4-(geterotsiklicheskikh)-5-methoxy-6-(2-methoxyphenoxy)- 2-phenyl - or pyridinediamine as antagonists of the endothelin receptor and pharmaceutical composition

 

(57) Abstract:

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction. In the compounds of formula (I) R1denotes pyridyl, thiazolyl, optionally substituted with halogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl; R2means R21, -Y-R22or monovalent aromatic 5-membered carbocyclic radical containing at least one heteroatom selected from nitrogen and oxygen, despite the fact that this carbocyclic radical may be optionally substituted lower alkyl; R21denotes cyano, hydroxy-lower alkyl, carboxy, -C(O)NRaRb, -(CH2)1-4OTHERc, -(CH2)1-4NHC(O)NH(CH2)0-3CH3, amidino, hydroxyamino, lower alkoxycarbonyl or hydroxy-lower alkoxycarbonyl; R22denotes hydrogen, lower alkanoyl, carboxy-lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl-NISSEI alkyl; Radenotes hydrogen or lower alkyl, optionally substituted hydroxy-group; Rbdenotes hydrogen or lower alkyl; Rcdenotes hydrogen, acetyl or lower alkylsulfonyl; X represents-CH - or-N-; and Y represents-O-, -NH-. The invention also relates to a pharmaceutical composition having inhibitory ability against endothelioma receptors, comprising the compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant. 2 S. and 11 C.p. f-crystals, 5 PL.

The present invention relates to heterocyclic sulfonamides and their use as medicines. More specifically the present invention relates to compounds of formula (I)

where R1denotes pyridyl, pyrrolyl, imidazolyl, thiazolyl, thiazolyl or oxazolyl, optionally substituted with halogen, (ness.)by alkyl, hydroxy(ness.)the alkyl or (ness.)alkenyl;

R2means R21, -Y-R22or heterocyclyl where heterocyclyl optionally can be substituted one, two or three substituents, independently of one another selected from the series comprising hydroxy, (ness.)alkenyl, amino, (ness.)alkanolamine, (ness.)alkoxide is, carboxy, -C(O)NRaRb, -(CH2)1-4OTHERc, -(CH2)1-4NHC(O)NH(CH2)0-3CH3, amidino, hydroxyamino, (ness.)alkoxycarbonyl or hydroxy(ness.)alkoxycarbonyl;

R22denotes hydrogen, (ness.)alkanoyl, carboxy (ness.)alkyl, (ness.)alkoxycarbonyl, (ness.)alkoxycarbonyl-(ness.)alkyl, carbarnoyl(ness.)alkyl, di(ness.)allylcarbamate-(ness.)alkyl, alyl, (ness.)alkyl or hydroxy (ness.)alkyl;

Radenotes hydrogen or (ness.)alkyl, optionally substituted by hydroxy or (ness.)alkoxygroup;

Rbdenotes hydrogen or (ness.)alkyl;

Rcdenotes hydrogen, acetyl or (ness.)alkylsulfonyl;

X represents-CH - or-N-; and

Y represents-O-, -NH-;

and their pharmaceutically acceptable salts and esters.

The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant.

The present invention also relates to the use of such compounds for the preparation of drugs intended for the treatment and/or prevention of diseases associated with abnormal vessel the teachings of the compounds of formula (I).

In addition, the present invention relates to a method of prophylactic and/or therapeutic treatment of diseases associated with abnormal vascular tone and endothelial dysfunction, which provides for the introduction of the compounds of formula (I) human or animal.

The sulfonamides of the present invention are inhibitors of endothelial receptors. As a result, they can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction.

In EP 0713875 and EP 0799209 described sulfonamidnuyu derivatives as inhibitors of endothelial receptors. Thus compounds of the present invention have high antagonistic activity in vitro and characterized by unexpectedly high plasma levels after oral administration, resulting in high efficiency in vivo by oral administration.

The following definitions are provided to illustrate and clarify the meaning and scope of various terms used in the description of the invention, unless otherwise indicated.

In the context of the present description, the term "(ness.)" used to refer to groups containing from 1 to 7, preferably from 1 to 4 adamowski hydrocarbon radical, comprising from 1 to 20 carbon atoms, preferably from 1 to 16 carbon atoms.

The term "(ness.) alkyl" refers to monovalent alkyl radicals of branched or straight chain, containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

The term "(ness.)alkenyl" means (ness.)alkyl group containing one or more double bonds in alkalinous chain.

The term "(ness.)alkoxy" denotes the group-O-R', where R' denotes (ness.) alkyl.

The term "carboxy" refers to a group-C(O)HE.

The notion of "formylamino" denotes a formyl group attached to aminogroup, i.e.,- NHC(O)H.

The term "(ness.)alkanoyl" denotes the group-C(O)-R', where R' denotes hydrogen or (ness.)alkyl.

The term "(ness.)alkanolamine" means (ness.)alkanoyloxy group attached to aminogroup.

The term "carboxy(ness.)alkyl" means a group-R'-C(O)OH, where R' denotes (ness.)alkyl.

The term "(ness.)alkoxycarbonyl" denotes the group-C(O)-R', where R' denotes (ness.)alkoxy.

The term "(ness.)al is I.

The concept of "carbarnoyl(ness.)alkyl" means a group-R'-C(O)NH2where R' denotes (ness.)alkyl.

The term "di(ness.)allylcarbamate-(ness.)alkyl" means a group-R'-C(O)N(R")R"', where R', R" and R"' each, independently of one another denotes (ness.)alkyl group.

The term "acetyl" refers to the group-COCH3.

The concept of "acetylamino" denotes the group-NHCOCH3.

The term "(ness.)alkylsulfonyl refers to the group-SO2-R', where R' denotes (ness.)alkyl.

The concept of "heterocyclyl" means ninasimone or aromatic, preferably aromatic, monovalent 5 - or 6-membered carbocyclic moiety containing at least one heteroatom, i.e., nitrogen, oxygen, or sulfur, or a combination thereof. Examples of such heterocyclyl fragments are pyrimidinyl, imidazolyl, oxadiazolyl, oxazolyl and thiazolyl.

The term "halogen" denotes fluorine, chlorine, bromine and iodine, and chlorine is preferred.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of formula (I) with inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, postorna acid, methansulfonate acid, para-toluensulfonate acid, etc. which are non-toxic to living organisms. They also include the salts with inorganic or organic bases, such as alkali metal salts, for example salts of sodium and potassium, salts of alkaline earth metals, for example calcium salts and magnesium salts of N-methyl-D-glutamine and salts of amino acids such as arginine, lysine, etc.

More specifically the present invention relates to compounds of the above formula (I), where

R1denotes pyridyl, pyrrolyl, imidazolyl, thiazolyl, thiazolyl or oxazolyl, optionally substituted with halogen, (ness.)by alkyl, hydroxy(ness.)the alkyl or (ness.)alkenyl. IN R1the term "(ness.)alkyl" preferably means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, more preferably methyl, isopropyl or tert-butyl, most preferably methyl or isopropyl. The term "hydroxy(ness.)alkyl" preferably refers to hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or-C(CH3)2OH, more preferably hydroxymethyl or-C(CH3)2OH. The term "(ness.)alkenyl" preferably denotes vinyl, 1-PDEC is respectful fragments R1are pyridyl or thiazolyl, optionally substituted with halogen, (ness.)by alkyl, hydroxy(ness.)the alkyl or (ness.)alkenyl. More preferred are pyridyl or thiazolyl, optionally substituted (ness.)the alkyl, such as stands or isopropyl, or (ness.)alkenyl, such as isopropanol. Most preferred are 5-methylpyridin-2-yl, 5-isopropylpyridine-2-yl, 5-isopropylpyridine-2-yl and 5-methylthiazole-2-yl.

R2means R21, -Y-R22or heterocyclyl where heterocyclyl optionally can be substituted one, two or three substituents, independently of one another selected from the series comprising hydroxy, (ness.)alkenyl, amino, (ness.)alkanolamine, (ness.)alkoxycarbonyl, (ness.)alkyl or hydroxy(ness.)alkyl. These definitions in the Vice heterocyclyl fragments in R2the term "(ness.)alkenyl" preferably denotes vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl or 3-butenyl, more preferably allyl. The term "(ness.)alkanolamine" preferably refers to formylamino, acetylamino or propionamido, more preferably, formylamino or acetylamino. The term "(ness.)alkoxycarbonyl" preferably the seat is carbylamine, solutionline or tert-butoxycarbonylamino, more preferably tert-butoxycarbonylamino. The term "(ness.)alkyl" preferably means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, more preferably methyl, ethyl or isopropyl, most preferably methyl. The term "hydroxy(ness.)alkyl" preferably represents hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl, more preferably hydroxymethyl.

Preferred heterocyclyl fragments in R2are 2-pyrimidinyl, 2-imidazolyl, [1,2,4]oxadiazol-3-yl, 2-oxazolyl and 2-thiazolyl, more preferably 2-pyrimidinyl, 2-imidazolyl and [1,2,4]oxadiazol-3-yl, most preferably [1,2,4]oxadiazol-3-yl. These heterocyclyl fragments in R2optionally can be substituted one, two or three substituents, independently of one another selected from the series comprising (ness.)alkyl, hydroxy(ness.)alkyl, (ness.)alkenyl, (ness.)alkoxycarbonyl, (ness.)alkanolamine, hydroxy or amino, preferably (ness.)alkyl, for example methyl, isopropyl, tert-butoxycarbonylamino, formylamino, acetylamino, hydroxy, amino or hydroxymethyl, more preferably (yavlyaetsya [1,2,4]oxadiazol-3-yl, optionally substituted by a hydroxy-group or (ness.)the alkyl, for example the stands.

R21denotes cyano, hydroxy(ness.)alkyl, carboxy, -COONRaRb, -(CH2)1-4OTHERc, -(CH2)1-4NHC(O)NH(CH2)0-3CH3, amidino, hydroxyamino, (ness.)alkoxycarbonyl or hydroxy(ness.)alkoxycarbonyl. IN R21the term "hydroxy(ness.)alkyl" preferably represents hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl, preferably hydroxymethyl. "-(CH2)1-4NHC(O)NH(CH2)0-3CH3" preferably denotes-CH2NHC(O)NHCH2CH3. The term "(ness.)alkoxycarbonyl" preferably denotes methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, second-butoxycarbonyl or tert-butoxycarbonyl, more preferably methoxycarbonyl or etoxycarbonyl. The term "hydroxy(ness.)alkoxycarbonyl" preferably denotes 2-hydroxyethoxyethyl and 3-hydroxypropionitrile, more preferably 2-hydroxyethoxyethyl.

Preferred substituents R21are cyano, hydroxy(ness.)alkyl, for example hydroxymethyl, carboxy, (ness.)alkoxycarbonyl, for example IU is 2NHC(O)NHCH2CH3where Ra, Rband Rcmatter referred to in paragraph 1 of the claims. Most preferable are cyano, carboxy, carbarnoyl, (ness.)alkoxycarbonyl, such as methoxycarbonyl or etoxycarbonyl, acetamidomethyl, methylsulfonylamino or hydroxy(ness.)alkyl, for example hydroxymethyl.

R22denotes hydrogen, (ness.)alkanoyl, carboxy (ness.)alkyl, (ness.)alkoxycarbonyl, (ness.)alkoxycarbonyl-(ness.)alkyl, carbarnoyl(ness.)alkyl, di(ness.)allylcarbamate-(ness.)alkyl, alyl, (ness.)alkyl or hydroxy(ness.)alkyl. IN R22the term "(ness.)alkanoyl" preferably denotes acetyl, propionyl or butyryl, most preferably acetyl. The term "carboxy(ness.)alkyl" preferably denotes a carboxymethyl, carboxyethyl, carboxypropyl or carboxybutyl, most preferably carboxymethyl. The term "(ness.)alkoxycarbonyl" preferably denotes methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, second-butoxycarbonyl or tert-butoxycarbonyl, more preferably n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, second-butoxycarbonyl or tert-butoxyethanol denotes methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl or ethoxycarbonylethyl, more preferably methoxycarbonylmethyl or ethoxycarbonylmethyl. The concept of "carbarnoyl(ness.)alkyl" preferably refers to carbamoylmethyl, carbamoylethyl or carbamoylmethyl, more preferably carbamoylmethyl. The term "di(ness.)allylcarbamate- (ness.)alkyl" preferably refers to dimethylcarbamoyl, ethylmethylketone, dimethylcarbamoyl, ethylmethylketone or diethylcarbamoyl, most preferably dimethylcarbamoyl. The term "(ness.)alkyl" preferably means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, more preferably methyl or ethyl, most preferably methyl. The term "hydroxy(ness.)alkyl" preferably denotes a hydroxyethyl or hydroxypropyl, more preferably hydroxyethyl.

