6-DMSO): 1,2(s, 6H), and 3.7(s, 2H), 4,55(s, 1H), 6,9(d, 2H), and 7.4(d, 2H).

(ii) a Solution of 1-(4-bromophenoxy)-2-methylpropan-2-ol (1.23 g) in tetrahydrofuran (25 ml) are added to nestorgames oil to sodium hydride (132 mg) in an argon atmosphere. The mixture is stirred for 30 minutes and then cooled to -78oC. Add A 1.6 M utility in hexane (6.9 ml) for 5 minutes and the solution stirred at -78oC for 30 minutes. Add trimethylboron (1,14 g) for 1 minute and the mixture is stirred 1 hour at -78oC. Add a saturated solution of ammonium chloride (25 ml) and the mixture allowed to warm to room temperature. Add water (25 ml) and the mixture extracted with diethyl ether (2 x 25 ml). The extracts washed with water (25 ml), saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile compounds are removed by evaporation and the residue clean flash chromatography, elwira ethyl acetate/hexane (7:3 in volume ratio) to give 4-(2-hydroxy-2-methylpropoxy)phenylboronic acid (355 mg);

1H NMR (d6-DMSO): 1,2 (s, 6H), and 3.7 (s, 2H), 4,5(user.average 4-(2-hydroxy-2-methylpropoxy)phenylboronic acid, get (36% yield) 2-[4-(2-hydroxy-2-methylpropoxy)phenyl] -N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine-3 - sulfonamide;

1H NMR (d6-DMSO): 0,6(d, 6H), 1,25(S, 6H), of 1.5-1.7(m, 1H), to 2.55(s, 3H), of 3.75(s, 2H), and 3.8(d, 2H), 3,95(s, 3H), 4,6(s, 1H), 7,0(d, 2H), 7.5(d, 2H), of 7.75(DD, 1H), 8,15(s, 1H), 8,8-8,95(m, 2H).

Example 54

Using a method similar to that described in example 45, but from 2-[4-(2-hydroxy-1,1-dimethylmethoxy)phenyl] -N- (isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamida receive (49% yield) 2-[4-(2-hydroxy-1,1-dimethylmethoxy)phenyl] -N-(3-methoxy - 5-methylpyrazine-2-yl)pyridine-3-sulfonamide, so pl. 182-184oC;

1H NMR (d6-DMSO): 1,25 (s, 6H), of 2.25(s, 3H), 3,4(d, 2H), and 3.8(s, 3H), around 4.85(t, 1H), 6,95(d, 2H), 7,35(d, 2H), and 7.4-7.5(m, 1H), 7,55(DD, 1H), and 8.4(DD, 1H), up 8.75(d, 1H), of 10.25 to 10.5(user. s, 1H).

The original 2-[4-(2-hydroxy-1,1-dimethylmethoxy)-phenyl]-N- (isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine - 3-sulfonamide was obtained as follows:

(i) Using a method similar to that described in example 46, but on the basis of 2-(4-bromophenoxy)-2-methylpropanoic acid, receive (87% yield) of 2-(4-bromophenoxy)-2-methylpropanol in the form of butter;

1H NMR (d6-DMSO): 1,2(s, 6H), to 3.35(d, 2H), around 4.85(t, 1H), 7,0(d, 2H), and 7.4(d, 2H).

(ii) Using the method of analogically-1,1-dimethylmethoxy) phenylboronic acid (355 mg);

1H NMR (d6-DMSO): to 1.15 (s, 6H), 3,4(d, 2H), and 4.8 (t, 1H), 6,95(d, 2H), 7,65(d, 2H), and 7.8(s, 2H).

(iii) Using a method similar to that described in example 11, part (ii) but using 4-(2-hydroxy-1,1-dimethylmethoxy)phenylboronic acid, receive (40% yield) 2-[4-(2-hydroxy-1,1-dimethylmethoxy) phenyl]-N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)-pyridine - 3-sulfonamide;

1H NMR (d6-DMSO): 0,6(d, 6H), 1,25(s, 6H), of 1.5-1.7(m, 1H), to 2.55(s, 3H), of 3.45(d, 2H), and 3.8(d, 2H), 3,95(s, 3H), around 4.85(t, 1H), 7,05(d, 2H), 7,45(d, 2H), 7,7-7,8(m, 1H), 8,15(s, 1H), 8,8-8,95(m, 2H).

Example 55

1 M Solution of acetic acid in dimethoxyethane (5.6 ml) is added dropwise over 3 hours to a mixture of 2-[4-(2- [methoxycarbonyl]vinyl)phenyl]-N-(isobutoxide)-N-(3 - methoxy-5-methylpyrazine-2-yl)-pyridine-3-sulfonamida (250 mg) and azodicarboxylate potassium (1.4 g) in dry dimethoxyethane (20 ml) at 45oC. the Mixture is heated at 45oC 18 hours. Insoluble compounds are removed by filtration and the filtrate concentrated. The residue is passed through a layer of silica gel, elwira ethyl acetate/hexane (1:3 in volume ratio) and the resulting solid product (230 mg) dissolved in a mixture of tetrahydrofuran (16 ml) and methanol (4 ml). Add a solution of lithium hydroxide (118 mg) in water (4 ml) and the solution stirred for 18 hours. Bats wishes is up 20% aqueous citric acid. The mixture is extracted with ethyl acetate (2 x 15 ml) and the extracts washed with water (10 ml), saturated sodium chloride solution (50 ml) and dried (MgSO4). Volatile compounds are removed by evaporation and the residue triturated with diethyl ether, obtaining 2-[4-(2-carboxyethyl)phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine - 3-sulfonamide (42 mg), so pl. 166-168oC;

1H NMR (CDCl3): of 2.25(S, 3H), and 2.6(t, 2H), 3,0(t, 2H), and 3.8(s, 3H), 7,2-7,3(m, 5H), 7,45-of 7.55(m, 1H), 8,65(d, 1H), and 8.8(d, 1H), of 10.25 to 10.5(user. s, 1H).

The original N-isobutoxide-2-[4-(2-[methoxycarbonyl] vinyl)phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide was obtained as follows:

A solution of 2-(4-itfeel)-N-(isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)-pyridine-3-sulfonamida (1.5 g), methyl acrylate (0.25 ml), palladium acetate (58 mg) and triethylamine (1,79 ml) in dimethylformamide (45 ml) and water (5 ml) is heated for 1 hour at 100oC. the Volatiles removed by evaporation and to the residue water is added (50 ml). The mixture podkalyvayut to pH 3 with 1 M hydrochloric acid and extracted with ethyl acetate (2 x 50 ml). The extracts washed with water (50 ml) and saturated sodium chloride solution (50 ml), treated with activated charcoal and dried (MgSO4). The solvent is removed by evaporation and the residue triturated with diethyl is(3-methoxy-5-methylpyrazine-2 - yl)pyridine-3-sulfonamide (0,99 g), so pl. 149-151oC; microanalysis

found: C, to 57.7; H, 5,2; N, 10.6 percent; for C26H28N4O7S

in theory: C, of 57.8; H, 5,2; N, 10.4 percent.

Example 56

The monohydrate of lithium hydroxide (87 mg) are added to a solution of N-isobutoxide-2-[4-(2-[methoxycarbonyl] vinyl)phenyl]-N- (3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida (250 mg) in tetrahydrofuran (6.2 ml), then methanol (2.5 ml) and water (2.5 ml). The reaction mixture was stirred at ambient temperature for 18 hours and evaporated to dryness. The residue is dissolved in water (50 ml), washed with ethyl acetate (50 ml), podkalyvayut 8% aqueous citric acid to pH 3-4 and extracted with ethyl acetate (100 ml). The organic layers extracted with saturated sodium bicarbonate solution (50 ml) and the aqueous phase is separated podkalyvayut 8% aqueous citric acid and extracted with ethyl acetate (3 x 30 ml). The combined organic extracts dried (MgSO4) and evaporated, obtaining 2-[4-(2-carboxyvinyl) phenyl]-N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (108 mg) as a solid substance, so pl. 233-235oC;

1H NMR (d6-DMSO): 2,2(s, 3H), and 3.8(s, 3H), 6,55(d, 1H), 7,35(user. s, 1H), 7,45(d, 2H), 7,55 to 7.75(m, 4H), to 8.45(DD, 1H), 8,8(DD, 1H), 10,1(user. s, 1H); mass spectrum (+ve ESP): 427 (M+N)+.

