Aromatic compounds and containing pharmaceutical compositions

 

(57) Abstract:

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula NRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; RAlkyl optionally substituted hydroxy-group or halogen, or their pharmaceutically acceptable salt or in vivo hydrolyzable esters. The compounds are antagonists boleutolyayuschee actions of prostaglandins type that is Disclosed also is a method of obtaining these compounds, intermediate compounds for their production, pharmaceutical composition for the treatment of pain and how pain relief. 5 S. and 6 C.p. f-crystals, 1 table.

The invention relates to new aromatic compounds and their pharmaceutically acceptable salts possess valuable pharmacological properties. More specifically, the compounds according to the invention are antagonists boleutolyayuschee action of prostaglandin E-type. The invention relates also to methods for aromatic compounds and their pharmaceutically acceptable salts; to the containing new pharmaceutical compositions and to the use of compounds for the relief of pain.

Compounds according to the invention can be used for the relief of pain such as pain associated with disease of the joints (e.g. rheumatoid arthritis and osteoarthritis), postoperative pain, postpartum pain, pain associated with tooth disease (e.g., dental caries and gingivitis), pain associated with burns (including solpugida); for the relief of pain associated with sports injuries and sprains, as well as for treatment of any other medical conditions, in which the prostaglandin E-type in whole or in part play a pathophysiological role.

Non-steroidal anti-inflammatory drugs (NSPs) and opiates are a major class of analgesics. However, both of these groups of compounds have undesirable side effects. It is known that NSPs cause irritation of the gastrointestinal tract, and opiates, as you know, are drugs.

Applicants have discovered a class of compounds that are structurally different from NSPs and opiates and which can be used as painkillers.

Compounds according to the invention may also have anti-inflammatory, antipyretic and protivopolozhnym properties and to be effective in the treatment of other conditions in which prostaglandin E2-(PGE2) in whole or in part plays a pathophysiological role.

In European patent application 0000816 (Example 28) described 2-[2-methoxybenzylamine] pyridine-5-carboxylic acid, which, as indicated, may be used for the treatment of Diab is inania has hypolipidemic activity. 3-[2-Methoxybenzylamine] -4-chloro-5-sulfamoylbenzoic acid and 3-[2,3-dimethoxybenzamide]-4-chloro-5-sulfamoylbenzoic acid described R. Feit and others (J. Med. Chem., 1970, 13, 1071) as diuretics. 5-[2,5-Dimethoxyphenethylamine]-2-hydroxybenzoic acid described R. Nussbaumer and others (J. Med. Chem., 1994, 34, 4079) as an antiproliferative agent.

The present invention relates to a compound of formula I:

< / BR>
where a is optionally substituted:

phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl or thiadiazolyl having at least two adjacent ring carbon atom;

provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-positions relative to one another on ring carbon atoms and the ring carbon atom located in anthopology towards or SIG4-joined the group (and therefore in the 3-position relative to the-CHR3NR2- joined the group), is unsubstituted;

B is optionally substituted:

phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl, imidazolyl, pyrazinyl, pyridazinyl or pyrimidyl;

R1is the ring B in a 1,3 - or 1,4-state is, tetrazolyl, tetrazolyl1-3alkyl, tetronic acid, hydroxamic acid, sulphonic acid, or R1represents a group of formula-CONRaRa1where Rarepresents hydrogen or C1-6alkyl, and Ra1represents hydrogen, C1-6alkyl (optionally substituted with halogen, amino, C1-4alkylamino, di-C1-4alkylamino, hydroxy, nitro, cyano, trifluoromethyl, C1-4alkoxy or C1-4alkoxycarbonyl)2-6alkenyl (provided that the double bond is not in the 1-position)2-6quinil (assuming that the triple bond is not in the 1-position), carboxyphenyl, 5 - or 6-membered heterocyclic1-3alkyl, 5 - or 6-membered heteroaryl1-3alkyl, 5 - or 6-membered heterocyclyl or 5 - or 6-membered heteroaryl; or Raand Ra1taken together with the nitrogen atom of amide group to which they are attached (NRaRa1) form amino acid residue or ester, or R1represents a group of formula CONHSO2Rbwhere Rbrepresents C1-6alkyl (optionally substituted with halogen, hydroxy, nitro, cyano, trifluoromethyl, C1-4alkoxy, amino, C1-4alkylamino, di-C1-4alkylamino or1-4kenil (provided that the triple bond is not in the 1-position), 5 - or 6-membered heterocyclic1-3alkyl, 5 - or 6-membered heteroaryl1-3alkyl, panels1-3alkyl, 5 - or 6-membered heterocyclyl, 5 - or 6-membered heteroaryl or phenyl;