Preferred substituents R22are hydrogen, (ness.)alkyl, carboxymethyl, (ness.)alkoxycarbonyl-(ness.)alkyl, such as methoxycarbonylmethyl or ethoxycarbonylmethyl, carbamoylmethyl, dimethylcarbamoyl, acetyl or hydroxy(ness.)alkyl such as hydroxyethyl. Most preferred are hydrogen, (ness.)Ala is l, or hydroxy(ness.)alkyl such as hydroxyethyl.

Preferred options for implementation of R2are the substituents R21and-Y-R22.

Radenotes hydrogen or (ness.)alkyl, optionally substituted by hydroxy or (ness.)alkoxygroup. IN Rathe term "(ness.)alkyl" preferably means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, more preferably methyl or ethyl, most preferably methyl. The term "(ness.)alkoxy" preferably represents methoxy, ethoxy, propoxy or butoxy, more preferably methoxy.

Preferred substituents Raare hydrogen, methyl, ethyl, hydroxyethyl or methoxyethyl, most preferably hydrogen or methyl.

Rbdenotes hydrogen or (ness.)alkyl. IN Rbthe term "(ness.)alkyl" preferably means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, more preferably methyl or ethyl, most preferably methyl.

Preferred substituents Rbare hydrogen, methyl and ethyl, more preferably hydrogen or methyl, most preferably hydrogen.

Rcoboznachaet the AET methylsulphonyl, ethylsulfonyl, propylsulfonyl or butylsulfonyl, more preferably methylsulphonyl or ethylsulfonyl, most preferably methylsulphonyl.

Preferred substituents Rcare acetyl or methylsulphonyl, most preferably acetyl.

X represents-CH - or-N-. In a preferred embodiment, Deputy X is-N-. In another preferred embodiment of the invention Deputy X is-CH-.

Y represents-O - or-NH-. In a preferred embodiment of the invention Deputy Y is-O-.

Especially preferred compounds of formula (I) are:

4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid,

methyl ester of 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid,

[2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

ethyl ester of 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl] pyridine-2-carboxylic acid,

methyl e is slots

N-hydroxy-4-14-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxamidine,

{6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl[1,2,4]oxadiazol-3-yl) pyridine-4-yl]pyrimidine-4-yl}amide 5-methylpyridin-2-sulfonic acid,

[2-[2-(methanesulfonylaminoethyl)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-[2-(methanesulfonylaminoethyl)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

{6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl[1,2,4]oxadiazol-3-yl)pyridine-4-yl]pyrimidine-4-yl}amide 5-isopropylpyridine-2-sulfonic acid,

[2-(2-lepirudin-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-[3-(2-hydroxyethoxy)phenyl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid and

[2-[2-(2-hydroxyethoxy)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

[2-(2-hydroxypyridine-4-yl)-6-3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenoxy] acetic acid,

[2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

N-{4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-ylmethyl]ndimethylacetamide,

4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

isopropyl ester 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

ethyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

[2-[2-(2-hydroxyethoxy)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulfonic acid,

amide 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5- (2-methoxyphenoxy)pyrimidine-2-yl] pyridine-2-carboxylic acid,

N-hydroxy-4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl] pyridine-2-carboxamidine,

3-[4-methoxy-5-(2-methoxyphenoxy-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenyl ester of acetic acid,

methyl ester of 4-[4-(5-isopropylpyridine ketelbey ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic-acid.

More preferred compounds of formula (I) are:

[2-[3-(2-hydroxyethoxy)phenyl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-(2-lepirudin-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

4-[4-methoxy-5-(2-methoxyphenoxy-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid,

methyl ester of 4-[4-methoxy-5-(2-methoxyphenoxy-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid,

[2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

ethyl ester of 4-[4-methoxy-5-(2-methoxyphenoxy-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl] pyridine-2-carboxylic acid,

[2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

amide 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

Adilov the acid,

{6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl[1,2,4]oxadiazol-3-yl)pyridine-4-yl]pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid and

1-ecotoxicology ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid.

The most preferred compounds of formula (I) are:

4-[4-methoxy-5-(2-methoxyphenoxy-6-(5-methylpyridin-2-sulfonylamino) pyrimidine-2-yl] pyridine-2-carboxylic acid,

[2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

1-ecotoxicology ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid.

The compounds of formula (I) can be obtained according to the following methods:

a) For compounds of General formula (I), where X denotes-N-, by reacting according to the scheme 1 the compounds of formula (II) with trialkylsilanes and trialkylamines obtaining compounds of General formula (Ia).

Scheme 1

In the alternative in which abode of sodium methylate in Meon with the formation of appropriate iminoethylene intermediates of formula (IV), which can then be converted into compounds of formula (Ia) by treatment with base, such as NaH.

Scheme 1a

Cyano in the compounds of General formula (Ia) can be converted into karbamoilnuyu group by treatment with an aqueous solution of sodium hydroxide, which can then be converted into carboxypropyl by hydrolysis with dilute aqueous acid. Alternatively, the cyano may be converted into alkoxyimino using sodium alkoxide and then may be subjected to interaction in aqueous acidic media in the presence of a suitable alcohol with getting alkoxycarbonyl or in aqueous alkaline medium with the formation of carboxypropyl. In an alternative embodiment, methoxycarbonyl and carboxyprimaquine can be obtained, as described above, directly from the intermediate product of formula (IV).

Hydroxy(ness.)alkoxycarbonyl, or alkoxycarbonyl, or alkoxycarbonyl carrying a specific functional group (functionalized), as described above, can also be obtained from carboxypropanoyl and the corresponding alcohol by activation using the appropriate binding agents, such as lexapto nepizdin (DMAP), or using tarifitsiruemih agent such as 3-alkyl-1-pair-tolyltriazole, or by prior conversion of carboxyl groups in the acid chloride and subsequent treatment with alcohol. They can also be obtained from carboxypropanoyl by reacting with an appropriately substituted alkylhalogenide in the presence of a base such as potassium carbonate or 1,1,3,3-tetramethylguanidine, for example, using DMF as solvent.

Alkoxycarbonyl can be restored by using a metal hydride, such as LiAlH4or NaBH4in the presence of CaCl2getting hydroxymethyl.

The carboxyl group can be converted into a group of General formula (Ib) where R21denotes-C(O)NRaRbby interaction with the amine of the formula with otheraRband a suitable binding agent, such as 1,3-DICYCLOHEXYL-carbodiimide (DCCI) or BOP. The carboxyl group can also be converted using the Hoffmann rearrangement or Schmidt in compounds of General formula (IC), in which-Y-R22denotes-NH-R22where R22has the above values, and which can be derived from the amino (-Y-R22denotes-NH2good is K homolog, following the General procedure of synthesis of the Arndt-Eistert, resulting after interconversion of functional groups, as described above, can be obtained from compounds in which R21denotes hydroxy(ness.) alkyl.

Cyano formula (Ia) can be recovered by using gaseous hydrogen and containing the appropriate transition metal catalyst, such as palladium, obtaining after acetylation or processing alkylsulfonamides compounds of formula (IC), where R21denotes-CH2OTHERc. Higher homologues, in which R21represents -(CH)2-4OTHERccan be obtained from the above hydroxy(ness.)the alkyl well-known interconversion of functional groups.

In addition, cyano can be converted into hydroxyamide or amidinopropane by processing under standard conditions, respectively, with hydroxylamine or ammonia.

Compounds of General formula (I), where R2means heterocyclyl can be obtained:

(I) From the above gidroksietilirovannogo by closing the loop using an appropriate bearing carbon atom in position 1 of the structural Velia formic acid and/or their respective activated form, such as acetic anhydride, to obtain the similar known methods, optionally substituted [1,2,4] -oxadiazole.

(II) From the above amidinopropane by interacting with the corresponding optionally substituted structural elements, bearing carbon atom in position 2, such as optionally substituted chlorate or chloroacetaldehyde, obtaining optionally substituted imidazoles.

(III) From the above amidinopropane by interacting with appropriately functionalized bearing carbon atom in position 3 of the structural elements, such as the diethyl ester of malonic acid or 3-(dimethylamino)acrolein or malonaldehyde bis(dimethylacetal), with a well-known method of substituted pyrimidine.

(IV) From the above cyano - or methoxybenzophenone by condensation with an appropriately functionalized bearing carbon atom in position 2 of the structural elements, such as optionally substituted hydroxyacetone or 1-mercapto-2-propanone, obtaining optionally substituted oksazolov or thiazolo, or alternatively of carbamoyl or thiocarbamoyl and substituted chlorate or chloroacetaldehyde, working similarly to standard methods.

Compounds of General formula (I), where R2denotes unsaturated heterocycle, such as optionally substituted oxazoline or imidazoline, can be obtained from the above cyano - or alkoxyimino by condensation with optionally substituted by ethanolamine or Ethylenediamine similarly to the methods described in Tetrahedron Lett. 34(40), 6395 (1993).

Compounds of General formula (Ic), where Y denotes-O-, can be obtained from compounds of formula (II) by reacting with the corresponding functionalized alcohol using as reagent taillored in the presence of a base, such as triethylamine, at elevated temperatures similar to the method described in Zh. Org. Khim., volume 28, 430 (1991). Functional groups included in the alcohol fragment can then be converted to a well-known method.

Used original products if they are not known to obtain or are not described below, can be obtained by analogy with known processes or processes described below in the examples and generalized in scheme 2.

The main intermediate product of General formula (II) can be synthesized from 4-[4,6-Dave with the appropriate sulfonamide of General formula (VI) in a suitable solvent, such as DMSO or DMF, at room temperature or at elevated temperature and in the presence of a suitable base such as potassium carbonate, to obtain the chlorinated derivatives of General formula (VII).

Scheme 2

The corresponding sulfonamides can be used in the above reaction in the form of their pre-formed sodium or potassium salts. Then the compounds of formula (VII) can be converted by treatment with methanol to obtain an intermediate product of the formula (II).

The main intermediate product of General formula (III) can be obtained from 5-(2-methoxyphenoxy)-2-pyridin-4-yl)pyrimidine-4,6-diol (EP 0799209) according to scheme 2A through the introduction of carbamoyl in the interaction of the above pyridine derivative with formamide and an oxidizer, such as hydrogen peroxide, in an aqueous acid solution such as the solution of the sulfonic acid, in the presence of 15-40 mol.% salts of iron(II) obtaining the compounds of formula (VIII). Then this compound can be converted into a compound of formula (IX) by treatment removes water and halogenation agent such as POCl3, PCl5or SOCl2. Introduction sulfonamidnuyu fragment of General formula (VI) is the soup of the formula (VI) are already known from the literature, can be obtained analogously to known methods and/or can be obtained from the appropriate mercaptopropionic similar known sequence of reactions involving oxidation using Cl2in aqueous acidic medium, such as a dilute aqueous solution of Hcl, the corresponding sulphonylchloride, which can be converted to sulfonamides using liquid ammonia or aqueous ammonium hydroxide. The corresponding sodium or potassium salts can be obtained by treatment with sodium alkoxide or potassium in the corresponding alcohol, such as methanol.

b) the compounds of formula (I), where X represents-CH-, can be obtained according to the following scheme 3:

Scheme 3

In accordance with scheme 3 may be carried out analogously to known processes for the synthesis of pyrimidines. It includes:

(I) the Interaction appropriately protected or of functionalized benzamidine General formula (X), and their inorganic salts (such as bromide, chloride or tetrafluoroborate) with diethyl or dimethyl(2-methoxyphenoxy)malonate education dihydroxypyrimidine General formula (XI).