The source of N-isobutan edusim follows:

(i) Using a method similar to that described in example 11, part (ii), but on the basis of 4-formylphenylboronic acid, receive (51% yield) of N-isobutoxide-2-(4-formylphenyl)-N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide, so pl. 154-156oC;

1H NMR (CDCl3): of 0.68(d, 6H), 1,7 (septet, 1H), 2,53 (s, 3H), 3,83(d, 2H), 4,0(s, 3H), 7,58(DD, 1H), 7,79(d, 2H), and 7.9(s, 1H), 7,95 (d, 2H), 8,87(DD, 1H), 8,97(DD, 1H), 10,1 (s, 1H); mass spectrum (+ve ESP): 485 (M+N)+.

(ii) N-isobutoxide-2-(4-formylphenyl)-N-(3-methoxy - 5-methylpyrazine-2-yl)-pyridine-3-sulfonamide (500 mg) is added to the bromide karboksimetilirovaniya (429 mg) in a mixture of a saturated aqueous solution of sodium hydroxide (1.25 ml) and methylene chloride (4 ml), vigorously stirred at ambient temperature for 1.5 hours. Add water (20 ml) and the mixture extracted with dichloromethane (2 x 20 ml). The combined organic layers washed with water (5 ml), dried (MgSO4) and evaporated. The residue is cleaned by chromatography on silikagelevye Mega Bond Elut column, using a gradient elution of 0-30% ethyl acetate in hexane. Combine the fractions containing the product, evaporated, the residue triturated with diethyl ether/isohexane (1:1 in volume) and filtered, obtaining N-isobutoxide-2-[4-(2-[methoxycarbonyl]vinyl)Fe): 0,65(d, 6H), 1,7(septet, 1H), 2,53 (s, 3H), 3,82(s, 3H), 3,85(d, 2H), 3,98(s, 3H), 6.48 in(d, 1H), 7,4-7,8(m, 7H), and 7.9(s, 1H), 8,86(DD, 1H), 8,98(DD, 1H).

Example 57

2-[4-(3-hydroxy-2-methylpropyl " phenyl] -N-(3-methoxy-5-methylpyrazine - 2-yl)pyridine-3-sulfonamide from example 19 (100 mg) is heated in a mixture of acetic acid (0.5 ml) and acetic anhydride (0.5 ml) to 80oC for 10 minutes and allowed to cool to ambient temperature. After 16 hours carefully add an excess of saturated aqueous sodium bicarbonate and the product extracted with ethyl acetate (3 x 20 ml). The combined organic extract is dried (MgSO4) and evaporated. The residue is cleaned by chromatography on silikagelevye Mega Bond Elut column (1 g) using a gradient elution of 0-30% ethyl acetate/hexane, and get 2-[4-(3-acetoxy-2-methylpropyl " phenyl]-N- (3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (70 mg) as a white foam;

1H NMR (CDCl3): and 0.98(d, 3H), 1,58(s, 3H), 2,11(s, 3H), to 2.1-2.3(m, 1H), of 2.51(q, 1H), 2,85(kV, 1H), 3,80(s, 3H), of 3.97(m, 2H), 6,69(s, 1H), 7,2(d, 2H), 7,29(d, 2H), 8,67(d, 1H), 8,80(DD, 1H); mass spectrum (+ve ESP): 471,1 (M+N)+.

Example 58

Using a method similar to that described in example 9, but on the basis of 2-[4-(2-carboxypropyl)phenyl] -N-(isobutoxide) -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida receive (31% yield) 2-[4-(2-kN NMR (CDCl3): of 1.23(d, 3H), of 2.28(s, 3H), 2,80(m, 1H), 3,13(m, 1H), 3,83(s, 3H), 7,71-7,33(m, 5H), 7,51(kV, 1H), 8,68(DD, 1H), 8,80(DD, 1H); mass spectrum (+ve ESP): 443,1 (M+N)+.

The original 2-[4-(2-carboxypropyl)phenyl] -N- (isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide was obtained as follows:

(i) a Solution of diethylmalonate (87 g) in absolute ethanol (100 ml) is added to the previously obtained solution of sodium (11.5 g) in ethanol (400 ml) in an argon atmosphere. Quickly add a hot solution of p-bromobenzylamine (125 g) in absolute alcohol (200 ml) with vigorous stirring which continued for 3 days, and the formed solid product removed by filtration. The filtrate is evaporated and the residue is dissolved in ethyl acetate (1 l), washed with salt solution (250 ml), dried (MgSO4) and evaporated. The remaining oil is distilled in vacuum, obtaining diethyl-(4 - bromophenyl)methylmalonate (to 150.7 g), so Kip. 130-133oC, 0.03 mm Hg;

1H NMR (d6-DMSO): of 1.33(t, 6H), 1,4(s, 3H), of 3.27(s, 2H), 4,30(kV, 4H), of 7.23(d, 2H), and 7.6(d, 2H).

(ii) sodium hydroxide Solution (175 g) in water (800 ml) was added to a solution of diethyl-(4-bromophenyl)methylmalonate (150 g) in ethanol (850 ml) and the mixture is heated to boiling point under reflux 9 hours. Volatiles are removed by evaporation and ostate the major fridge for about 2.5 hours, filtered through a layer of diatomaceous earth and the filtrate podkalyvayut 6 M sulfuric acid. The mixture is extracted with diethyl ether (4 x 500 ml) and the extracts dried (MgSO4). The solution is concentrated and the residue is heated at 200oC to stop carbon dioxide. The residue is dissolved in 1 M sodium hydroxide solution (500 ml) and the solution podkalyvayut 6 M sulfuric acid. The mixture is extracted with diethyl ether (4 x 500 ml) and the extracts dried (MgSO4). The solvent is removed by evaporation, getting 3-(4-bromophenyl)-2-methylpropionic acid (91 g), so pl. 72-73oC;

1H NMR (d6-DMSO): 1,0(d, 3H), 2.05 is-of 2.15 (m, 2H), 2,85 is 2.9(m, 1H), and 7.1(d, 2H), and 7.4(d, 2H).

(iii) 3-(4-Bromophenyl)-2-methylpropionic acid (40 g) accurately divided into portions, which are added dropwise within 30 minutes to thionyl chloride (75 ml). The mixture is stirred for 48 hours and then add toluene (300 ml). Volatiles are removed by evaporation and the residue re-dissolved in toluene (300 ml), the solution is treated with activated carbon and concentrated. The remaining oil (36,6 g) dissolved in dichloromethane (150 ml) and the solution is added dropwise within 1 hour to a solution of 2-amino-2 - methylpropanol (25 g) in dichloromethane (300 ml) and toluene (300 ml) at -20oC. the Mixture is stirred for 17 hours, and we use the C ethyl acetate, receiving N-(1-hydroxy - 2-methylpropan-2-yl)-3-(4-bromophenyl)-2-methyl-propionamide (34.4 g), so pl. 120-121oC; microanalysis

found: C, 53,9; H, 6.5; the N, 4,5%; for C14H20BrNO2,

in theory: C, a 53.5; H, 6,4, N, 4,5%.