where any heterocyclic or heteroaryl group, Ra1is optionally substituted with halogen, hydroxy, nitro, cyano, trifluoromethyl, C1-4alkoxy or1-4alkoxycarbonyl and any phenyl, heterocyclic or heteroaryl group, Rbis optionally substituted with halogen, trifluoromethyl, nitro, hydroxy, amino, cyano, C1-6alkoxy, C1-6S(O)p(p=0, 1 or 2), C1-6the alkyl, carbamoyl,1-4allylcarbamate, di(C1-4alkyl) carbamoyl,2-6alkenyl,2-6the quinil,1-4alkoxycarbonyl,1-4alkanolamine,1-4alkanoyl(N-C1-4alkyl) amino, C1-4alkanesulfonyl, benzosulfimide, aminosulfonyl,1-4alkylaminocarbonyl, di(C1-4alkyl) aminosulfonyl,1-4alkoxycarbonyl,1-4alkanoyloxy, C1-6alkanoyl, formals1-4the alkyl, hydroxyimino1-6the alkyl, C1-4alkoxyimino1-6the alkyl Hai>c
represents hydrogen or C1-4alkyl, and Rc1represents hydrogen or C1-4alkyl;

or R1represents a group of formula (IA), (IB) or (IC):

< / BR>
< / BR>
< / BR>
where X represents CH or nitrogen, Y is oxygen or sulfur, Y' is oxygen or NRdand Z is CH2, NRdor oxygen, provided that the ring has no more than one oxygen atom and at least two heteroatom, and where Rdrepresents hydrogen or C1-4alkyl.

R2represents hydrogen, C1-6alkyl, optionally substituted by hydroxy, cyano or trifluoromethyl; WITH2-6alkenyl (provided that the double bond is not in the 1-position)2-6quinil (assuming that the triple bond is not in the 1-position), phenyl C1-3alkyl or pyridyl1-3alkyl;

R3represents hydrogen, methyl or ethyl;

R4represents optionally substituted C1-6alkyl, C3-7cycloalkyl1-3alkyl or C3-7cycloalkyl;

and N-oxides of the group-NR2where it is chemically possible;

and S-oxides of serosoderjaschei rings, where chemically possible;

and their pharmaceutically acceptable salts and in vivo hydrolyzable Sino] benzoic acid, 3-[2-methoxybenzylamine] -4-chloro-5-sulfamoylbenzoic acid, 3-[2,3-dimethoxybenzamide]-4-chloro-5-sulfamoylbenzoic acid and 5-[2,5-dimethoxy-benzylamino]-2-hydroxybenzoic acid.

5 - or 6-membered heteroaryl ring system is monocyclic aryl ring system having 5 or 6 ring atoms, where 1, 2 or 3 ring atoms selected from nitrogen atoms, oxygen and sulfur.

5 - or 6-membered saturated or partially saturated heterocyclic ring is a ring system having 5 or 6 ring atoms, where 1, 2 or 3 ring atoms selected from nitrogen atoms, oxygen and sulfur.

The particular 5 - or 6-membered monocyclic heteroaryl rings are pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl, furyl and oxazolyl.

The particular 5 - or 6-membered saturated or partially saturated heterocyclic ring systems are pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidine, piperidyl, piperazinil and morpholinyl.