(IUB> or SOCl2or a mixture of two of them, not necessarily in the presence of an appropriate base, such as triethylamine, to obtain the compounds of General formula (XII).

(III) Additional conversion is carried out similarly to the stages of the synthesis described for scheme 2, to obtain the compounds of General formula (Id).

Compounds of General formula (Id), where R2means R21or heterocyclyl can be obtained from the corresponding cyanide derivatives of General formula (XII) (R represents-CN) by converting a functional group, as described in section a).

Compounds of General formula (Id), where R2represents-Y-R22can be obtained from compounds of General formula (Id), where2represents-Y-H, by alkylation of suitably functionalized alkylhalogenide in the presence of a base such as sodium hydride, in a suitable solvent, such as DMF or DMSO, at room temperature.

The functional group contained in the fragment R22these compounds can then be converted using standard methods, as shown below:

(I) (Ness.)alkoxycarbonyl-(ness.)alkyl as R22- carboxy(ness.) is lcil by restoring using a reducing agent, such as borohydride sodium, in the presence of calcium chloride or lithium aluminum hydride.

(III) Carboxy(ness.)alkyl as R22- di(ness.)allylcarbamate-(ness.)alkyl by combining with substituted amine and a suitable binding agent, such as DCCI or BOP.

Compounds where R2represents-Y-R22and R22means (ness.)alkanoyl, derived from compounds containing hydroxy or amino group as R2and the corresponding carboxylic acid using a binder, such as DCCI or BOP.

Derivatives, where R2means (ness.)alkoxycarbonyl, can be obtained from compounds containing hydroxy or amino group as2and alkylsulfonate or alkoxycarbonylmethyl.

In an alternative embodiment, the fragment-Y-R22may already be present in free form or in protected form in the composition of the compounds of formula (X).

Getting the original products.

Required functionalityand benzamidine salt of General formula (X) having as R2deputies, representing a hydroxyl or amino group, a suitably protected using benzyl or allyl is s similar to the method described by Weintraub, J. Org. Chem., 33, 1679 (1968), capable of handling perborate triethyloxonium with obtaining relevant perborates of benzimidate and subsequent interaction with an excess of ammonia to the obtainment of benzamidines as tetrafluoroborate General formula (X).

(II) substituted benzonitriles by the reaction of Silver with getting halides of benzimidate and subsequent treatment with ammonia with formation of compounds of formula (X) in the form of halogenated salts (chlorides or bromides).

Inhibiting activity of the compounds of formula (I) in respect of endothelin receptors can be demonstrated using the following test:

I. Inhibition of binding of endothelin with recombinant human ETAreceptors expressed in infected with a baculovirus insect cells

cDNA encoding human ETAreceptors from human placenta, cloned (M. Adachi, Y-Y. Yang, Y. Furuichi and S. Miyamoto, BBRC 180. 1265-1272) and expressed in the system of the baculovirus-insect cell. Infected with a baculovirus insect cells from the fermenter volume 23 l centrifuged (3000xg, 15 min, 4°C) after 60 h after infection, re-suspender is tiravanija and centrifugation of cells suspended in 800 ml of the same buffer and dried by freezing at -120°C. Cells were destroyed after thawing of the suspension in this hypotonic buffer mixture. After repeating the cycle of freeze-drying/thawing, the suspension is homogenized and centrifuged (25000xg, 15 min, 4°C). After suspension in Tris-buffer (75 mm, pH of 7.4, 25 mm MgCl2, 250 mm sucrose) aliquots of 1 ml (protein content of about 3.5 mg/ml) was stored at -85°C.

For analysis linking dried by freezing the membrane preparations were subjected to thawing and after centrifugation at 20°C and 25000xg for 10 min, re-suspended in buffer for analysis (50 mm Tris-buffer, pH of 7.4, containing 25 mm MnCl2, 1 mm etc and 0.5% bovine serum albumin). 100 µl of this suspension of membranes containing 70 μg of protein were incubated with 50 μl of125I-endothelin (specific activity 2200 CI/mmol) in the buffer for analysis (25000 pulses/min to a final concentration of 20 PM) and 100 μl of buffer for analysis containing different concentrations of the tested compounds. Incubation was carried out at 20°C for 2 h or at 4°C for 24 h Separation of free and membrane-bound radio-carried out by filtering through a glass fiber filter. Data on the inhibitory activity of compounds of the formula (tion [nm] required for 50% inhibition of specific binding125I-endothelin.

II. Inhibition of binding of endothelin with recombinant human ETAreceptors expressed in cells SNO

Cell culture. Cells SNO expressing recombinant human ETAthe receptor were grown in minimum support alpha medium (Minimal Essential Alpha Medium; firm Gibco Laboratories, Paisley, Scotland) supplemented with 0.1 μm methotrexate, 5% subjected to dialysis fetal calf serum, 100 U/ml penicillin and 100 μg/ml streptomycin.

Analyses of binding to intact attached cells was carried out in 500 μl of modified according to the method of Dulbecco environment Needle (DMEM) containing 2 mg/ml bovine serum albumin and 25 mm Hepes. After incubation (2 h, 22°C) in the presence of 35 PM [125I]-ET-1 (endothelin-1) and increasing concentrations of various antagonists, the cells were extensively washed and was finally solubilizers in 1% (wt./about.) LTOs, 0.5 M NaOH and 100 mm etc. Each analysis was performed three times in triplicate, and the nonspecific binding was assessed in the presence of 100 nm unlabeled ET-1. Specific binding was determined as the difference between about the data binding table.2.

III. The inhibition induced by endothelin reductions in selected rings of rat aorta

From the thoracic aorta of adult rats Wistar-Kyoto cut rings with a length of 5 mm, the Endothelium was removed by gentle scraping of the inner surface. Each ring was immersed at 37°C in 10 ml of Krebs-Henseleit in a separate bath with aeration gas mixture of 95% O2and 5% CO2. Estimated isometric stretching rings. Rings were stretched using the preliminary tension forces are equal to 3, After incubation for 10 min with the test compound or with a carrier was added to the cumulative dose of endothelin-1. The activity of test compounds was determined by detectable shift to the right of the graph according to the dose-activity of endothelin-1 in the presence of different concentrations of antagonist. This shift to the right (or "doses" OD) corresponds to the private, obtained by dividing the values of the EU50endothelin-1 in the presence of the antagonist and the antagonist, where the value of the EU50represents the concentration of endothelin needed to reduce, represents half of the maximum.

The corresponding value of RA2which of the following equation based on the relationship of dose OD for each dependency dose of activity.

pA2=log(AR-1)-log(concentration of antagonist)

Is EU50endothelin-1 in the absence of test compounds is 0.3 nm.

The values of RA2obtained by applying the compounds of formula (I) shown in table 3.

IV. Pharmacokinetic characteristics of receptor antagonists endothelin

The pharmacokinetic characteristics of newly synthesized antagonists of endothelin receptor was evaluated using Wistar rats. Test compounds were dissolved in DMSO at a concentration of 5 mg/ml and administered orally via a stomach tube at a dose of 1 ml/kg body weight, which corresponds to 5 mg/kg of body weight. For each of the tested compounds used in two rats. Blood samples were taken from the retro-orbital sinus at the same rats after 1 and 5 h after treatment, while the second rat after 3 and 7 h after treatment. In addition, using cardiac puncture both rats after 24 h took the last blood sample. Blood was collected on add-NaF. Plasma was obtained by centrifugation at 2000xg at +4°C for 15 min, the plasma Samples were analyzed in relation to the product associated with the active drug through biological analysis based on competitive the assessment of plasma samples was performed by comparison with a calibration curve obtained by introducing into the plasma of control rats of known concentrations of the test compounds. Some data are summarized in table 4.

Due to their ability to inhibit binding of endogenous endothelin compounds of formula (I) can be used as pharmaceuticals for treatment of diseases associated with abnormal vascular tone and endothelial dysfunction.

Therefore, the scope of the compounds of formula (I) may be heart failure (acute and chronic), systemic and pulmonary hypertension, acute ischemic coronary syndrome, angina, renal failure (acute and chronic), organ transplantation (e.g., liver, heart, kidney), caused by cyclosporine nephrotoxicity, angiospastic disease (subarachnoid hemorrhage, and hemorrhagic and negemorragicheskoy stroke, Raynaud's syndrome), peripheral arterial occlusal disease, prevention of restenosis after stent-angioplasty or angioplasty using balloon, septic shock or multiple violation of the body, what is happening in intensive care, asthma, chronic obstruc is technical), inflammatory bowel disease, fibrosis, atherosclerosis, obesity, glaucoma, prostatic hypertrophy, migraine, dysfunction erectile tissue, in addition, the compounds of formula (I) can represent an adjuvant therapy for cancer and other disorders associated with the activity of endothelin.

The compounds of formula (I) can also be administered in combination with anti-hypertensive drugs, anti-arrhythmic means, means against angina, antithrombotic tools and agents that reduce the level of lipids, and antioxidants.

Compounds of General formula (I) according to the invention can also be derivatization on the functional groups with obtaining derivatives, which are prodrugs that have the ability to turn back into the parent compound in vivo. Examples of such prodrugs include physiologically acceptable and metabolically labile ester derivatives, such as acetoxymethyl esters, ecotoxicologie esters, (ness.)alkylcarboxylic esters, (ness.)alkoxycarbonylmethyl esters, cycloalkylcarbonyl esters, cycloalkylcarbonyl platinovye esters, hydroxy(ness.)acylcarnitine esters, hydroxy(ness.)alkylcarboxylic ester, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethylene ester, 5-methyl-2-oxo-[1,3]dioxol-4-retrovia esters, methoxymethyl esters, methylthiomethyl esters, pivaloyloxymethyl esters, etc., the Preferred prodrugs in the form of esters are, for example, 1-acetoxyethyl esters, 2,2-dimethylphenylacetate esters, 1-ethoxycarbonylmethylene esters, 1-cyclohexyloxycarbonyloxy esters, 2-ombrophilous ester, 3,3-dimethyl-2-oxobutyrate esters, 2-oxo-2-phenethyl ester, 4-methyl-2-oxopentanoate esters, 3-hydroxy-2-oxopropyl ester and 5-methyl-2-oxo[1,3]dioxol-4-ylmethylene esters. For example, the preferred prodrugs of 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl] pyridine-2-carboxylic acids include 1-ecotoxicology ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid, 2,2-dimethylphenylacetate ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid, 1-ethoxycarbonylmethyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-toxi-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid, 2-oxopropyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl] pyridine-2-carboxylic acid, 3,3-dimethyl-2-oxobutyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid, 2-oxo-2-phenethyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid, 4-methyl-2-oxopentanoic ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid, 3-hydroxy-2-oxopropyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid, 5-methyl-2-oxo[1,3]dioxol-4-ymetray ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid and so on; the most preferred prodrug is 1-ecotoxicology ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid.

In addition, under the scope of the present invention fall within any physiologically acceptable equivalents of the compounds of General formula (I), similar metabolically labile complex is mentioned earlier, the object of the present invention are also medicinal product containing a compound of the formula (I), and the method of preparation of such medicines, which provides for on the basis of one or more compounds of the formula (I) and optionally one or more other therapeutically valuable substances intended for the introduction of the galenical forms.

The pharmaceutical compositions can be administered orally, for example in the form of tablets, filmtabletten, pills, gelatin capsules with hard or soft coating, solutions, emulsions or suspensions. The introduction can also be carried out rectally, for example, with the use of suppositories; topically or transdermally, for example, using ointments, creams, gels or solutions; or parenterally, for example intravenously, intramuscularly, subcutaneously, nutritarian or transdermal, using, for example, injectable solutions. In addition, the introduction can be sublingual, or in the form of ophthalmic drugs, or in the form of aerosols, for example in the form of a spray.