(iv) a Solution of methanesulfonamide (11.4 g) in dichloromethane (50 ml) is added dropwise over 1 hour to a stirred mixture of N-(1-hydroxy-2-methylpropan-2-yl)-3-(4-bromophenyl)-2 - methylpropionamide (of 31.4 g) and triethylamine (20.2 g) in dichloromethane (400 ml). The mixture is stirred for 2.5 hours and then add water (300 ml). The organic phase is separated, washed with water (200 ml) and saturated sodium chloride solution (200 ml) and dried (MgSO4). Volatiles are removed by evaporation, obtaining 2-[1-(4-bromophenyl)propan-2-yl]-4,4-dimethyloxazole (26,4 g) as a syrup;

1H NMR (CDCl3): to 1.15(d, 3H), 1,2(s, 3H), 1,25(s, 3H), of 2.25 to 2.35(m, 2H), 2.95 points to 3.0(m, 1H), 3,85(s, 2H), 7,05(d, 2H), and 7.4(d, 2H).

(v) Using a method similar to that described in example 8 part (ii), but on the basis of 2-[1-(4-bromophenyl)propan-2-yl]-4,4 - dimethyloxazole receive (51% yield) of 4-[2-(4,4 - dimethyloxazole-2-yl)propyl]-phenylboronic acid, so pl. 155-156oC;

1H NMR (d6-DMSO): of 1.05 (s, 6H) and 1.15 (d, 3H), 2,6-2,7(m, 2H), 2,8-2,9(m, 1H), 3,85(s, 2H), 7,15(d, 2H), 7.7(d, 2H), and 7.9(s, 2H).

(vi) 4-[2-(4,4-dimethyloxazole-2-mesheanii within 45 minutes. After cooling to ambient temperature the solution is saturated with sodium chloride and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts dried (MgSO4) and evaporated. The residue is triturated with isohexane, receiving 4-(2-carboxypropyl)phenylboronic acid (1,59 g):

1H NMR (d6-DMSO): of 1.02(d, 3H), 2,55 of 2.68 (m, 2H), 2,83-of 2.97(m, 1H), 7,15(d, 2H), 7,68(d, 2H), 7,85(s, 2H), 11,98(user. s, 1H).

(vii) Tetrakis(triphenylphosphine)palladium(0) (500 mg) are added to obeskislorozhennaja solution of sodium carbonate (3,74 g), 4-(2-carboxypropyl)phenylboronic acid (3,67 g) and 2-chloro-N-(isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)-pyridine-3-sulfonamida (6,1 g) in a mixture of water (30 ml), ethanol (75 ml) and toluene (75 ml). The mixture is stirred and heated in an argon atmosphere at 80oC 17 hours, then allowed to cool to ambient temperature. Add ice water (5 g) and the reaction mixture is extracted with ethyl acetate (75 ml). The combined organic layers extracted with saturated aqueous sodium carbonate (2 x 15 ml), the combined aqueous extracts podkalyvayut to pH 2 with 2 M hydrochloric acid and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts dried (MgSO4) and evaporated to reduce objremovectrl)-2-(4- (2-carboxypropyl)phenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine - 3-sulfonamide (3.11 g);

1H NMR (d6-DMSO): 0,61(d, 6H), of 1.09(d, 3H), 1,50-of 1.73(m, 1H), 2, 55(partially invisible due to DMSO, 3H), 2,6-2,77(m, 2H), 2,72-to 3.09(m, 1H), and 2.83(d, 2H), 3.96 points(s, 3H), 7,25(d, 2H), 7,43(d, 2H), 7,78(DD, 1H), 8,15(s, 1H), 8,83-8,96(m, 2H), 12,14 (user. s, 1H); mass spectrum (-ve ESP): 541,1 (M-H)-.

Example 59

2-[4-(3-Hydroxy-2-methylpropyl " phenyl] -N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide from example 19 (100 mg) in dichloromethane (1 ml) is treated triperoxonane acid (133 mg) and then n-utilitarianism (254 mg) in an argon atmosphere. The reaction mixture is left for 16 hours. Add an excess of saturated sodium bicarbonate and the mixture extracted with dichloromethane (2 x 10 ml). The combined organic extracts are washed with salt solution (10 ml), dried (MgSO4) and evaporated. The residue is cleaned by chromatography on silikagelevye Mega Bond Elut column (1 g) using a gradient elution 0-100% ethyl acetate/hexane. Enriched product fractions clean then preparative reversed-phase GHUR on a Dynamax 60A C18-column, elwira acetonitrile in water gradient 10-80%. Get 2-[4- (2-methyl-3-[N-butylcarbamoyl] propyl) phenyl]-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide as a colorless oil (17,1 mg);

1H NMR (CDCl3): of 0.94(m, 6H), 1,25-to 1.60(m, 4H), 2,15(user. m, 1H), 2,50(kV, 1H), 2,81(to the example 60

2-[4-(3-Hydroxy-2-methylpropyl " phenyl] -N-(3-methoxy-5-methylpyrazine - 2-yl)pyridine-3-sulfonamide (100 mg) obtained in example 19 was dissolved in pyridine (3 ml) and add pivaloate (309 mg; 0,32 ml). After 2 hours at ambient temperature, then add an excess of 8% aqueous citric acid and the reaction mixture is extracted with ethyl acetate (2 x 15 ml). The combined organic extracts are washed with salt solution (15 ml), dried (MgSO4) and evaporated. The residue is cleaned preparative reversed-phase GHUR on a Dynamax 60A C18-column, elwira acetonitrile in water gradient 20-80% will receive 2-[4-(2-methyl-3-pivaloyloxymethyl)phenyl] -N- (3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (64 mg);

1H NMR (CDCl3): of 0.95(d, 3H), of 1.23(s, 12H), 2.05 is was 2.25(user. m, 1H), 2,6-2,9(user. m, 1H), 2,3(s, 3H), 2,75-2,9(user. m, 1H), 3,80(s, 3H), 3,90-4,08(m, 2H), 6,55-6,8(user. m, 1H), and 7.1 to 7.4(m, 5H), 7.5(q, 1H), 8,68(DD, 1H), 8,80(DD, 1H); mass spectrum (+ve ESP): was 513.3 (M+N)+, 535,3 (M+Na)+.

Example 61

Using a method similar to that described in example 9, but proceeding from N-(isobutoxide)-2-(4-propanolol)-N- (3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamida get (13%) of 2-(4 - propanolol)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide, so pl. output reached 125.5-RUB 127.3oC;

1H NMR (CDCl+.

The original N-(isobutoxide)-2-(4-propanol phenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

Using a method similar to that described in example 11, part (ii), but on the basis of 4-propenylboronic acid (obtained by the method described in UK patent application GB2276161) receive (51% yield) N-(isobutoxide)-2-(4-propanolol)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide;

1H NMR (CDCl3): 0,65(d, 6H), 1,25(t, 3H), 1,6-of 1.85(m, 1H), 2,5(s, 3H), to 3.02(q, 2H), 3,82(d, 2H), 4,0(s, 3H), 7,55(DD, 1H), 7.7(d, 2H), and 7.9(s, 1H), 8,02(d, 2H), 8,86(DD, 1H), 8,95(DD, 1H); mass spectrum (+ve ESP): 513 (M+N)+.

Example 62

Using a method similar to that described in example 9, but proceeding from N-(isobutoxide)-2-(4-butanolide)-N- (3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamida, get (39%) of 2-(4 - butanolide)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide, so pl. 130-131oC;

1H NMR (CDCl3): of 1.05(t, 3H), 1.8 m(m, 2H, in), 2.25(s, 3H), 2.95 and(t, 2H), and 3.8(s, 3H), 6,68(user. s, 1H), and 7.3 and 7.6(m, 4H), a 7.85-with 8.05(m, 2H), and 8.7(d, 1H), 8,8(DD, 1H); mass spectrum (+ve ESP): 427 (M+N)+.