Specific substituents at the ring carbon atoms in a (heterocyclic and heteroaryl kiano, C1-6alkoxy, C1-6alkyl S(O)p(p=0, 1 or 2), C1-6alkyl (optionally substituted by hydroxy, amino, halogen, nitro or cyano), CF3S(O)p(p=0, 1 or 2), carbarnoyl,1-4allylcarbamate, di(C1-4alkyl) carbarnoyl,2-6alkenyl,2-6quinil, C1-4alkoxycarbonyl,1-4alkanolamine,1-4alkanoyl (N-C1-4alkyl) amino, C1-4alkanesulfonyl, benzosulfimide, aminosulfonyl,1-4alkylaminocarbonyl,1-4alkanolamines, di(C1-4alkyl) aminosulfonyl,1-4alkoxycarbonyl,1-4alkanoyloxy, C1-6alkanoyl, formals1-4alkyl, drifters1-3alkylsulfonyl, hydroxyimino1-6alkyl, C1-4alkoxyimino1-6alkyl and C1-6alkylcarboxylic.

In the case where a ring nitrogen atom And may be substituted, but not quaternity, he is unsubstituted or substituted WITH1-4the alkyl.

Specific substituents at the ring carbon atoms in include halogen, trifluoromethyl, nitro, hydroxy, C1-6alkoxy, C1-6alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano, C1-6S(O)p(p=0, 1 or 2), carbarnoyl,1-4Alki the puppy, but not quaternity, he is unsubstituted or substituted WITH1-4the alkyl.

The term "alkyl" used in the present description, means alternates with a straight or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl; and a functional group on the alkyl chain may be present in any part of this circuit, for example, hydroxyimino1-4the alkyl is 1-(hydroxyimino)propyl and 2-(hydroxyimino)propyl.

C1-6the alkyl substituted by halogen, is trifluoromethyl.

Amino acid residues that are made up of Raand Ra1taken together with the nitrogen atom to which they are attached, are the remains (-NHCH(R)COOH), derivatives, natural or not naturally occurring amino acids. Examples of suitable amino acids include glycine, alanine, serine, threonine, phenyl-alanine, glutamic acid, tyrosine, lysine and dimethylglycine.

Suitable ring systems of formulae (1A), (1B) or (1C) include 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl, 3-dioxo-2,3-dihydro-1,2,4-oxadiazol-5-yl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 5-oxo-4,5-dihydro-1,2,4-triazole-3-yl, 5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-2-pyrazol-3-yl.

Examples of C1-6alkoxycarbonyl are methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl; examples carboxy1-3the alkyl are carboxymethyl, 2-carboxyethyl, 1-carboxyethyl and 3-carboxypropyl; examples of C1-6alkoxycarbonyl1-3the alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples tetrazolyl1-3the alkyl are tetrazolyl and 2-tetrazolyl; examples of C1-4alkoxy are methoxy, ethoxy, propoxy, isopropoxy; examples2-6alkenyl are vinyl and allyl; examples2-6the quinil are atenil and PROPYNYL; examples of C1-4alkanoyl are formyl, acetyl, propionyl, butyryl; examples of halogen are fluorine, chlorine, bromine and iodine; examples of C1-4alkylamino are methylamino, ethylamino, propylamino, isopropylamino; examples of di(C1-4alkyl) amino are dimethylamino, diethylamino, ethylmethylamino; examples of C1-6alkyl S(O)pare methylthio, methylsulfinyl and methylsulphonyl; examples1-4allylcarbamate are methylcarbamoyl and ethylcarbitol; examples of di(C1-4alkyl) carbamoyl are dimethylcarbamoyl, diethylcarbamoyl and ethylcarbitol; pavlata methoxycarbonylamino, ethoxycarbonylethyl; examples1-4alkanolamine are acetamido, propionamido; examples1-4alkanoyl(N-C1-4alkyl) amino are N-methylacetamide and N-methylpropionamide; examples1-4alkanesulfonyl are methanesulfonamido, acanalonia; examples of C1-4alkylaminocarbonyl are methylaminomethyl and acylaminoalkyl; examples of di(C1-4alkyl) aminosulfonyl are dimethylaminoethanol, Diethylaminoethanol, ethylmethylamino-sulfonyl; examples1-4alkanoyloxy are the atomic charges and propionyloxy; examples of formals1-4the alkyl are formylmethyl and 2-formylated; examples hydroxyimino1-6the alkyl are gidroksilaminami and 2-(hydroxyimino) ethyl and examples1-4alkoxyimino1-6the alkyl are methoxyaminomethyl, toksienosti and 2-(methoxyimino)ethyl.