For the preparation of tablets, filmtabletten, tablets or gelatin capsules with solid coating compounds according to the present invention malamig of excipients for tablets, tablets or gelatin capsules with solid surface include lactose, corn starch or its derivatives, talc or stearic acid or its salts.

Acceptable excipients for use in gelatin capsules with a soft coating are, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols etc; however, depending on the nature of active substances, in some cases, in the manufacture of gelatin capsules, soft coated excipients do not apply.

For the preparation of solutions or syrups excipients that may be used include, for example, water, polyols, saccharose, invert sugar and glucose.

Excipients that can be used for injectable solutions, include, for example, water, alcohols, polyols, glycerine and vegetable oils.

In suppositories and preparations for local and percutaneous application as excipients can be used, for example, natural or hydrogenated oils, waxes, fats and semi-solid or liquid polyols.

Pharmaceutical compositions may also include preservatives, soljubilizatory, stabilizers, wetting agents, emulsifying agents, sweetening ve is or antioxidants. As mentioned above, they can also contain other therapeutically valuable agents.

It is necessary that all adjuvants used for the preparation of drugs were non-toxic.

The preferred route of administration is intravenous, intramuscular or oral. The most preferred route of administration is oral. Dose containing an effective amount of compounds of formula (I), depend on the specific nature of the active substance, the age and characteristics of the patient and route of administration. In General, the application offers a dose of about 0.01 to 10 mg/kg of body weight per day.

The following examples serve to illustrate preferred embodiments of the present invention, but not intended to limit the scope of the invention. In the used abbreviations DMSO means dimethylsulfoxide, DMF refers to dimethylformamide, THF refers to tetrahydrofuran, EtOAc means ethyl acetate; TLC means thin layer chromatography, CT denotes room temperature, IHVR denotes liquid chromatography high resolution, ISP refers to mass spectrometry with ionization by ion beam - positive form, ISN denotes mass spectrometry blow, tPLdenotes the melting temperature, and M denotes the molecular mass.

Example 1

a) of 1.46 g of [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl] amide 5-methylpyridin-2-sulfonic acid was dissolved in dioxane (25 ml) at low heat, then added ethanol (50 ml), cyclohexadiene (6 g) and 10% palladium on coal (1,46 g). The solution was boiled under reflux for 20 h, the catalyst was removed by filtration and the solution was concentrated on a rotary evaporator. Precipitated in crystalline precipitate the yellow substance was collected, washed with ether, and dried in vacuum, to receive the desired [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of crystals off-white color. MC(ISP): m/e 495,2 (M+1 calculated for C24H22N4O6S1:495), tPL211 to 216°C.

Obtaining source material

b) To a solution of 13.7 g of 3-hydroxybenzamide and 25.6 g of benzylbromide in acetone (400 ml) at room temperature (RT) was added 25.6 g of potassium carbonate. The mixture was boiled under reflux for 6 h, which was sufficient to complete the reaction according to the results of TLC (CH2Cl2/MeOH 20/1). R is blockhead sodium and concentrated in vacuum. The resulting crystalline residue is suspended in n-hexane (200 ml), the crystals were separated by filtration under vacuum and dried in vacuum, to receive 3-benzyloxybenzoate in the form of a crystalline substance in white, tPL136-140°C.

in) 11,36 g 3-benzyloxybenzoate suspended in CH2CL2(200 ml) in an argon atmosphere and under ice cooling was added dropwise 9.5 g of perborate triethyloxonium in CH2Cl2(100 ml). Then the reaction mixture was stirred at RT for 20 h to complete the reaction according to the results of TLC (CH2Cl2/MeOH 15/1). The obtained solid substance was separated by filtration and was washed with ether, it was required tetrafluoroborate meta-benzyloxybenzaldehyde ether as white crystals, tPL152-154°C, which was used in the next stage without additional purification.

g) the Suspension to 8.57 g tetrafluoroborate meta-benzyloxybenzaldehyde ether in ethanol (120 ml) was cooled to -70°C. and treated with liquid ammonia (100 ml). The cooling bath was removed and the reaction mixture was stirred for 69 h to complete the reaction (TLC results).

The solvent was removed in vacuum, while required tetraborate pure and was used in the subsequent stage without further purification.

d) 6.3 g of Dimethyl ether (2 methoxyphenoxy) of malonic acid were added dropwise within 5 min in an argon atmosphere to a solution 1,72 g of sodium in methanol (150 ml) at 5°C. Stirring at 5°C was continued for 30 minutes, then for 5 min at 5°C was added a 7.85 g tetrafluoroborate meta-benzyloxybenzaldehyde in methanol (50 ml) and the mixture was stirred at RT for 20 h the Solvent was removed in vacuum and the residue was distributed between water and EtOAc (each 50 ml). Chilled water layer was acidified by adding dropwise concentrated HCl, the precipitate was separated by filtration under vacuum, washed with water and dried under reduced pressure, to receive the desired 2-(3-benzyloxyphenyl)-5-(2-methoxyphenoxy)pyrimidine-4,6-diol in the form of a solid off-white color, tPL192-195 (in Russian)°C. Additional product was obtained by washing the EtOAc phase 3h. HCl, drying the organic layer over Na2SO4and subsequent removal of the solvent in vacuo.

(e) suspension of 4.16 g of 2-(3-benzyloxyphenyl)-5-(2-methoxyphenoxy) pyrimidine-4,6-diol in POCl3(18.2 ml) at RT was added 4,58 g l5then of 5.1 ml of N-ethyldiethanolamine and of 3.31 g of the chloride of tetraethylammonium. The mixture was boiled under reflux in tachimawari water, was treated with activated charcoal and dried over Mg2SO4. The solvent was removed in vacuo, the residue was applied to a short column with silica gel (120 g) and suirable ether. After combining the fractions containing the pure substance, and concentration in vacuo received the desired 2-(3-benzyloxyphenyl)-4,6-dichloro-5-(2-methoxyphenoxy) pyrimidine in the form of a crystalline substance, light brown, tPL127-132°C.

g) a 4.53 g of 2-(3-benzyloxyphenyl)-4,6-dichloro-5-(2-methoxyphenol-C)pyrimidine and 4.2 g of potassium salt of 5-methylpyridin-2-sulfonamida (the receipt of which is described in EP 713875 and in Bioorg. Med. Chem. Let., 7, 2223-2228 (1997)) was dissolved in DMSO (120 ml) and the solution was stirred at RT for 12 h and Then the reaction mixture was distributed between EtOAc and 1N. HCl, the organic layer was washed with water, dried over Na2SO4and the solvent was removed in vacuum. The solid residue triturated in ether and separated by filtration under vacuum, thus received [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of crystals light brown, tPL176-180°C.

C) To a solution of 0.92 g of sodium in Meon (75 ml) at RT was added 2.35 g of [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy)pyrim the completion of the reaction (TLC results). The mixture is then poured into a chilled 1H. HCl and the product was extracted with EtOAc. The organic layer was dried over Na2SO4and the solvent was removed in vacuum. The solid residue triturated in ether and separated by filtration under vacuum, thus received [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of crystals of dirty-white color, tPL180-183°C.

Example 2

0,41 g of [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl] amide 5-methylpyridin-2-sulfonic acid, described in example 1 was dissolved in DMF (30 ml) and cooled in an ice bath was treated with NaH (0,061 g 65% suspension of NaH in oil). The mixture was stirred at RT for 1 h, was added dropwise 0.11 g of methyl ester of Chloroacetic acid and stirred at RT for 20 h to complete the reaction according to the results of TLC (CH2Cl2/EtOAc 4/1). The mixture was distributed between brine and EtOAc, the organic layer was dried over Na2SO4and the solvent was removed in vacuum. The residue was purified by chromatography on a column of silica gel (elution CH2Cl2/EtOAc 7/1). After combining the fractions containing the pure substance, and concentration in vacuo received meliloti in the form of a crystalline substance is light yellow in color. MC(ISP): m/e 567,2 (M+1 calculated for C27H26N4O8S:567).

Example 3

Analogously to example 2 from [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid and ethyl ester of Chloroacetic acid was obtained ethyl ester {3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonium)pyrimidine-2-yl]phenoxy}acetic acid in the form of a solid white color. MC(ISP): m/e 581,1 (M+1 calculated for C28H28N4O8S:581).

Example 4

Analogously to example 2 from [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl] amide 5-methylpyridin-2-sulfonic acid and 2-chloracetamide received 2-{3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenoxy}ndimethylacetamide in a solid white color. MC(ISP): m/e 552,1 (M+1 calculated for C26H25N5O7S:552).

Example 5

Analogously to example 2 from [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid and 2-chloro-N,N-dimethylacetamide was obtained 2-{3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenoxy}-N,N-dimethylacetamide as firmly the EP 6

85 mg of the methyl ester {3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenoxy}acetic acid, described in example 2, dissolved in Meon (30 ml) was treated with 1H at RT. NaOH (0.9 ml) and the solution was stirred for 1 h to complete the reaction according to the results of TLC (CH2Cl2/EtOAc 3/1). The reaction mixture was distributed between 1N. HCl and CH2Cl2, the organic layer was dried over Na2SO4and the solvent was removed in vacuum. After trituration of the residue in ether was obtained the desired [3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenoxy]acetic acid in a solid white color. MC(ISN): m/e 551 (M-1 calculated for C26H24N4O8S:551).

Example 7

70 mg of methyl ester {3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenoxy}acetic acid, described in example 2, was dissolved in a mixture of EtOH/THF (each 3 ml) under low heat and sequentially processed by CT 27.4 mg CaCl2and 18.7 mg NaBH4. The reaction mixture was stirred at RT for 1.5 h until complete consumption of starting material by TLC results (CH2Cl2/EtOAc 3/1). The mixture was distributed between the IU. The residue was purified by chromatography on a column of silica gel (elution CH2Cl2/EtOAc 3/1). After combining the fractions containing the purified substance, and evaporation in vacuum was obtained [2-[3-(2-hydroxyethoxy)phenyl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of a solid white color. MC(ISP): m/e to 539.3 (M+1 calculated for C26H26N4O7S:539).

Example 8

49,5 mg [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid, described in example 1, dissolved in acetonitrile (3 ml) was treated at RT sequentially to 25.8 mg n-atindianapolis-amine, 53 mg hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium and after 0.5 h 72 mg of acetic acid. The mixture was stirred for 12 h and was distributed between water and EtOAc. The organic layer was dried over Na2SO4and the solvent was removed in vacuum. The residue was purified by chromatography on a column of silica gel (elution CH2Cl2/EtOAc 8/1). After combining the fractions containing the purified substance, and evaporation in vacuum was obtained 3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenyl what SUB>N4O7S:537).

Example 9

a) a Solution of 0.35 g of [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulfonic acid, dissolved in CH2Cl2(40 ml), cooled to 0°C. and was treated dropwise 4.8 ml of 1 M solution of TiCl4in CH2CL2. The orange solution was stirred at 0°C for 0.5 h until complete consumption of starting material by TLC results (CH2Cl2/EtOAc 4/1). Then the reaction mixture was poured into ice, the product was extracted with CH2Cl2, the organic layer was dried over Na2SO4and the solvent was removed in vacuum. The residue was washed with ether/hexane, thus received [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulphonic acid in the form of crystalline substances off-white color. MC(ISN): m/e 499,1 (M-1 calculated for C22H20N4O6S2:499).

Obtaining source material

b) of 2.23 g of 5-methylthiazolidine-2-thione (the receipt of which is described in Liebigs Ann. Chem., 58-64 (1985)) was dissolved in 36% aqueous HCl (150 ml), cooled to -20°C and through the solution for 0.5 h missed Cl2maintaining the temperature below -20°C. Then was added 400 ml of ether, the Kim NH3(200 ml) and the mixture was slowly heated to CT. The solvent was removed in vacuum, it was received amide 5-methylthiazole-2-sulphonic acid in the form of a solid off-white color. MS(EI): m/e 178 (M calculated for C4H6N2O2S2:178). The corresponding potassium salt was obtained by processing sulfonamida tert-butyl potassium in the Meon.