The original N-(isobutoxide)-2-(4-butanolide)-N- (3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) 1-Tim refrigerator in benzene (50 ml) for 6 days. The reaction mixture is cooled and poured into saturated aqueous sodium bicarbonate solution (50 ml) and extracted with toluene (3 x 50 ml). The combined organic extracts are washed with salt solution (50 ml), dried (MgSO4) and evaporated. The remaining oil is distilled in vacuum, obtaining 2-(4-bromophenyl)-2-propyl-1,3-dioxolan (4,25 g), so Kip. 102oC at 0.2 mm Hg;

1H NMR (free acid CDCl3): of 0.85(t, 3H), 1,2-1,4(m, 2H), about 1.75 to 1.9(m, 2H), 3,65 to 3.8(m, 2H), 3,85-of 4.05(m, 2H), 7,27-7,35(m, 2H), and 7.4-7.5(m, 2H).

(ii) 2-(4-Bromophenyl)-2-propyl-1,3-dioxolan (4,2 g) dissolved in anhydrous tetrahydrofuran (50 ml) and cooled to - 78oC in argon atmosphere. Add with stirring a 1.25 M solution of n-utility in hexane (12,65 ml), keeping the temperature below -70oC. After 30 minutes, slowly add trimethylboron (1,96 ml) and the solution stirred an additional 4 hours at -78oC. Allowing the solution to warm to -5oC add 2 M hydrochloric acid (50 ml) and the mixture is stirred for 18 hours. Separate the organic phase and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic phases are washed with saturated aqueous sodium bicarbonate (50 ml), salt solution (50 ml), dried (MgSO4) and evaporated. The obtained solid product peracre

1H NMR (CDCl3): 1,05(kV, 3H), 1.8 m(m, 2H), 2,9-3,1(m, 3H), 7,8 and 8.1(m, 3H), and 8.3(d, 1H); mass spectrum (-ve ESP): 191 (M-H)-.

(iii) Using a method similar to that described in example 11, part (ii), but on the basis of 4-butanoyl-phenylboronic acid, receive (71% yield) N-(isobutoxide)-2-(4-butanolide) -N-(3 - methoxy-5-methyl, pyrazin-2-yl) pyridine-3-sulfonamide, so pl. 141-143oC;

1H NMR (CDCl3): 0,65(d, 6H), and 1.0(t, 3H), 1,6-1,9(m, 3H), of 2.5(s, 3H), 2.95 and(t, 2H), and 3.8(d, 2H), 4,0(s, 3H), 7,55(m, 1H), 7.7(d, 2H), and 7.9(s, 1H), 8.0 a(d, 2H), 8,87(DD, 1H), 8,98(DD, 1H); mass spectrum (+ve ESP): 527(M+N)+.

Example 63

Using a method similar to that described in example 9, but proceeding from N-(isobutoxide)-2-[4-(2-methylpropanoyl) phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida receive (output 71,5%) 2-[4-(2-methylpropanoyl)-phenyl] -N- (3-methoxy-5-methyl-pyrazin-2-yl)pyridine-3-sulfonamide;

1H NMR (CDCl3): a 1.25(d, 6H), 2,3(s, 3H), 3.45 points to 3.7(m, 1H), and 3.8(s, 3H), 6,7(user. s, 1H), and 7.3 and 7.6(m, 4H), 7,87-8,07(m, 2H), 8,68(d, 1H), 8,82(DD, 1H); mass spectrum (+ve ESP): 427(M+N)+.

The original N-(isobutoxide)-2-[4-(2-methylpropanoyl)phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) 4-Bromobenzonitrile (10 g) is dissolved in anhydrous diethyl ether (125 ml) and gamavor heated to the boiling temperature under reflux for 18 hours. The reaction mixture is allowed to cool to ambient temperature slowly with stirring saturated aqueous solution of ammonium chloride. The stirring is continued for another 2 hours. The organic phase is separated and the aqueous layer was extracted with diethyl ether (3 x 100 ml). The combined organic phases are washed with water (50 ml), then a salt solution (50 ml), dried (MgSO4) and evaporated, obtaining 1-bromo-4-(2-methylpropanol)benzene (11.6 g);

1H NMR (CDCl3): to 1.15(d, 6H), 3,1(septet, 1H), 7.5 to about 7.6(m, 4H); mass spectrum (Cl+): 226(M)+.

(ii) Using a method similar to that described in example 62, part (i), but on the basis of 1-bromo-4-(2-methylpropanol) benzene and 1,3-propane diol, get (42%) of 2-(4-bromophenyl)-2 - isopropyl-1,3-dioxane (4,25 g), so Kip. 116oC at 0.4 mm Hg;

1H NMR (free acid CDCl3): 0.8 in(d, 3H), 1,15-1,25 (m, 1H), of 1.85(m, 2H), 2,0-2,1(m, 1H), 3,68(dt, 2H), 3.75 to of 3.85 (m, 2H), 7,15-7,25 (m, 2H), 7,45-of 7.55 (m, 2H); mass spectrum (Cl+): 285(M+N)+.

(iii) Using a method similar to that described in example 62, part (ii), but on the basis of 2-(4-bromophenyl)-2 - isopropyl-1,3-dioxane, receive (82%) of 4-(2 - methylpropanoyl) phenylboronic acid;

1H NMR (CDCl3): 1,15-1,25(m, 6H), 3,4-of 3.85(m, 2H), 7,75 and 8.1(m, 3H), 8,25 an 8.4(d, 1H); mass spectrum; (a measure 11, part (ii), but on the basis of 4-(2-methylpropanoyl)phenylboronic acid, receive (48%) of N-(isobutoxide)-2-[4-(2- methylpropanoyl)phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine - 3-sulfonamide;

1H NMR (CDCl3): of 0.68(d, 6H), of 1.25(d, 6H), 1,7(septet, 1H), 2,5(s, 3H), to 3.58 (septet, 1H), 3,82(d, 2H), 4,0(s, 3H), 7,55 (kV, 1H), 7.7(d, 2H), and 7.9(s, 1H), 8,02(d, 2H), 8,9(DD, 1H), 8,98 (DD, 1H); mass spectrum (+ve ESP): 527 (M+H)+.

Example 64

2-[4-(2-Carboxy-2-methylpropyl " phenyl] -N-(ISO - butoxycarbonyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide (334 mg) was dissolved in methanol (10 ml) and add sodium methylate (324 mg). The solution is heated to boiling point under reflux for 4 hours, cooled and evaporated to dryness. The residue is partitioned between water (20 ml) and ethyl acetate (15 ml), the organic layer is separated and washed with water (20 ml). The combined aqueous phase podkalyvayut 2 M hydrochloric acid and extracted with ethyl acetate (3 x 25 ml). The combined organic extracts dried (MgSO3) and evaporated. The residue is triturated with isohexane, receiving 2-[4-(2-carboxy-2-methylpropyl " phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (117 mg);

1H NMR (d6-DMSO): 1,1(s, 6H), 2,24(s, 3H), 2,85(user., 2H), 3,80(s, 3H), 7,13(user. , 2H), 7,35(user. d, 2H), 7,50(user. s, 1H), EUR 7.57(q, 1H), 8,78(d is isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3 - sulfonamide was obtained as follows:

(i) 1.25 M Solution of n-utility in hexane (32 ml) cooled to 0oC in argon atmosphere and slowly add Diisopropylamine (4,05 g; 5,24 ml). The resulting mixture is cooled to -70oC and with stirring, add dropwise methylisobutyl (4,08 g; 4,58 ml), keeping the temperature <-60C. After another 30 minutes added at -70oC solution of 4-bromobenzylamine (10.0 g) in anhydrous tetrahydrofuran (20 ml), maintaining the temperature was then at -70oC for 1.5 hours. The reaction mixture is allowed to warm to ambient temperature and then heated to the boiling temperature under reflux for 18 hours. After cooling, the mixture podkalyvayut 8% aqueous citric acid and extracted with ethyl acetate (3 x 75 ml). The insoluble product on the surface of the partition is removed by filtration and the combined organic phase is washed with salt solution (20 ml), dried (MgSO4) and evaporated. The residue is cleaned by vacuum flash chromatography on silica, elwira with a gradient of 0-10% ethyl acetate in hexane, which gives 1-bromo-4-(2-methoxycarbonyl-2 - methylpropyl " benzene (7,79 g);

1H NMR (d6-DMSO): of 1.13(s, 6H), and 2.79(s, 2H), 3,60(s, 3H),? 7.04 baby mortality(m, 2H), 7,46(dt, 2H);

mass spectrum (Cl+): 272 (M+N)+.