It should be noted that, if the compounds of formula I have a chiral center, the compounds according to the invention can exist and can be isolated in optically active or racemic form. The invention includes any optically active or racemic form the compounds of formula I, which has analgesic properties. Synthesis optical is the illusion for example, by separation of the racemic form by synthesis from optically active starting compounds or by asymmetric synthesis. In addition, it should be noted that some compounds of formula I can exist as geometric isomers. The present invention includes any geometrical isomer of the compounds of formula I, which has analgesic properties.

It should also be noted that some compounds of the present invention may exist in solvated, for example hydrated, and resolutional form. In addition, the present invention includes all of these solvated forms that possess analgesic properties.

It should also be noted that the scope of the present invention includes tautomers of compounds of formula (I).

Preferably a is optionally substituted: phenyl, naphthyl, thiadiazolyl, thienyl, pyridyl or pyrimidyl.

Preferably represents optionally substituted: pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl or oxazolyl.

Most preferably a is optionally substituted phenyl or thienyl.

More preferably prestressed optionally substituted phenyl.

In particular, is optionally substituted: pyrid-2,5-diyl, pyridazin-3,6-diyl, Hairdryer-1,4-diyl or Tien-2,5-diyl.

Particularly preferably represents optionally substituted pyridazin-3,6-diyl or pyrid-2,5-diyl.

Especially preferably is pyridazinyl.

Preferred optional substituents for ring carbon atoms in a are halogen, nitro, trifluoromethyl, cyano, amino, C1-6alkoxy, carbarnoyl,1-4allylcarbamate, di(C1-4alkyl) carbarnoyl,1-4alkanolamine, C1-6S(O)p- WITH1-4alkanesulfonyl, benzosulfimide, C1-6alkanoyl,1-4alkoxyimino1-4alkyl and hydroxyimino1-4alkyl.

If a represents a 6-membered ring, And is preferably unsubstituted or substituted in the 4-position relative to the group-OR4.

Preferred optional substituents for ring carbon atoms in b are halogen, trifluoromethyl, C1-4alkyl, amino, C1-4alkylamino, dis1-4alkylamino, nitro, hydroxy, C1-6alkoxy and cyano.

Preferably, a is unsubstituted or substituted by one Deputy who or chlorine.

Most preferably, a is unsubstituted or substituted by bromine or chlorine.

Preferably is unsubstituted or substituted by one Deputy.

Most preferably is unsubstituted.

Preferably R1represents carboxy, carbarnoyl or tetrazolyl or R1represents a group of formula-CONRaRa1where Rarepresents hydrogen or C1-6alkyl, and Ra1represents C1-6alkyl, optionally substituted by hydroxy; C2-6alkenyl; 1-morpholinyl; 1-piperidinyl; 1-pyrrolidinyl; pyridyl1-3alkyl; or R1represents a group of formula CONHSO2Rbwhere Rbrepresents optionally substituted C1-6alkyl, phenyl or 5 - or 6-membered heteroaryl.

In particular, R1represents carboxy, tetrazolyl or a group of the formula-CONRaRa1where Rarepresents hydrogen, and Ra1represents C1-6alkyl, optionally substituted by hydroxy or pyridylmethyl; or R1represents a group of formula CONHSO2Rbwhere Rbrepresents C1-6alkyl (optionally substituted by hydroxy or fluorine), phenyl (optionally substituted by Aceto).

Most preferably, R1represents carboxy, tetrazole or a group of the formula-CONHRa1where Ra1is pyridylmethyl; or (C1-4alkyl, optionally substituted by hydroxy; or a group of the formula-CONHSO2Rbwhere Rbis1-4alkyl, 3,5-dimethylisoxazol-4-yl or 5-acetamido-1,3,4-thiadiazole-2-yl.

In another aspect of the present invention R1represents carboxy, carbarnoyl or tetrazolyl; or R1represents a group of formula-CONRaRa1where Rarepresents hydrogen or C1-6alkyl, a Ra1represents C1-6alkyl, optionally substituted hydroxy, C2-6alkenyl; 1-morpholinyl; 1-piperidinyl; 1-pyrrolidinyl; pyridyl1-3alkyl; or R1represents a group of formula CONHSO2Rbwhere Rbis C1-6the alkyl or phenyl.