C) Analogously to example 1G) of the potassium salt of amide 5-methylthiazole-2-sulfonic acid and 2-(3-benzyloxyphenyl)-4,6-dichloro-5-(2-methoxyphenoxy) pyrimidine as described in example 1E), were obtained [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulphonic acid in the form of a solid off-white color. MC(ISN): m/e 593 (M-1 calculated for C28H23lN4ABOUT5S2:593).

d) Analogously to example 1H) processing [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulfonic acid NaOCH3in the Meon received [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulphonic acid in the form of a solid off-white color. MC(ISP): m/e to $ 591.1 (M+1 calculated for C29H26N4O6S2:591).

Example 10

Analogically, described in example 9, and the methyl ester of Chloroacetic acid was obtained methyl ester {3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylthiazole-2-sulfonylamino)pyrimidine-2-yl]phenoxy} acetic acid in the form of a solid white color. MC(ISN): m/e 571 (M-1 calculated for C25H24N4O8S2:571).

Example 11

Analogously to example 6 by the hydrolysis of methyl ester {3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylthiazole-2-sulfonylamino)pyrimidine-2-yl]phenoxy} acetic acid, described in example 10, in the presence of 1H. aqueous NaOH in the Meon received {3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylthiazole-2-sulfonylamino)pyrimidine-2-yl]phenoxy} acetic acid in the form of a solid white color. MC(ISN): m/e 557 (M-1 calculated for C24H22N4O6S2:557).

Example 12

Analogously to example 7 with the recovery of the methyl ester {3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylthiazole-2-sulfonylamino)pyrimidine-2-yl]phenoxy}acetic acid, described in example 10, in the presence of NaBH4/CaCl2received [2-[3-(2-hydroxyethoxy)phenyl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulphonic acid in the form of a solid white color. MC(ISN): m/e 543,1 (M-1 RAS is at 1a) the cleavage of benzyl ether in the reaction conditions of the hydrogenation in the presence of cyclohexadiene and palladium on coal from [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-hydroxymethyluracil-2-sulfonic acid was obtained [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-hydroxymethyluracil-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 509,2 (M-1 calculated for C24H22N4O7S:509).

Obtaining source material

b) of 5.1 g of 5-methylpyridin-2-sulfonamida in water (100 ml) was treated with 60 ml of 1N. NaOH and 9,48 g KMNO4and the mixture is boiled under reflux for 2.5 hours, the Reaction mixture was cooled to CT and was filtered. The filtrate is washed with AcOEt, the pH of the aqueous layer was brought to 1 with the use of KHSO4added NaCl and the product was extracted with AcOEt. The organic layer was dried over Na2SO4and the solvent was removed in vacuum, while the required 5-carboxyphenyl-2-sulfonamide in the form of a solid white color. MC(ISN): m/e 201,1 (M-1 calculated for C6H6N2ABOUT4S:201).

To the solution 2,02 g 5-carboxyphenyl-2-sulfonamida in THF (100 ml) was added 1,49 g 3-methyl-1-pair-tolyltriazole and the solution was stirred at RT until complete consumption of starting material by TLC results (CH2Cl2/MeOH 30/1). The reaction mixture was concentrated in vacuo, precipitated precipitated crystalline substance is triturated in ether, separated by filtration under vacuum and dried in a vacuum, when it received 5-methoxycarbonylmethyl-2-sulfonamide in the form of crystalline substances off-white color who Ridel-2-sulfonamida in THF (20 ml) was added dropwise to a suspension of LiAlH4in a mixture of THF/ether (each 10 ml) at -10°C. the Mixture was stirred at RT for 10 min and cooled to -5°C. the Reaction was stopped by addition of EtOAc (5 ml) and then 10% aqueous citric acid (20 ml). The product was extracted with ether, which was dried and after evaporation of the solvent was obtained 5-hydroxymethyluracil-2-sulfonamide. MC(ISN): m/e 187,1 (M-1 calculated for C6H8N2O3S:218). The product was used in subsequent reactions without further purification.

d) Analogously to example 1G) of 5-hydroxymethyluracil-2-sulfonamida and 2-(3-benzyloxyphenyl)-4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine as described in example 1E), were obtained [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-hydroxymethyluracil-2-sulphonic acid in the form of an amorphous solid off-white color. MC(ISN): m/e 603 (M-1 calculated for C30H25ClN4ABOUT6S:603).

e) Analogously to example 1H) processing [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-hydroxymethyluracil-2-sulfonic acid NaOCH3in the Meon received [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl] amide 5-hydroxymethyluracil-2-sulphonic acid in the form of solids tx2">

a) Analogously to example 1A) the cleavage of benzyl ether in the reaction conditions of the hydrogenation in the presence of cyclohexadiene and palladium on coal from [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl)pyridine-2-sulfonic acid was obtained [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl)pyridine-2-sulfonic acid in the form of a solid white color. MC(ISP): m/e to 539.3 (M+1 calculated for C26H26N4O4S:539).

Obtaining source material

b) To a solution of the potassium salt of 5-isopropylpyridine-2-sulfonamida (the synthesis of which is described in EP 0799209) in water (10 ml) at RT was added 1.2 g KMnO4and the mixture is boiled under reflux for 30 minutes, the Reaction mixture was cooled to CT, acidified with diluted HCl and the product was extracted with AcOEt. The organic layer was washed with water, dried over Na2SO4and concentrated in vacuum to receive amide 5-(1-hydroxy-1-methylethyl)pyridine-2-sulfonic acid in the form of a yellow oil. MC(EI): m/e 216 (M calculated for8H12N2O3S:216).

The material was used without additional purification.

Appropriate sakalavas amide salt (5-(1-hydroxy-1-methylethyl) pyridine-2-sulfonic acid and 2-(3-benzyloxyphenyl)-4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine, described in example 1E), were obtained [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl)pyridine-2-sulfonic acid in the form of a solid off-white color. MC(ISP): m/e 633,1 (M+1 calculated for C32H29ClN4O6S:633).

d) Analogously to example 1H) processing [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl)pyridine-2-sulfonic acid NaOCH3in the Meon received [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl)pyridine-2-sulfonic acid in the form of a solid off-white color. MC(ISP): m/e 629,1 (M+1 calculated for C33H32N4ABOUT7S:629).

Example 15

a) Analogously to example 9a) the cleavage of benzyl ether [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid in the presence of TiCl4in CH2Cl2received [2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid white color. MC(ISN): m/e 519,1 (M+1 calculated for C26H24N4O6S:519).

Getting ishodnogo example 14b), in CF3CO2H (2 ml) was boiled under reflux for 20 hours Then the solvent was removed in vacuum, it was received amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid white color in a fairly pure form. MC(EI): m/e 198 (M calculated for C8H10N2O2S:198).

The corresponding potassium salt was obtained by processing sulfonamida tert-butyl potassium in the Meon.

C) Analogously to example 1G) of the potassium salt of amide 5-isopropylpyridine-2-sulfonic acid and 2-(3-benzyloxyphenyl)-4,6-dichloro-5-(2-methoxyphenoxy) pyrimidine as described in example 1E), were obtained [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy) pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid off-white color. MC(ISP): m/e 613,1 (M-1 calculated for C32H27ClN4O5S:613+).

d) Analogously to example 1H) processing [2-(3-benzyloxyphenyl)-6-chloro-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid NaOCH3in the Meon received [2-(3-benzyloxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid white color. MC(ISN): m/e 609,1 (M-1 calculated for C3330H30N4O8S:605).

Example 17

Analogously to example 6 by the hydrolysis of ethyl ester {3-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]phenoxy]acetic acid, described in example 16, in the presence of 1H. aqueous NaOH in the Meon received {3-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]phenoxy}acetic acid in the form of a solid off-white color. MC(ISN): m/e 576,9 (M-1 calculated for C28H26N4O8S:577).

Example 18

Analogously to example 7 with the recovery of the ethyl ester {3-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenol-C)pyrimidine-2-yl]phenoxy}acetic acid, described in example 16, in the presence of NaBH4/CaCl2received [2-[3-(2-hydroxyethoxy)phenyl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid white color. MC(ISN): m/e 563,2 (M-1 calculated for C28H28N4ABOUT7S:563).

Example 19

a) To a suspension of 0.5 g of [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid C is reflux for 20 h, was cooled to CT and distributed between water, acetic acid and EtOAc. The organic layer was twice washed with water, dried over Na2SO4and then the organic solvent was removed in vacuum. The residue was purified by chromatography on a column of silica gel (elution CH2Cl2/MeOH 95/5). After combining the fractions containing the purified substance, and evaporation in vacuo received [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl] amide 5-methylpyridin-2-sulphonic acid in the form of a solid off-white color. MC(ISP): m/e 505,2 (M+1 calculated for C24H20N5O6S:505).

Obtaining source material

b) a Solution of 30 g of 1-oxide 4-[4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine-2-yl] pyridine and 31.1 g of potassium salt of 5-methylpyridin-2-sulfonamida (the receipt of which is described in EP 0799209) in DMSO (100 ml) was stirred at RT for 20 h the Reaction mixture under vigorous stirring slowly poured into a mixture of water/Et2O (each 100 ml), the precipitate was separated by filtration, suspended in EtOAc (1 l) and was treated with 2n. aqueous HCl (37.5 ml) with vigorous stirring for 15 minutes Crystalline substance was separated by filtration under vacuum and dried for 12 h in the h-2-sulfonic acid as off-white crystalline substance, which was led from AcOEt, tPL239-240°C.

C) To a solution of 1.83 g of sodium in Meon (50 ml) was added at RT 6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-alamid 5-methylpyridin-2-sulfonic acid and the mixture is boiled under reflux for 20 h until the reaction is completed. The mixture is then poured into a chilled 1H. aqueous HCl and the product was extracted with CH2CL2. The organic layer was dried over Na2SO4and the solvent was removed in vacuum. The crude product was led from Et2O/AcOEt (1:1), was obtained [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of crystals off-white color. MC(ISP): m/e 496,1 (M+1 calculated for C23H21N5O6S:496).

Example 20

0,356 g of [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid, described in example 19 is dissolved in EtOH (5 ml) was treated at RT 2n. NaOH (0.7 ml) and the solution boiled under reflux for 30 min before termination of the reaction by TLC results. The reaction mixture was cooled to 0°C, the pH was brought to 1. The crystalline substance was separated by filtration, washed Weiden-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid off-white color. MC(ISN): m/e 521,1 (M-1 calculated for C24H22N6O6S:521).

Example 21

1 g of amide 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino) pyrimidine-2-yl] pyridine-2-carboxylic acid, described in example 20 dissolved in a mixture of THF/dioxane (40 ml/30 ml) was treated at RT for 3h. HCl (40 ml) and the solution boiled under reflux for 24 h, after which was added THF (12 ml) and 3M HCl (12 ml) and the solution boiled under reflux for 24 h to complete the reaction by TLC results. The reaction mixture was concentrated in vacuum and the product was extracted with CH2Cl2. The organic layer was dried over Na2SO4the solvent was removed in vacuum. The crystalline residue was washed with ether and dried under vacuum, was obtained 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid off-white color. MC(ISN): m/e 522 (M-1 calculated for C24H21N5O7S:522).

Example 22

220 mg of 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, suspended in acetonitrile (10 ml) treatment is eazol-1-yloxytris(dimethylamino)phosphonium (THIEF). The mixture was stirred at RT for 12 h, and then distributed between cold diluted HCl and EtOAc. The layers were separated, the organic layer was dried over Na2SO4and the solvent was removed in vacuum. The residue was purified through column chromatography with silica gel (elution CH2Cl2/MeOH 95/5). After combining the fractions containing the purified substance, and evaporation in vacuum was obtained methyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 536,2 (M-1 calculated for C25H23N5O7S:536).

Example 23

Analogously to example 22 from 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, and ethanol were obtained ethyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonium)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 550,1 (M-1 calculated for C26H25N5O7S:550).