(ii) 1-Bromo-4-(2-methoxycarbonyl). The solution is heated to boiling point under reflux for 2 hours and then cooled. Volume reduced to ~25 ml by evaporation and the residue extracted with ethyl acetate (15 ml), then podkalyvayut 2 M hydrochloric acid and re-extracted with ethyl acetate (3 x 25 ml). The combined organic extract was acidified aqueous phase is dried (MgSO4) and evaporated, obtaining 1-bromo-4-(2-carboxy-2-methylpropyl " benzene (6,1 g);

1H NMR (d6-DMSO): 1,08(s, 6H), 2,78(s, 2H), 7,11(m, 2H), 7,46(m, 2H); mass spectrum (C1+): 256 (M+N)+.

(iii) 1-Bromo-4-(2-carboxy-2-methylpropyl " benzene (1, 93 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -70oC. Add a 1.25 M solution of n-utility in hexane (18 ml) dropwise with stirring in an argon atmosphere so that the temperature did not exceed -65oC. After 20 minutes, slowly add trimethylboron at -65oC and the reaction mixture allowed to warm to -15oC. the Reaction being removed by adding a saturated aqueous solution of ammonium chloride (50 ml) and the mixture podkalyvayut by adding 2 M hydrochloric acid. The organic phase is separated and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined organic phase is washed with salt solution (15 ml) and evaporated, the residue grow the MCO): 1,06(s, 6H), 2,78(s, 2H), 7,11(d, 2H), to 7.67(d, 2H), 7,9(user. s, 2H), 12,2(user. s, 1H); mass spectrum (-ve ESP): 221 (M-H)-.

(iv) (2-Carboxy-2-methylpropyl)phenylboronic acid (608 mg), 2-chloro-N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine-2 - yl)pyridine-3-sulfonamide (1,03 g) and sodium carbonate (583 mg) are added to a mixture of toluene (25 ml), ethanol (25 ml) and water (10 ml). The mixture obeskislorozhennuju, alternately barbotine argon through it and vacuuming (3 cycles) add tetrakis(triphenylphosphine) palladium (0) (100 mg). The reaction mixture is heated at 85oC 18 hours, cooled to ambient temperature and partitioned between water (15 ml) and ethyl acetate (25 ml). The organic phase is extracted with saturated aqueous sodium carbonate (15 ml) and the combined aqueous phase is washed with ethyl acetate (15 ml). The aqueous phase podkalyvayut 2 M hydrochloric acid to pH 1 and extracted with ethyl acetate (3 x 30 ml). The combined organic extracts dried (MgSO4) and evaporated, obtaining 2-[4-(2-carboxy-2 - methylpropyl " phenyl] -N-(isobutoxide)-N-(3-methoxy-5 - methylpyrazine-2-yl)pyridine-3-sulfonamide (495 mg);

1H NMR (d6-DMSO): 0,6(d, 6H), 1,10(s, 6H), 1,51 was 1.69(m, 1H), 2,52(partially superimposed DMSO), 2,87(s, 2H), 3,82(d, 2H), 3,95(s, 3H), 7,20(m, 2H), 7,43(d, 2H), 7,79(DD, 1H), 8,16(s, 1H), 8,84-8,97(m, 2H); mass spectralis-3-sulfonamide (55 mg), obtained as described in example 63, was dissolved in ethanol (2 ml) and add sodium borohydride (20 mg). The resulting mixture was stirred at ambient temperature for 45 minutes and then add water (5 ml). The mixture podkalyvayut by adding 2 M hydrochloric acid to pH 2, and extracted with ethyl acetate (50 ml). The organic phase is dried (MgSO4) and evaporated, the residue is crystallized from ethyl acetate/hexane, obtaining 2-[4-(1-hydroxy-2-methyl-propyl) phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (33 mg);

1H NMR (CDCl3+ CD3CO2D): or 0.83 (d, 3H), of 0.95(d, 3H), of 1.95(m, 1H, in), 2.25(s, 3H), and 3.8(s, 3H), 4,4(d, 1H), and 7.3(s, 5H), was 7.45(DD, 1H), 8,65(DD, 1H), up 8.75(DD, 1H); mass spectrum (+ve ESP): 429 (M+N)+.

Example 66

2-(4-Cyclopropylmethyl)-N-(isobutoxide)-N-(3-methoxy - 5-methylpyrazine-2-yl)pyridine-3-sulfonamide (1,02 g) dissolved in a mixture of tetrahydrofuran (30 ml) and ethanol (8 ml). Add water (8 ml) and the monohydrate of lithium hydroxide (420 mg). The mixture was stirred at ambient temperature for 18 hours, podkalyvayut 2 M hydrochloric acid and extracted with diethyl ether (4 x 30 ml). The combined organic extract is dried (MgSO4) and evaporated. The remainder of the clean flash chromatography on a Mega Bond Elut column, using a gradient elution 0-100% utilized : hexane (50 ml), getting 2-[4-(2 - cyclopropylmethyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine - 3-sulfonamide (378 mg);

1H NMR (d6-DMSO): 0,23(kV, 2H), 0.52 in(m, 2H), 1,0(user. m, 1H), 2,24(s, 3H), of 2.51(partially superimposed DMSO), of 3.32(s, 3H), 7.23 percent(OSiR. d, 2H), 7,38(d, 2H), EUR 7.57(DD, 1H), 8,42(DD, 1H), 8,78(DD, 1H), from 10.1 to 10.7(user. s, 1H); mass spectrum (+ve ESP): 411,1(M+N)+.

The original 2-(4-cyclopropylmethyl)-N-(ISO-butoxycarbonyl)-N- (3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide was obtained as follows:

(i) 4-Bromophenylacetate (5,63 g), hydrazinoacetate (2.5 ml) and potassium hydroxide (3.33 g) is added to ethylene glycol (25 ml) and the mixture is heated to boiling point under reflux for 1 hour. The reaction mixture is cooled and partitioned between water (20 ml) and ethyl acetate (30 ml) and separate the organic layer. The aqueous layer was extracted with ethyl acetate (30 ml) and the combined organic phases are washed with 2 M hydrochloric acid (15 ml) and water (15 ml), then dried (MgSO4) and evaporated. The residue is cleaned by chromatography on a Mega Bond Elut column, elwira hexane, which gives 1-bromo-4-(cyclopropylmethyl) benzene (2.6 g);

1H NMR (CDCl3): 0,2(m, 2H), 0,55(m, 2H), 2,50(d, 2H), 7,14(d, 2H), 7,41(d, 2H); mass spectrum (EI+): 210(M)+.

(ii) 1-Bromo-4-(cyclopropylmethyl) benzene (2,11 g) is dissolved in the development in hexane (8,8 ml) with such speed, to ensure that the temperature did not exceed -65oC using the stirring, which is continued for another 30 minutes. Slowly add trimethylboron, keeping the temperature below -60oC, and the reaction mixture is stirred for additional 1.5 hours at -70oC. After warming to -5oC the reaction being removed by adding a saturated aqueous solution of ammonium chloride (50 ml) and the organic phase is separated. The aqueous layer was extracted with ethyl acetate (2 x 30 ml) and the combined organic phase is dried (MgSO4) and evaporated, obtaining 4-(cyclo-propylether)phenylboronic acid (1.52 g);

1H NMR (d6-DMSO): 0,2(d, 2H), 0,5(d, 2H), 0,9-of 1.07(m, 1H), 2,5 (partially overlapped by DMSO), 7,2(d, 2H), 7.7(d, 2H); mass spectrum (-ve ESP): 175 (M-H)-.