Preferably R2represents hydrogen, methyl, ethyl, 2,2,2-triptorelin, cyanomethyl, allyl, or 3-PROPYNYL.

More preferably R2represents hydrogen, methyl, ethyl or propyl.

Even more preferably R2represents hydrogen or ethyl.

Most preferably, R2is ethyl.

More preferably R4optionally substituted by fluorine, chlorine or bromine.

Most preferably, R4optionally substituted by fluorine, trifluoromethyl, cyano or hydroxy.

Preferably R4is1-4alkyl, C3-6cycloalkyl or3-6cycloalkylation.

More preferably R4is propyl, isobutyl, butyl, 2-ethylbutyl, 2(R)-methylbutyl, 2(S)-methylbutyl, 2,2,2-triptorelin, cyclopentylmethyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

Most preferably, R4is propyl, isobutyl, butyl, 2-ethylbutyl, cyclopentyl, cyclopropylmethyl or cyclopropyl.

A preferred class of compounds are the compounds of formula (II):

< / BR>
where R1and R2defined above; R4is1-4alkyl, C3-6cycloalkyl or3-6cycloalkenyl; R5represents hydrogen or as defined above for the substituents of the ring carbon atoms in a and b represents phenyl, thienyl, pyridazinyl, pyridyl or thiazolyl.

In vivo hydrolyzable complex ester compounds of formula (I) containing carboxypropyl is, for example, pharmaceutically acceptable ester which is hydrolysed in the human or animal with the formation of the original acid, for example, pharmaceutically acceptable ester formed (C1-6)alcohol, such as methanol, ethanol, ethylene glycol, propanol or butanol or phenol or benzyl alcohol, such as phenol or benzyl alcohol or a substituted phenol or benzyl alcohol, where the substituents are, for example, halogen (such as fluorine or is the train includes-aryloxyalkyl esters and a source connection, which decompose with the formation of the original hydroxy-group. Examples-aryloxyalkyl esters are acetoxymethyl and 2,2-diethylpropionandambieney.

In vivo hydrolyzable complex ester compounds of formula (I) containing a hydroxy-group is, for example, pharmaceutically acceptable ester which is hydrolysed in the human or animal with the formation of the original alcohol. The term includes inorganic esters such as esters of phosphoric acid and aryloxyalkyl ethers, as well as the starting compounds, which are formed in the in vivo hydrolysis of ester, degradable obtaining the original hydroxy-group. Examples simple-aryloxyalkyl esters are azoxymethane and 2,2-dimethoxyphenylacetone. Groups forming in vivo hydrolyzable ester with the release of the hydroxy-group selected from alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (with the formation of esters alkalicarbonate acid), dialkyl-carbamoyl and N-(dialkylaminoalkyl)-N-allylcarbamate (for the formation of carbamates), dialkylaminoalkyl and carboxyethyl.

p, N-(1-6C)alkyl - or N, N-di-(1-6C)alkylamide, such as N-methylamide, N-ethylamide, N-propylamide, N,N-dimethylamide, N-ethyl-N-methylamide or N,N-diethylamide.

A suitable pharmaceutically acceptable salt of the compounds of formula (I) is, for example, an acid additive salt of the compound of formula I which is sufficiently basic, for example an acid additive salt formed with an inorganic or organic acid, such as chloromethane, Hydrobromic, sulfuric, triperoxonane, citric or maleic acid; or, for example, the salt of the compounds of formula (I) which is sufficiently acidic, for example, salts of alkali or alkaline earth metal, such as a salt of calcium or magnesium, or ammonium salt or a salt formed with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-(2-hydroxyethyl)amine.

In another aspect the present invention relates to a method for producing compounds of formula (I) or their pharmaceutically acceptable salts or in vivo hydrolyzable amides or esters; and this method involves removing the protection from the compounds of formula (III):

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where R6is R1or protected R
and then, if necessary:

i) obtaining a pharmaceutically acceptable salt;

ii) obtaining in vivo hydrolyzable of ester or amide;

iii) conversion of one optional substituent other optional Deputy.