Example 24

Analogously to example 22 from 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino) pyrimidine-2-yl]pyridine-2-carbon(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl] pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 564,2 (M-1 calculated for C27H27N5O7S:564).

Example 25

Analogously to example 22 from 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, and ethylene glycol was obtained 2-hydroxyethyloxy ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 566,1 (M-1 calculated for C26H25N5O8S:566).

Example 26

70 mg of 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21 is dissolved in DMF (5 ml) was treated at RT 30 mg 4-methylmorpholine, then was cooled to 0°and treated With 26 mg of 2-chloro-4,6-dimethoxy-1,3,5-triazine. The solution was stirred at RT for 90 min, then was treated with 10 mg of methylamine hydrochloride and stirred at RT for 12 h the Mixture was distributed between cold diluted HCl and EtOAc. The layers were separated, the organic layer was washed with water, dried over Na2SO4and the solvent was removed in vacuum. The solid residue triturated in ether, separated by filtration and dried under high n-2-yl]pyridine-2-carboxylic acid in the form of a crystalline substance of white color. MC(ISN): m/e 535,2 (M-1 calculated for C25H24N6O6S:535).

Example 27

Analogously to example 26 from 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, and ethanolamine after purification of the crude product by chromatography on a column using as eluent CH2Cl2/MeOH (95/5) received (2-hydroxyethyl)amide 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 566,1 (M-1 calculated for C26H26N6ABOUT7S:566).

Example 28

Analogously to example 26 from 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, and Isopropylamine after purification of the crude product by chromatography on a column with elution AcOEt received isopropylated 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 563,2 (M-1 calculated for C27H28N6O6S:563).

Example 29

100 mg methyl is acid, described in example 22 was dissolved in a mixture of EtOH/THF (each 15 ml) under low heat and sequentially processed in CT 42 mg CaCl2and 28 mg NaBH4. The reaction mixture was stirred at RT for 18 h until consumption of starting material by TLC results. The mixture was distributed between dilute HCl and CH2Cl2. The organic layer was dried over Na2SO4and the solvent was removed in vacuum, it was received [2-(2-hydroxymethylene-DIN-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of a solid white color. MC(ISN): m/e 508,3 (M-1 calculated for C24H23N5O6S:508).

Example 30

a) To a solution of 6.6 mg of acetic acid and 22.3 mg of 4-methylmorpholine in DMF (5 ml) under cooling in an ice bath was added to 22.3 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine and then the solution was stirred at RT for 90 min and Then was added 60 mg of hydrochloride [2-(2-aminomethylpyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid and continued stirring at RT for 12 h the Mixture was distributed between cold diluted HCl and EtOAc. The layers were separated, the organic layer was washed with water, dried over Na2SO26H26N6O6S:549).

Obtaining source material

b) a Solution of 100 mg of [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid, described in example 19 is dissolved in the Meon (5 ml), treated 47,5 mg benzylchloride, 10 mg of 10% palladium on coal and hydrogenosomal at RT for several hours until the reaction is completed according to TLC results. The catalyst was separated by filtration, the solution was concentrated in vacuum. Precipitated crystalline substance was collected by filtration, washed with ether, and dried in a high vacuum, it was received hydrochloride [2-(2-aminomethylpyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl] amide 5-methylpyridin-2-sulphonic acid in the form of crystals of light-yellow color. MC(ISP): m/e 509,3 (M+1 calculated for C24H24N6O5S:509).

Example 31

A solution of 70 g of the hydrochloride [2-(2-aminomethylpyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid described in example 30B), CH2CL2(5 ml) was treated at RT with 50 mg of N-ethyldiethanolamine, 15 mg methanesulfonanilide, and then capatilise was poured into cold diluted HCl and the product was extracted with CH2CL2. The organic layer was dried over Na2SO4and the solvent was removed in vacuum. The residue was purified by chromatography on a column of silica gel (elution CH2Cl2/MeOH 95/5). After combining the fractions containing the purified substance, and evaporation in vacuum was obtained [2-[2-(methanesulfonylaminoethyl)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 585 (M-1 calculated for C25H26N6O7S2:585).

Example 32

Analogously to example 31 from hydrochloride [2-(2-aminomethylpyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid described in example 30B), and acanaloniidae received [2-[2-(ethanolamine)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of a solid light brown color. MC(ISN): m/e 599 (M-1 calculated for C26H28N6O7S2:599).

Example 33

A solution of 70 mg of the hydrochloride [2-(2-aminomethylpyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid, describe the under reflux until completion of the reaction by TLC results (CH2Cl2/MeOH 95/5). The mixture was poured into cold diluted HCl and the product was extracted with CH2Cl2. The organic layer was dried over Na2SO4and the solvent was removed in vacuum. The solid residue was led out of CH2Cl2/Et2O, it was received[2-{2-[(3-ethylurea)methyl}pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of crystals dirty-white, MC(ISP): m/e 580,1 (M+1 calculated for C27H29N7O6S:580).

Example 34

A suspension of 100 mg of [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid, described in example 19, in dioxane (10 ml) was treated at RT 0,17 ml of N-ethyldiethanolamine, then 69 mg of hydroxylamine hydrochloride and boiled under reflux for 12 h to complete the reaction by TLC results. The mixture was poured into cold diluted HCl and the product was extracted with AcOEt. The organic layer was dried over Na2SO4and the solvent was removed in vacuum. The solid residue was led out of CH2Cl2/Et2O, it was obtained N-hydroxy-4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-O6S:536).

Example 35

A solution of 108 g of N-hydroxy-4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxamidine described in example 34, in acetic acid (3 ml) was treated at RT 0,057 ml of acetic anhydride and heated under reflux for 12 hours the Reaction mixture was distributed between CH2Cl2and diluted aqueous solution of knso3, the organic layer was dried over Na2SO4and the solvent was removed in vacuum. The residue was purified by chromatography on a column of silica gel (elution AcOEt). After combining the fractions containing the purified substance, and evaporation in vacuo received [6-methoxy-5-(2-methoxyphenoxy) -2-[2-(5-methyl[1,2,4]oxadiazol-3-yl)pyridine-4-yl]pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 560,1 (M-1 calculated for C26H23N7O6S:560).

Example 36

170 mg of [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl) pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid described in example 19c), in ethylene glycol (10 ml) was treated under cooling in an ice bath to 0.14 ml of triethylamine and 85 mg of Teilhard. The ice bath was removed and the ski layer was separated, dried over Na2SO4and the solvent was removed in vacuum. The residue was purified by chromatography on a column of silica gel (elution AcOEt). After combining the fractions containing the purified substance, and evaporation in vacuum was obtained [2-[2-(2-hydroxyethoxy)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of a solid white color. MC(ISP): m/e 540,3 (M+1 calculated for C25H25N5ABOUT7S:540).

Example 37

Analogously to example 36 from [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid described in example 19c), and methanol were obtained [6-methoxy-5-(2-methoxyphenoxy)-2-(2-methoxypyridine-4-yl)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of a solid of light yellow color. MC(ISP): m/e 510,3 (M+1 calculated for C24H23N5O6S:510).

Example 38

Analogously to example 36 from [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] amide 5-methylpyridin-2-sulfonic acid described in example 19c), and ethanol were obtained [2-(2-ethoxypyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid in B4).

Example 39

Analogously to example 36 from [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl) pyrimidine-4-yl] amide 5-methylpyridin-2-sulfonic acid described in example 19c), and allyl alcohol was obtained [2-(2-allyloxymethyl-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 534,2 (M-1 calculated for C26H25N5O6S:534).

Example 40

60 mg [2-(2-allyloxymethyl-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid, described in example 39, suspended in THF (5 ml) was treated at RT 2.2 mg tetrakis(triphenylphosphine) palladium and was stirred for 5 min, then was added 6.4 mg NaBH4. The mixture was stirred for 2 h until completion of the reaction by TLC results. The reaction mixture was poured into cold diluted HCl, the product was extracted with AcOEt. The organic layer was dried over Na2SO4and the solvent was removed in vacuum, it was received [2-(2-hydroxypyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 494,1 (M-1 calculated for Cthe ester 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboximidic in DMF (60 ml) in an ice bath was added NaH (0.8 g of 60% suspension of NaH in oil). The mixture was stirred at 0°C for 1.5 hours Then the mixture was poured into water, the pH was brought to 6 and the product was extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4and the solvent was removed in vacuum. The residue was purified by chromatography on a column of silica gel (elution CH2Cl2/EtOAc 9/1). After combining the fractions containing the purified substance, and evaporation in vacuo received [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a crystalline substance is light yellow in color. MC(ISN): m/e 531,1 (M-1 calculated for C26H24N6O5S:531).

Obtaining source material

b) Analogously to example 1G) of the potassium salt of 5-isopropylpyridine-2-sulfonamida (the receipt of which is described in EP 713875 and in Bioorg. Med. Chem. Lett., 7, 2223-2228 (1997)) and 4-[4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carbonitrile received [6-chloro-2-(2-cyano-4-yl)-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid light brown color, tPL255-259°N

Starting material, 4-[4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carbonitrile, was obtained from 5-(2-Eeagle type reaction Minici (Minisci) in the presence of formamide in water and H2O2/FeSO4(see Minisci and others, Tetrahedron, 41, 4157 (1985)), was obtained amide 4-[4,6-dihydroxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a crystalline substance beige color, which was led from DMF/N2Acting Analogously to example 1E) in collaboration with POCl3received 4-[4,6-dichloro-5- (2-methoxyphenoxy)pyrimidine-2-yl] pyridine-2-carbonitrile in a solid beige color, which was led from AcOEt/CH2Cl2, tPL211-212°C.

To the solution to 2.29 g of sodium in Meon (250 ml) at RT was added lower than the 5.37 g of 6-chloro-2-(2-cyano-4-yl)-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid and the mixture is boiled under reflux for 20 h to complete the reaction. Then the mixture was poured into water and the product was extracted with CH2Cl2. The organic layer was dried over Na2SO4and the solvent was removed in vacuum. The solid residue triturated in ether, separated by filtration in vacuo and dried in high vacuum, it was obtained sodium salt of methyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboximidic in the form of a solid light-brown, the x2">

Example 42

Analogously to example 20 of [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid described in example 41, in the processing of 2n. NaOH received amide 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid off-white color. MC(ISN): m/e 549,1 (M-1 calculated for C26H26N6O6S:549).

Example 43

To 0,586 g of sodium salt of methyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)-pyrimidine-2-yl]pyridine-2-carboximidic described in example 41C), in methanol (10 ml) was added 6N. HCl (3 ml) and the mixture is boiled under reflux for 1 h to complete the reaction according to the results of TLC (eluent: CH2Cl2/EtOAc 4/1). The mixture was poured into water and the product was extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4and the solvent was removed in vacuum. The residue was purified by chromatography on a column of silica gel (elution CH2Cl2/EtOAc 4/1). After combining the fractions containing the purified substance, and evaporation in vacuum was obtained methyl ester 4-[4-(5-isopropylpyridine-2-sulfona-white. MC(ISN): m/e 564,2 (M-1 calculated for C27H27N5O7S:564).

Example 44

Analogously to example 29 when recovering methyl ester 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 43, NaBH4in the presence of CaCl2received [2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid white color. MC(ISN): m/e 536,2 (M-1 calculated for C26H27N5O6S:536).

Example 45

To a solution of 56.6 mg of methyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 43 was added at RT 0.5 ml of 1N. NaOH and the solution was stirred for 1 h before termination of the reaction by TLC results. The mixture was poured into cold diluted HCl and the product was extracted with AcOEt. The organic layer was washed with water, dried over Na2SO4and the solvent was removed in vacuum. The solid residue was washed with ether and dried in high vacuum, it was obtained 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-and what about the C26H25N5O7S:550).

Example 46

Analogously to example 22 from 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid, described in example 45, and ethanol were obtained ethyl ester 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenol-C)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 578 (M-1 calculated for C28H29N5O7S:578).

Example 47

Analogously to example 22 from 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid, described in example 45, and isopropanol were obtained isopropyl ester 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 592,1 (M-1 calculated for C29H31N5O7S:592).