(iii) 4-(Cyclopropylmethyl)bendovervideo acid (1.5 g), 2-chloro-N-isobutoxide-N-(3-methoxy-5-methylpyrazine-2 - yl)pyridine-3-sulfonamide (2,99 g) and sodium carbonate (912 mg) are added to a mixture of toluene (66 ml), ethanol (33 ml) and water (24 ml). The mixture obeskislorozhennuju, alternately barbotine argon through it and vacuuming (3 cycles) and add tetrakis(triphenylphosphine) palladium (0) (347 mg). The reaction mixture is heated to 80oC 18 hours with efficient stirring and, after cooling, add ethyl acetate (50 ml) and water (30 the basics washed with salt solution (15 ml), dried (MgSO4) and evaporated. The residue is cleaned by chromatography on a Mega Bond Elut column, using gradient elution (0-100% ethyl acetate in hexane, obtaining 2-(4-cyclopropylmethyl)-N- (isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine - 3-sulfonamide (1.85 g);

1H NMR (d6-DMSO): 0,25(kV, 2H), 0,54(m, 2H), of 1.03(m, 1H), 1,64(m, 1H) to 2.55(s, 3H), 2,60(d, 2H), 3,83(d, 2H), 3,98(s, 3H), 7,33(d, 2H), 7,46(d, 2H), to 7.77(DD, 1H), 8,15(s, 1H), 8,10-8,95(m, 2H); mass spectrum (+ve ESP): 511 (M+N)+.

Example 67

Racemic 2-[4-(2-carboxypropyl)phenyl] -N- (3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (50 mg) obtained by the method of example 58, divided into separate essentially optically pure isomers by GHWR small aliquot on a Chiralpak A. D. chiral column, eluruumi a mixture of hexane : ethanol : triperoxonane acid (85:15:0.1 to). The fractions containing the isomer with less retention time, unite, the solvent evaporated, receiving an isomer of A 2-[4-(2-carboxypropyl) phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida (2.5 mg); 99% optical purity established analytical chiral GHUR on Chiralpak A. D. chiral column, retention time 10,832 minutes, elution with a mixture of hexane : ethanol : triperoxonane acid (85:15:0,1) at a flow rate of 1 ml/min, ismaterial evaporated, getting the Isomer 2-[4-(2-carboxypropyl)phenyl] -N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida (1.1 mg); 91% optical purity established analytical chiral GHUR on a chiral column Chiralpak A. D., retention time 12,336 minutes, elution with a mixture of hexane : ethanol : triperoxonane acid (85:15:0,1) at a flow rate of 1 ml/min, measuring at a wavelength of 240 nm.

Example 68

2-[4-(2-Carboxy-2-methylpropyl " phenyl] -N-(3 - methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (229 mg) obtained in example 64, dissolved in dry dimethylformamide (6 ml) in an argon atmosphere and add sodium bicarbonate (42 mg) and methyliodide (30 μl). The reaction mixture is stirred for 18 hours and add water (20 ml). The solvent is decanted and the resulting solid product is dissolved in ethyl acetate (30 ml), dried (MgSO4) and evaporated. The residue is triturated with diethyl ether (15 ml) and filtered, obtaining 2-[4-(2-methoxycarbonyl-2-methylpropyl " phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide (36 mg);

1H NMR (CDCl3): of 1.20(s, 6H), 2.40 a(s, 3H), of 2.75(s, 3H), of 2.92(s, 2H), 3,80(s, 3H), of 7.23(d, 2H), 7,41(DD, 1H), 7,54(d, 2H), 7,19(s, 1H), 8,48(DD, 1H), 8,81(DD, 1H); mass spectrum (+ve ESP): 471,2 (M+N)+.

Example 69

2-[4-(2-Carboxy-2-methylpropyl " phenyl] -N-(3 - methoxy-5-methylpyrazine-vannoy sulfuric acid (5 drops). The reaction mixture is heated to boiling point under reflux for 4 hours, cooled, alkalinized to pH 8 by addition of saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 x 10 ml). The combined organic phases are evaporated and the residue is cleaned by chromatography on a Mega Bond Elut column (1 g), elwira with ethyl acetate in hexane gradient 0-100%, which gives 2-[4-(2 - propoxycarbonyl-2-methylpropyl)-phenyl]-N-(3-methoxy-5 - methylpyrazine-2-yl) pyridine-3-sulfonamide (24 mg);

1H NMR (CDCl3): of 0.94(t, 3H), of 1.20(s, 6H), of 1.66(q, 2H), 2,28(s, 3H), of 2.92(s, 2H), of 3.84 (s, 3H), of 4.05(t, 2H), 7,14(user. d, 2H), 7.24 to (partially overlaps CHCl3), of 7.48(DD, 1H), 8,66(DD, 1H), 8,79(DD, 1H); mass spectrum (+ve ESP): 499,1 (M+N)+.

Example 70

60% Dispersion of sodium hydride in mineral oil (50 mg) is suspended in dry dimethylformamide (10 ml) and added in one portion to 2-amino-5-chloro-3-methoxypyrazine (obtained according to example 5(a-d)) (100 mg). The mixture was stirred at ambient temperature for 45 minutes, cooled to 0oC and added slowly at 0oC solution of 4-nitrophenyl-2-(4-acetylphenyl)pyridine-3-sulfonate (250 mg) in dry dimethylformamide (10 ml).

The reaction mixture is allowed to warm to ambient temperature and stirred for 18 hours. Prov.hydrated layer is extracted with ethyl acetate (2 x 50 ml). The combined extracts dried (MgSO4), evaporated and the residue is cleaned by chromatography on a Mega Bond Elut column, elwira 25% ethyl acetate in isohexane. Get 2-(4-acetylphenyl)-N-(5-chloro-3 - methoxypyrazine-2-yl)pyridine-3-sulfonamide (35 mg); so pl. 225-226oC;

1H NMR (CDCl3): of 2.15(s, 3H), 3,85(s, 3H), 6.75 in(s, 1H), 7,45-to 7.6(m, 4H), 7.95 is-with 8.05(m, 2H), and 8.7(DD, 1H), cent to 8.85(DD, 1H).

The original 4-nitrophenyl-2-(4-acetylphenyl)pyridine-3-sulfonate get a way similar to that described in example 5(ii), but on the basis of 4-acetylphenylalanine acid (obtained by the method described in UK patent application GB 2276161) yield 54%;

1H NMR (CDCl3): 2,7(s, 3H), of 7.0 to 7.1(m, 2H), 7.5 to about 7.6(m, 1H), 7,7-7,8(m, 2H), and 8.0 to 8.1(m, 2H), and 8.1 to 8.2(m, 2H), 8,45(DD, 1H), and 9.0(DD, 1H); mass spectrum (+ve ESP): 399 (M+N)+.

Example 71

(Note: All parts by weight)

Compounds according to this invention can be introduced with a therapeutic or prophylactic purpose of a warm-blooded animal, such as man, in the standard form of pharmaceutical compositions, typical examples of which include the following:

(a) Capsule (for oral administration)

Active ingredient - 20

Powder lactose - 578,5

Magnesium stearate and 1.5

b) Tablets (for oral administration)

Aktywny,5

Magnesium stearate - 2,5

(C) Solution for injection (for intravenous injection)

Active ingredient - 0,05 - 1,0

Propylene glycol - 5,0

Polyethylene glycol (300) - 3,0 - 5,0

Purified water Up to 100%

d) Suspension for injection (intramuscular)

Active ingredient - 0,05 - 1,0

Methylcellulose - 0,5

Twin 80 - 0,05

Benzyl alcohol - 0,9

Benzylaniline - 0,1

Purified water Up to 100%

Note: the Active ingredient is usually a connection of one of the examples above, or its pharmaceutically acceptable salt. The compositions of the tablets and capsules may be coated accepted way to change or delay the dissolution of the active ingredient. For example, they can be covered with conventional absorbable in the gastrointestinal tract sheath.