Example 48

Analogously to example 26 from 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid, described in example 45, and methylamine hydrochloride were obtained of methylamide 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-C(ISN): m/e 563,2 (M-1 calculated for C27H28N6ABOUT6S:563).

Example 49

Analogously to example 26 from 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid, described in example 45, and ethanolamine were received (2-hydroxyethyl)amide 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 593,1 (M-1 calculated for C28H30N6O6S:593).

Example 50

Analogously to example 26 from 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid, described in example 45, and Isopropylamine received isopropylated 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISP): m/e 593,2 (M+1 calculated for C29H32N6O6S:593).

Example 51

Analogously to example 26 from 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid, described in example 45, and dimethylamine hydrochloride was obtained dimethylamide 4-[4-(5-isopropylpyridine-2-Savelovo color. MC(ISP): m/e 579,1 (M+1 calculated for C28H30N6O6S:579).

Example 52

a) Analogously to example 30A) of the hydrochloride [2-(2-amino-methylpyridin-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid and acetic acid was obtained N-{4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-ylmethyl}the ndimethylacetamide in the form of crystalline substances off-white color. MC(ISP): m/e 579,1 (M+1 calculated for C28H20N6O6S:579).

Obtaining source material

b) Analogously to example 30B) when hydrogenerating [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid described in example 41, received hydrochloride [2-(2-aminomethylpyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 535,2 (M-1 calculated for the free amine C25H28N6O5S:535).

Example 53

Analogously to example 31 from hydrochloride [2-(2-aminomethylpyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid off-white color. MC(ISN): m/e 613,1 (M-1 calculated for C27H30N6O7S2:613).

Example 54

Analogously to example 33 from hydrochloride [2-(2-aminomethylpyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid described in example b), and received utilizationof[2-{2-[(3-ethylurea)methyl]pyridine-4-yl}-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid in a solid yellow color. MC(ISN): m/e 606 (M-1 calculated for C29H33N7ABOUT6S:606).

Example 55

Analogously to example 34 from the sodium salt of methyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboximidic described in example 41C), and hydroxylamine hydrochloride was obtained N-hydroxy-4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxamide in the form of a crystalline salt light yellow color. MC(ISN): m/e 564,2 (M-1 calculated for C26H27N7O6S:564).

Example 56

Analogously to example 35 from N-hydroxy-4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-bifenox)-2-[2-(5-methyl[1,2,4]oxadiazol-3-yl)pyridine-4-yl]pyrimidine-4-yl}amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 588,2 (M-1 calculated for C28H27N7O6S:588).

Example 57

a) Analogously to example 36 from [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid and ethylene glycol were obtained [2-[2-(2-hydroxyethoxy pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid white color. MC(ISN): m/e 566,2 (M-1 calculated for C27H29N5O7S:566).

Obtaining source material

b) Analogously to example 19b) of the potassium salt of 5-isopropylacrylamide (the receipt of which is described in EP 0799209) and 1-oxide 4-[4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine was obtained 6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-alamid 5-isopropylpyridine-2-sulphonic acid in the form of a solid white color, which was led from AcOEt, tPL233-235°C.

C) Analogously to example 19c) of 6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide 5-isopropylpyridine-2-sulfonic acid and sodium methoxide received [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid in VI

Example 58

Analogously to example 36 from [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid described in example 57b), and methanol were obtained [6-methoxy-5-(2-methoxyphenoxy)-2-(2-methoxypyridine-4-yl)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 536,2 (M-1 calculated for C26H27N5O6S:536).

Example 59

Analogously to example 19 of [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-methylthiazole-2-sulfonic acid and trimethylsilylacetamide received [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulphonic acid in the form of a solid light orange color. MC(ISN): m/e xxx,X (M-1 calculated for C22H18N6O5S2:509).

Obtaining source material

b) Analogously to example 19b) of the potassium salt of amide 5-methylthiazole-2-sulfonic acid described in example 9b), and 1-oxide 4-[4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine was obtained [6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-methylthiazole-2-sulphonic acid in the form of a solid ve is 2">

C) Analogously to example 29b of [6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] amide 5-methylthiazole-2-sulfonic acid and sodium methoxide received [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-methylthiazole-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 500,1 (M-1 calculated for C21H19ClN5O6S2:500).

Example 60

Analogously to example 20 of [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulfonic acid described in example 59, when processing 2H. NaOH received amide 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylthiazole-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid of light yellow color. MC(ISN): m/e 527 (M+1 calculated for C22H20N6O6S2:527).

Example 61

Analogously to example 21 from amide 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylthiazole-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 60, when processing 3h. HCl in THF was obtained 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylthiazole-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of solid light yellow is

Analogously to example 22 from 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylthiazole-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 61, by condensation with Meon in the presence of hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (the THIEF) was obtained methyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylthiazole-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid off-white color. MC(ISP): m/e 544,2 (M+1 calculated for C23H21N5O7S2:544).

Example 63

Analogously to example 36 from [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-methylthiazole-2-sulfonic acid described in example V), and ethylene glycol was obtained [2-[2-(2-hydroxyethoxy)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulphonic acid in the form of a solid off-white color. MC(ISN): m/e 544,1 (M-1 calculated for C23H23N5O7S2:544).

Example 64

Analogously to example 36 from [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-methylthiazole-2-sulfonic acid described in example V), and methanol were obtained [6-methoxy-5-(2-methoxyphenoxy)-2-(2-matout. MC(ISN): m/e 514,1 (M-1 calculated for C22H21N5O6S2:514).

Example 65

a) Analogously to example 19a) of [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid and trimethylsilylacetamide received [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid light brown color. MC(ISN): m/e 529,2 (M-1 calculated for C26H22N6ABOUT5S:529).

Obtaining source material

b) Analogously to example 19b) of the potassium salt of amide 5-isopropylpyridine-2-sulfonic acid described in example 15B), and 1-oxide 4-[4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine was obtained [6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 524,3 (M-1 calculated for C24H20ClN5O5S:524).

C) Analogously to example 23C) of [6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid and sodium methoxide received [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)PI is N): m/e 520,2 (M-1 calculated for C25H23N5O6S:520).

Example 66

a) Analogously to example 43 when handling sodium salt of methyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboximidic in the presence of 2n. HCl in the Meon received methyl ester 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 562,2 (M-1 calculated for C27H25N5O7S:562).

Obtaining source material

b) K 0,72 g of [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid described in example 65, in a dry Meon (20 ml) was added at KT 3.4 ml of 1 M NaOMe in dry Meon and the solution was stirred at 50°C for 5 hours Then was added 1.7 ml of a solution of NaOMe and heating (50°C) was continued for 2 h to complete the reaction results GHUR. The solution was cooled to CT and concentrated in vacuum. The resulting crystalline material was separated by filtration under vacuum and washed with ether, was obtained sodium salt of methyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-marks the 561,3 (M-1 calculated for the free sulfonamida27H26N6O7S:561).

Example 67

0.1 g of sodium salt of methyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboximidic described in example b), Meon (10 ml) was treated with KT 1.8 ml 1N. NaOH and the solution was stirred at RT for 26 h and Then was added to 1.8 ml of 1N. NaOH and the solution continued to stir for 20 h to complete the reaction results GHUR. The solution was concentrated and then poured into dilute aqueous model HC1 and the product was extracted with AcOEt. The organic layer was washed with water, dried over Na2SO4and concentrated in vacuum. The resulting crystalline precipitate was collected by filtration under vacuum and washed with ether, was obtained 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of crystals of light-yellow color. MC(ISN): m/e 548 (M-1 calculated for C26H23N5O7S:548).

Example 68

Analogously to example 29 when recovering methyl ester 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 66, NaBHl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 534,2 (M-1 calculated for C26H25N5O6S:534).

Example 69

Analogously to example 34 [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid described in example 65, and hydroxylamine hydrochloride was obtained N-hydroxy-4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxamide in the form of a solid of light yellow color. MC(ISN): m/e 566,2 (M-1 calculated for C26H25N7O6S:562).

Example 70

Analogously to example 35 from N-hydroxy-4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxamidine described in example 69, when the treatment with acetic anhydride in acetic acid was obtained {6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl[1,2,4]oxadiazol-3-yl)pyridine-4-yl]pyrimidine-4-yl}amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid light brown color. MC(ISN): m/e 586,1 (M-1 calculated for C28H25N7ABOUT6S:586).

Example 71

Analogously to example 20 of [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulf is)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid light brown color. MC(ISN): m/e 547,1 (M-1 calculated for C26H24N6ABOUT6S:547).

Example 72

Analogously to example 26 from 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 67, and methylamine hydrochloride were obtained of methylamide 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 561,2 (M-1 calculated for C27H26N6O6S:561).

Example 73

Analogously to example 36 from [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid described in example V), and ethylene glycol was obtained [2-[2-(2-hydroxyethoxy)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulphonic acid in the form of a solid of light yellow color. MC(ISN): m/e 564,2 (M-1 calculated for C27H27N5O7:564).

Example 74

a) Analogously to example 66A) when processing the sodium salt of the ethyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboximidic 2 is rimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 575,9 (M-1 calculated for C28H27N5ABOUT7S:576).

Obtaining source material

b) Analogously to example b) of [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid described in example 65, and NaOEt in dry ethanol was obtained sodium salt of the ethyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboximidic in the form of a solid light brown color. MC(ISN): m/e 575,1 (M-1 calculated for the free sulfonamida C28H28N6O6S:575).

Example 75

a) Analogously to example 19 of [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl) pyridine-2-sulfonic acid and trimethylsilylacetamide received [2-(2-cyano-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl)pyridine-2-sulfonic acid in the form of a solid light brown color. MC(ISN): m/e 547,1 (M-1 calculated for C26H24N6ABOUT5S:547).

Obtaining source material

b) Analogously to example 19b) of the potassium salt of amide 5-(1-hydroxy-1-methylethyl)pyridine-2-sulli [6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl)pyridine-2-sulfonic acid in the form of a solid white color. MC(ISP): m/e 544,1 (M+1 calculated for C24H22ClN5O6S:544).

C) Analogously to example 19b) of [6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl))pyridine-2-sulfonic acid and sodium methoxide received [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl))pyridine-2-sulfonic acid in the form of a solid white color. MC(ISN): m/e 538,2 (M-1 calculated for C25H25N5O7S:538).

Example 76

Analogously to example 36 from [6-methoxy-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] amide 5-(1-hydroxy-1-methylethyl) pyridine-2-sulfonic acid described in example 75V), and ethylene glycol was obtained [2-[2-(2-hydroxyethoxy)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-(1-hydroxy-1-methylethyl))pyridine-2-sulfonic acid in the form of a solid of light yellow color. MC(ISN): m/e 582,4 (M-1 calculated for C27H29N5O8S:582).

Example 77

To a solution of 0.52 g of 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, in DMF (10 ml) was added at RT to 0.23 g of 1,1,3,3-tetramethylguanidine, and then the reaction mixture was heated at 60°C for 20 h, was cooled to CT and distributed between ice water and EtOAc. The organic layer was washed with water, dried over Na2SO4and the organic solvent was removed in vacuum. The residue was purified by chromatography on a column of silica gel (elution tert-butylmethylamine ether). After combining the fractions containing the purified substance, and evaporation in vacuo received 1-ecotoxicology ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 608 (M-1 calculated for C28H27N5O9S:608).

Example 78

Analogously to example 77 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, chlormethiazole ether mevalonovoy acid was obtained 2,2-dimethylphenylacetate ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 636 (M-1 calculated for C30H31N4O9S:636).

Example 79

Analogously to example 77 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonyl toxicologically ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 638,1 (M-1 calculated for C29H29N5O10S:638).

Example 80

Analogously to example 77 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, and cyclohexyl-1-charitycardonate (the synthesis of which is described in Riondel, A. and others, Tetrahedron, 44, 1619, (1988)) received 1-cyclohexyloxycarbonyloxy ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 692,1 (M-1 calculated for C33H35N5O10S:692).