The chemical formula

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5

1. Derivatives of N-heteroaryl-pyridinesulfonamide formula I

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in which one of the A1and3represents nitrogen and the other represents CH; each AND2and4represent CH;

AG represents a phenyl group which is either not locked or has one(1-4C)alkyl]amino(1-6C)alkyl, N, N-[di(1-4C)alkyl] amino(1-6C)alkyl, carboxy(1-6C)alkyl, (1-6C)-alkoxycarbonyl(1-6C)alkyl, N-(1-6C)allylcarbamate(1-6C)alkyl, N-(1-6C)allylcarbamate(1-6C)alkyl, carboxy(1-6C)alkoxy, (2-6C)alkenyl, carboxy(2-6C)alkenyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy, (2-6C)alkenylamine(1-6C)alkyl, (1-4C)alkoxy(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkoxy(1-6C)alkyl, carboxy(1-6C)alkoxy(1-6C)alkyl, hydroxy(1-6C)alkoxy(1-6C)alkyl, (3-6C)cycloalkyl, (3-8C)cycloalkyl(1-6C)alkyl, pyridyl(1-6C)alkoxy(1-6C)alkyl, halogen, hydroxy, (1-6C)alkoxycarbonyl, (1-6C)alkanoyl, (1-6C)alkylthio, (1-6C)alkanolamine, five-membered heterocyclyl containing 2 or 3 heteroatoms independently selected from nitrogen and oxygen, six-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, and the group-NRaRb, in which Ra and Rb are independently selected from hydrogen and (1-6C)alkyl or the group NRaRb taken together form morpholino ring;

IN1denotes hydrogen, (1-4C)alkyl, halogen and (1-4C)alkoxy; m is 1, 2 or 3; the ring containing W, X, Y, and Z and bearing the substituent R1selected from: (a) a ring in which W represents nitrogen; X is CH; Y is nitrogen and a is CRyin which Ryrepresents (1-4C)alkoxy, and the substituent R1AET (1-4C)alkoxy; X is nitrogen; Y is nitrogen and Z is CH, and the substituent R1represents a halogen, and where any of the said phenyl or benzene, or heterocyclyl fragments Deputy on AG can be unsubstituted or carries one Deputy, which is independently selected from (1-4C)alkyl or carboxy, or its N-oxide, or its pharmaceutically acceptable salt.

2. Connection on p. 1, where AG represents a phenyl group which is either not substituted or carries 1 Deputy, which is independently selected from the group comprising methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, sec-butyl, aminomethyl, 2-amino-ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy-ethyl, 3-hydroxy-2-methylpropyl, 1-hydroxy-2-methylpropyl, methylaminomethyl, 2-(methylamino)ethyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxypropyl, 2-carboxy-2-methylpropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(methoxycarbonyl)ethyl, 2-(methoxycarbonyl)ethyl, 1-(etoxycarbonyl)ethyl, 2-(etoxycarbonyl)ethyl, 2-(methoxycarbonyl)propyl, 2-(etoxycarbonyl)propyl, 2-methoxycarbonyl-2-methylpropyl, 2-propoxycarbonyl-2-methylpropyl, acetoxymethyl, pivaloyloxymethyl, 3-acetoxy-2-methylp is carboxymethylthio, vinyl, allyl, 1-propenyl, 2-butenyl, N-methylcarbamoylmethyl, N-ethylcarbodiimide, N-propylbromoacetate, N-butylcarbamoyl, 2-methyl-N-propylboronic, 2-methyl-N-ethylcarboxylate, 2-methyl-N-BUTYLCARBAMATE, 2-methyl-3-(N-propylgallate)propyl, 2-methyl-3-(N-butylcarbamoyl)propyl, 2-carboxyethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hydroxyethoxy, 1 hydroxyethoxy, 2 hydroxyethoxy, 2-hydroxy-2-methylpropoxy, 2-hydroxy-1,1-dimethylmethoxy, allyloxymethyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, (1-methoxycarbonyl-1-methyl)ethoxymethyl, (1-etoxycarbonyl-1-methyl)ethoxymethyl, carboxymethoxy, (1-carboxy-1-methyl)ethoxymethyl, (1 carboxymethoxy)methyl, (1-methyl-2-hydroxyethoxy)methyl, (1,1-dimethyl-2-hydroxyethoxy)methyl, (2-hydroxyethoxy)methyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, pyridylcarbonyl, 2-(pyridyloxy)ethyl, fluorine, chlorine, bromine, iodine, methoxycarbonyl, etoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, methylthio, ethylthio, acetamido, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl/SUB> independently selected from the group which consists of hydrogen, methyl, ethyl, propyl, isopropyl, or the group-NRaRbtaken together, forms morpholino ring; B1represents hydrogen; and the ring containing W, X, Y, and Z, and support R1selected from: (a) a ring in which W represents nitrogen; X is CH; Y is nitrogen and Z is CRywhere Ryis methoxy, ethoxy or propoxy; and the substituent R1represents chlorine, bromine, iodine, methyl, ethyl; (b) a ring in which W is CRzwhere Rzrepresents methoxy; X is nitrogen; Y is nitrogen and Z is CH; and the substituent R1represents chlorine, bromine, iodine; and where any of the said phenyl, benzene, or heterocyclyl fragments Deputy on AG can be unsubstituted or carry one Deputy, which is selected from methyl and carboxy; or its N-oxide, or its pharmaceutically acceptable salt.

3. Connection on p. 1, or its N-oxide, or pharmaceutically acceptable salt, or prodrug, as defined above, but excluding compounds, their N-oxides, their pharmaceutically acceptable salts, in which AG carries N-(1-6C)allylcarbamate(1-6C)alkyl, hydroxy(1-6C)alkoxy, (2-6C)alkenylamine(1-6C)already(1-6C)alkoxy(1-6C)alkyl, substituted or unsubstituted five-membered heterocyclyl containing 2 or 3 heteroatoms independently selected from nitrogen and oxygen; a substituted or unsubstituted six-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or morpholino ring.

4. Connection on p. 1, in which the group AG is phenyl, substituted in paraprotein Deputy selected from the group comprising (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio, N,N-di(1-4C)alkylamino, carboxy(1-4C)alkyl, carboxy(1-4C)alkoxy, halogen, (2-4C)alkenyl, hydroxy(1-4C)alkyl, (2-4C)alkanolamine, (2-4C)alkanoyl, N-(1-4C)alkylamino, (1-4C)alkoxycarbonyl and (1-4C)alkoxy(1-4C)alkyl.

5. Connection on p. 1, in which a group of AG is phenyl, substituted in paraprotein Deputy, selected from the group comprising a pyridyl, pyrimidinyl, oxadiazolyl, 3-methylisoxazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl, pyridyl(1-4C)alkoxy(1-4C)alkyl, (2-4C)alkenylamine(1-4C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkoxy(1-2C)alkyl, carboxy(1-4C)alkoxy(1-2C)alkyl, hydroxy(1-4C)alkoxy(1-2C)alkyl, hydroxy(1-4C)alkoxy(1-4C)alkyl, carboxy(1-4C)alkyl, carboxy(2-4C)alkenyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, N-(1-4C)allylcarbamate(1-4C)e group AG represents phenyl, substituted in paraprotein Deputy selected from the group comprising (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio, N,N-di(1-4C)alkylamino and carboxy(1-4C)alkyl.

7. The compound of formula II

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where B1, m, W, Ar, X, Y, Z, and R1take any of paragraphs.1 - 6 values, or its pharmaceutically acceptable salt.

8. Connection on p. 7, in which the ring containing W, X, Y, and Z, and support Deputy; R1denotes the ring, where W represents nitrogen; X is CH; Y is nitrogen and Z is CRywhere Ryrepresents (1-4C)alkoxy, and the substituent R1represents halogen or (1-4C)alkyl.

9. Connection on p. 8, where m is equal to zero, AG represents phenyl that carries parasagittal, which is selected from the group comprising (1-4C)alkyl, hydroxy(1-4C)alkyl, (2-6C)alkenyl, 3-pyridyl, 2-pyrimidinyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, hydroxy(1-4C)alkoxy(1-2C)alkyl, hydroxy(1-4C)alkoxy, (1-4C)alkylcarboxylic(1-4C)alkyl, carboxy(1-4C)alkyl, (2-4C)alkanoyl, (3-6C)cycloalkyl(1-2C)alkyl and (1-4C)alkoxycarbonyl(1-4C)alkyl, and where Ryis methoxy, and R1represents methyl, chlorine or bromine.

10. The compound of formula I under item 1, which is selected from the group including:

2-(4 is utility)pyridine-3-sulfonamide;

2-[4-(1-carboxymethoxy)phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-(4-ethylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-(4-tert-butylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-[4-(3-hydroxy-2-methylpropyl " phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-(4-acetylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-[4-(1-hydroxyethyl)phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-(4-allylphenol)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide and

2-[4-(2-hydroxy-2-methylpropyl " phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

or their pharmaceutically acceptable salts.

11. The compound of formula I under item 1, which is selected from the group including:

N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[3-pyridyl] phenyl)pyridine-3-sulfonamide;

N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[2-pyridyl] phenyl)pyridine-3-sulfonamide;

N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxidiazol-2-yl] phenyl)pyridine-3-sulfonamide;

N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,2,4-oxidiazol-2-yl] phenyl)pyridine-3-sulfonamide;

N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[pyrimidine-2-yl] phenyl)pyridine-3-sulfonamide;

2-{ 4-[(2-hydro is(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-[4-(3-acetoxy-2-methylpropyl " phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-[4-(2-carboxypropyl)phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-[4-(2-methylpropanoyl)phenyl]-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-[4-(2-carboxy-2-methylpropyl " phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide;

2-(4-cyclopropylmethyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide and

2-[4-(2-propoxycarbonyl-2-methylpropyl " phenyl] -N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide

or their pharmaceutically acceptable salts.

12. The compound of formula I or II according to any one of the preceding paragraphs in the form of a salt, which is selected from salts with bases, which give physiologically acceptable cations, and salts of the compounds of formula I or II, having a sufficiently basic properties with acids forming physiologically acceptable anions.

13. Pharmaceutical composition for combating one or more effects of endothelin on the body of man or other warm-blooded animal, which comprises a compound of formula I or II or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 12 antagonistically aim.

14. The method of obtaining the compounds of formula I or its pharmaceutically acceptable salts, characterized in that the detaching of the formula III

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where P represents a protective group, is subjected to unprotect, then the compound of the formula I can be converted into another compound of formula I by conventional mutual transformations of functional groups; and then the protective group, if present, may be removed; and then, if you want pharmaceutically acceptable salt of the compounds of formula I, it is produced by interaction with the appropriate acid or base, giving a physiologically acceptable ion, or any other accepted method of obtaining salts; and where A1, A2, A3, A4B1, m, Ar, W, X, Y, Z, and R1take the above values for PP.1 to 9, except where otherwise indicated.

15. The method of obtaining the compounds of formula I or its pharmaceutically acceptable salt, wherein the amine of formula VII

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or its salt with an alkaline metal is subjected to interaction with sulphonylchloride formula XI

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where Hal is a halide group,

or sulfonate of formula XIa

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where Re is the electron-deficient phenyl is th mutual transformations of functional groups; then the protective group, if present, may be removed; and then, if you want pharmaceutically acceptable salt of the compounds of formula I, it is produced by interaction with the appropriate acid or base, giving a physiologically acceptable ion, or any other accepted method of obtaining salt,

and where AND1AND2AND3AND4IN1, m, Ar, W, X, Y, Z, and R1take the above values for PP.1 to 9, except where otherwise indicated.

16. The compound of formula III

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where A1, A2, A3, A4B1, m, Ar, W, X, Y, Z, and R1take the above values for PP.1 to 9, and p represents a protective group.

17. The way to counter one or more effects of endothelin on human body or the body of another warm-blooded animal in need of such treatment, comprising the introduction of a specified person or another warm-blooded animal antagonistically - effectivehow against endothelioma receptors amount of the compounds of formula 1 or its pharmaceutically acceptable salt under item 1.

Priority signs:

07.06.1995 - all the features of the invention set forth in paragraphs.1, 7, 13, 14, 15, 16, 17;
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Same patents:

The invention relates to new pyrimidine compounds or their salts with pharmaceutically acceptable acids and pharmaceutical compositions based on them

The invention relates to novel triazole compounds of the General formula (1), where a denotes a linear or branched C1-C18-alkylenes group which may comprise at least one group which is selected from O, S, CONH, COO,3-C6-cycloalkene or double or triple bond; In denotes the radical of formula (a), (b) or (C); R1denotes H, NH2WITH3-C6-cycloalkyl or1-C8-alkyl, which is not substituted or substituted OS1-C8-alkyl; R2denotes H, HE, C1-C8-alkyl, C3-6-cycloalkyl, CF3, CN, NR3R4, SR3or CO2R3where R3denotes N or C1-C8-alkyl, a R4denotes H, C1-C8-alkyl, or COR3where R3stands WITH1-C8-alkyl; Ar represents naphthyl, phenyl with 1-2 substituent selected from C1-C8-alkyl, CF3, CHF2, NO2, SR3, SO2R3where R3means1-C8-alkyl; and pyridyl, pyrimidyl or triazinyl, which have from 1 to 3 substituents selected from C1-C8-alkyl, C2-C6-alkenyl, C2-C6-quinil, halogen, CN, CF3, OR4where R43-C6-lalouche possibly condensed, phenylalkylamine or 5-membered aromatic heterocycle with 1 to 2 nitrogen atoms, which may be condensed with a benzene ring

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of piperidine F.-ly (I), where R1- aryl, heterocyclyl, R2is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridine, diazines, triazoles, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl or furyl which may be substituted with halogen, hydroxy, cyano, CF3, alkyl, R3-H, hydroxy, alkoxy, alkenylacyl, R4-H, alkyl, alkenyl, alkoxy, benzyl, oxo, Q is ethylene or absent, X is a bond, oxygen, sulfur, W is oxygen or sulfur, Z - alkylen, albaniles, -Oh, -S; n = 1, m = 0 or 1

The invention relates to arylalkylamines formula I, where In - unsubstituted pyridyl, pyrazinyl, isoxazolyl or thienyl; Q - CH2; X - CH2or S; R1and R2each - H; and R3- OR5; R4OA; R5- Or cycloalkyl with 4-6 C atoms; And the alkyl with 1-6 C-atoms, and their physiologically acceptable salts

The invention relates to new substituted pyrimidinediamine or alkylating compounds, their pharmaceutically acceptable salts, hydrates, N-oxides and method for inhibition of reverse transcriptase of the virus

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Antiarrhythmic drug // 2163807
The invention relates to medicine, particularly cardiology

The invention relates to iododerma biologically active compositions containing iodine and halides of nitrogenous bases of the formula I, where the values of the radicals a, b, C, R, X and m are specified in the claims

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

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

14 cl, 36 ex

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