Example 81

Analogously to example 22 from 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, and hydroxyacetone received 2-oxopropyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISP): m/e 580,1 (M+1 calculated for C27H25N5O8S:580).

Example 82

Analogously to example 77 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-and-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 620,1 (M-1 calculated for C30H31N5O8S:620).

Example 83

Analogously to example 22 from 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21 and 2-hydroxyacetophenone received 2-oxo-2-phenethyl ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 640 (M-1 calculated for C32H27N5O8S:640).

Example 84

Analogously to example 77 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21, and 1-bromo-4-methylpentan-2-she (the synthesis of which is described in Catch and others, J. Chem. Soc., 278, (1948)) was obtained 4-methyl-2-oxopentanoic ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 620,1 (M-1 calculated for C30H31N5O8S:620).

Example 85

Analogously to example 22 from 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid, opsi)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISP): m/e 596,1 (M-1 calculated for C27H25N5O9S:596).

Example 86

Analogously to example 77 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid described in example 21 and 4-bromo-5-methyl[1,3]dioxol-2-she (the synthesis of which is described in Alpegiani M. and others, Synth. Commun., 22, 1277 (1992)) was obtained 5-methyl-2-oxo[1,3]dioxol-4-ymetray ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid in the form of a solid white color. MC(ISN): m/e 634,3 (M-1 calculated for C29H25N5O10S:634).

Example

Tablets containing the following ingredients can be prepared with the conventional method.

Ingredients mg per pill

The compound of formula (I) 10,0-100,0

Lactose 125,0

Corn starch 75,0

Talc 4,0

Magnesium stearate 1,0

Example B

Capsules containing the following ingredients can be prepared with the conventional method.

Ingredients mg / capsule

The compound of formula (I) 25,0

Lactose 150,0

Corn starch 20,0

Talc 5,0

The use of the S="ptx2">

Gelatin 150,0

Phenol 4,7

Water for injection To 1.0 ml

Example G

500 mg of the compounds of formula (I) are suspended in 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol. This suspension fill a container fitted with a metering valve. Through the valve into the container under pressure contribute 5.0 g of freon 12. Freon is dissolved in a mixture of Myglyol-benzyl alcohol shaking. This spray container contains approximately 100 single doses that can be entered by each one individually.

In the following table 5 shows the high activity of the new compounds and comparative data with the compounds described in EN 95120013.

1. The compound of formula (I)

in which R1denotes pyridyl, thiazolyl, optionally substituted with halogen, lower alkyl, hydrokinesis the alkyl or lower alkenyl;

R2means R21, -Y-R22or monovalent aromatic 5-membered carbocyclic radical containing at least one heteroatom selected from nitrogen and oxygen, despite the fact that this carbocyclic radical may be optionally substituted lower alkyl;

R21denotes cyano(CH2)0-3CH3, amidino, hydroxyamino, lower alkoxycarbonyl or hydroxylase alkoxycarbonyl;

R22denotes hydrogen, lower alkanoyl, carboxylate alkyl, lower alkoxycarbonyl, lower alkoxycarbonylmethyl alkyl, carbamoylmethyl alkyl, Denizli allylcarbamate alkyl, allyl, lower alkyl or hydroxylase alkyl;

Radenotes hydrogen or lower alkyl, optionally substituted hydroxy-group;

Rbdenotes hydrogen or lower alkyl;

Rcdenotes hydrogen, acetyl or lower alkylsulfonyl;

X represents-CH-or-N-;

Y represents-O-,-NH-,

and its pharmaceutically acceptable salts and esters.

2. Connection on p. 1, in which R1denotes pyridyl or thiazolyl, optionally substituted lower alkyl or lower alkenyl.

3. The compound according to any one of p. 1 or 2, in which R21denotes cyano, hidrogenesse alkyl, carboxy, -C(O)NRaRb,-CH2OTHERc, amidino, hydroxyamino or-CH2NHC(O)NHCH2CH3where Ra, Rband Rchave the values listed in paragraph 1.

4. The compound according to any one of paragraphs.1-3, in which R is Il or methylsulfonylamino.

5. The compound according to any one of paragraphs.1-4, in which R2means R21, -Y-R22or 5-membered carbocyclic radical containing at least one heteroatom selected from the series, including 2-imidazolyl, [1,2,4]oxadiazol-3-yl, 2-oxazolyl or 2-thiazolyl, optionally substituted lower alkyl.

6. The compound according to any one of paragraphs.1-5, in which R2means R21, -Y-R22or 5-membered carbocyclic radical containing at least one heteroatom selected from the series, including 2-imidazolyl, [1,2,4]oxadiazol-3-yl, optionally substituted lower alkyl.

7. The compound according to any one of paragraphs.1-6, in which R22denotes hydrogen, lower alkyl, carboxymethyl, lower alkoxycarbonylmethyl alkyl, carbamoylmethyl, dimethylcarbamoyl, hidrogenesse alkyl or acetyl.

8. The compound according to any one of paragraphs.1-6, in which R22denotes hydrogen, lower alkyl, lower alkoxycarbonylmethyl alkyl or hydroxylase alkyl.

9. Connection on p. 1, selected from the series, including

4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid,

methyl ester of 4-[4-methoxy-5-(2-methoxyphenoxy)-one-4-yl)-6-methoxy-5-(2-methoxyphenol-C)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

ethyl ester of 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid,

methyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

N-hydroxy-4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxamidine,

{6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl[1,2,4]oxadiazol-3-yl)pyridine-4-yl]pyrimidine-4-yl}amide 5-methylpyridin-2-sulfonic acid,

[2-[2-(methanesulfonylaminoethyl)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-[2-(methanesulfonylaminoethyl)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

{6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl[1,2,4]oxadiazol-3-yl)pyridine-4-yl}pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

[2-(2-lepirudin-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-[3-(2-hydrox>2-[2-(2-hydroxyethoxy)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

[2-(2-hydroxypyridine-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

ethyl ester {3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenoxy}acetic acid,

[2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy) pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

N-{4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-ylmethyl}ndimethylacetamide,

4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl] pyridine-2-carboxylic acid,

isopropyl ester 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

ethyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

[2-[2-(2-hydroxyethoxy)pyridine-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylthiazole-2-sulfonic acid,

amide 4-[4-(5-isopropylpyridine-2-sulfo propylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxamidine,

3-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]phenyl ester of acetic acid,

methyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

1-ecotoxicology ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid.

10. Connection on p. 1, selected from the group including

[2-[3-(2-hydroxyethoxy)phenyl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-(2-lepirudin-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl] pyridine-2-carboxylic acid,

methyl ester of 4-[4-methoxy-5-(2-methoxyphenoxy-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid,

[2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

e is th acid

[2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

amide 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

ethyl ester of 4-[4-(5-isopropylpyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid,

{6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl[1,2,4]oxadiazol-3-yl)pyridine-4-yl]pyrimidine-4-yl}amide 5-methylpyridin-2-sulfonic acid and

1-ecotoxicology ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid.

11. Connection on p. 1, selected from the group including

4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl]pyridine-2-carboxylic acid,

[2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

[2-(2-hydroxymethylpropane-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

1-ecotoxicology ester 4-[4-methoxy-5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)pyrimidine-2-yl is using against endothelioma receptors comprising the compound according to any one of paragraphs.1-11 and a pharmaceutically acceptable carrier and/or adjuvant.

13. Compounds according to any one of paragraphs.1-11, with inhibitory ability against endothelina receptor intended for the treatment of diseases associated with abnormal vascular tone and endothelial dysfunction.

 

Same patents:

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to a method for producing 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] methoxy] benzyl] thiazolidin-2,4-dione of formula (1), including the restoration of the compounds of formula (2'), where R is a (C1-C4)alkyl group, with the use of Raney Nickel or magnesium and, optionally, re-esterification using sulfuric acid in the temperature range from 0 to 60oWith obtaining the compounds of formula (3'), which is subjected to hydrolysis to obtain the acid of formula (4), the condensation of the acid of formula (4) with N-methyl-anthranilamide formula (7) without any pre-activation of the acid to obtain the compounds of formula (1), which is optionally transformed into a pharmaceutically acceptable salt

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to new derivatives of amine of the formula (I), where R1is karbamoilnuyu group (which may have one or two Deputydescribed later), thiocarbamoyl group (which may have one or two Deputydescribed later), sulfonyloxy group (which has one Deputydescribed next) or carbonyl group (which has one Deputydescribed below); R2represents a hydrogen atom; R3represents C1-C10alkyl group; W1, W2and W3each represents a single bond or C1-C8alkylenes group; X represents an oxygen atom or a sulfur atom; Y represents an oxygen atom; Q represents a sulfur atom; Z represents = CH-group or a nitrogen atom; Ar represents a benzene or naphthalene ring; L represents 1 to 2 substituents in Ar ring and each Deputy represents a hydrogen atom, a C1-C6alkyl group; Deputyrepresents (i) C1-C10alkyl group, (ii)3-Сu/chr/947.gif" ALIGN="ABSMIDDLE">described later), and so on; Deputyrepresents (i) C1-C6alkyl group, (ii) C1-C6halogenating group, (iii) C1-C6CNS group, (iv) halogen atom, (v) hydroxyl group, (vi) cyano, (vii) a nitro-group, (viii) alkylenedioxy; or its pharmaceutically acceptable salts or esters

The invention relates to new derivatives of phenylsulfonylacetate General formula (I), which are herbicide and regulating plant growth properties and can find application in agriculture

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to new imidazole-cyclic acetals of the formula I, where R1- optionally substituted 4-pyridyl or optionally substituted 4-pyrimidinyl; R2is phenyl, substituted with halogen; R3is hydrogen; R4refers to a group - L3-R14; R5is hydrogen, alkyl or hydroxyalkyl; or R4and R5when attached to the same carbon atom, may form with the specified carbon atom kernel cycloalkyl or the group C=CH2; R6is hydrogen or alkyl and m=1; L3and R14have the meanings specified in the description, and pharmaceutically acceptable salts and solvate (for example, hydrates), which have inhibitory activity against TNF-alpha, as well as to intermediate compounds, pharmaceutical compositions and method of treatment

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to derivatives of cyclic amines and their use as pharmaceuticals, particularly to a compound represented by the General formula (I), its pharmaceutically acceptable acid additive salts or its pharmaceutically acceptable C1-C6alcaldicios salt, R1-phenyl, C3-8-cycloalkyl, aromatic heterocycle with 1-3 heteroatoms selected from O, S, N, or combinations thereof, and these groups may be condensed with benzene ring or an aromatic heterocyclic group with heteroatoms, selected from O, S or N, or combinations thereof, and may also have different substituents

The invention relates to new chemical compounds, in particular derived 1,4,2,5-deoxidizing General formula I, where R denotes the formula II and R1denotes the N3or NO2

The invention relates to a derivative of benzamidine formula I, where R1denotes-C(=NH)-NH2; R2denotes H; R3refers to -[C(R5)2]m-СООR5, R3and X together represent well-CO-N-, form a 5-membered ring, with R3refers to - C = O, and X denotes N, R4means And, cycloalkyl, -[C(R5)2]mAr; X represents O, NR5or CH2Y represents O, NR5N[C(R5)2]m-Ar, N[C(R5)2]m-Het, - N[C(R5)2]m-СООR5W represents a bond, -SO2-, -CO - or-СОNR5-

The invention relates to new arylpiperazine derivative of General formula I

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and their pharmaceutically acceptable salts, esters, where Y is O; Q is CH; X, Z and Z' each independently represent CH or N; m=0-1; n=0-4; R1and R2independently selected from H, F, Cl, Br, OCH3OC2H5, OCH2CF3CH3WITH2H5, CF3isopropylate; R3represents H; R4and R5represent H or phenyl, except that R1represents H, R2represents H, Cl or CF3, R3, R4and R5=N, Y=0, and Q=CH, if m=0 and n=1; and also except that R1represents H, R2is OCH3, R3, R4and R5=H, Y=0, Q=CH, if m=0 and n=2
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