The protective group can be selected from any suitable group, described in the literature, and can be introduced by standard methods.

The protective group may be removed by any known method suitable for the removal of this protective group, and this method must be selected so that it effectively removed the protective group with minimal impact on any other group in the molecule.

A suitable group for the protection of the hydroxy-group is, for example, allmerica group (particularly benzyl), three-(C1-4) alkylsilane group (in particular, trimethylsilyl or tert-butyldimethylsilyl), Arild-(C1-4) alkylsilane group (in particular, dimethylphenylsilane), diaryl(C1-4) alkylsilane group (in particular, tert-butyldiphenylsilyl), (C1-4) alkyl is of SCP (in particular, methoxymethyl) or tetrahydropyranyl group (in particular, tetrahydropyran-2-yl). Conditions for removal of the above-mentioned protective groups can vary depending on the choice of protective groups. For example, allmerica group such as benzyl group may be removed by hydrogenation in the presence of a catalyst such as palladium-on-charcoal grill. Alternatively, trialkylsilyl or kildeangivelse group, such as tert-butyldimethylsilyl or dimethylphenylsilane group may be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulphuric, phosphoric or triperoxonane acid, or a fluoride of an alkali metal or ammonium, such as sodium fluoride or preferably of forinternational. Alternatively, the alkyl group may be removed, for example by treatment (C1-4) alkylsulfides alkali metal, such as titoxd sodium, or, for example, by processing diarylphosphino alkali metal such as lithium diphenylphosphide, or, for example, by treatment with trihalogen boron or aluminum, such as tribromide boron. Alternatively, (C1-4) alkoxymethyl group or tetrahydropyranyl group may be removed, for example, p is native, a suitable protecting group for a hydroxy-group is, for example, acyl group, for example (C2-4) alcoolica group (in particular, acetyl) or arolina group (in particular, benzoyl). Conditions for removal of the above-mentioned protective groups can vary depending on the choice of protective groups. So, for example, acyl group, such as alcoolica or arolina group may be removed, for example, by hydrolysis using a base such as an alkali metal hydroxide such as lithium hydroxide or sodium.

A suitable protecting group for amino-, imino - or alkylamino is, for example, acyl group, such as (C2-4) alcoolica group (in particular, acetyl), (C1-4) alkoxycarbonyl group (in particular, methoxycarbonyl, etoxycarbonyl or tert-butoxycarbonyl), alletocoerli-nilina group (in particular, benzyloxycarbonyl) or arolina group (in particular, benzoyl). Conditions for removal of the above-mentioned protective groups can vary depending on the choice of protective groups. So, for example, acyl group, such as alcoolica, alkoxycarbonyl or arolina group may be removed, for example, by hydrolysis with ispolzovaniem, acyl group, such as tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulphuric or phosphoric acid or triperoxonane acid, and armletaccessory group, such as benzyloxycarbonyl group may be removed, for example by hydrogenation in the presence of a catalyst such as palladium-on-charcoal grill.

A suitable protecting group for carboxypropyl is, for example, tarifitsiruyutsya group, for example (C1-4)alkyl group (particularly methyl or ethyl), which can be removed by hydrolysis with a suitable base, such as hydroxide of alkali metal such as lithium hydroxide or sodium; and tert-bucilina group may be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulphuric, phosphoric or triperoxonane acid.

In another aspect of the present invention compounds of formula (I) or (III) can be obtained:

a) restoration of the compounds of formula (IV):

< / BR>
b) when is activated heterocycle and R7represents hydrogen or C1-6alkyl, the interaction of the compounds of formula (V) with the compound formularies X2in R6in the compound of formula (IX)

< / BR>
e) when R7is not hydrogen, the interaction of the compounds of formula R7X3with the compound of the formula (X):

< / BR>
f) the interaction of the compounds of formula (XI) with the compound of the formula (XII):

< / BR>
(g) the interaction of the compounds of formula (XIII) with the compound of the formula (XIV):

< / BR>
h) the interaction of the compounds of formula (XV) with the compound of the formula X7R4:

< / BR>
where R3, R4, R7, R9, A and b defined above, and X and X1are leaving groups, X2is a predecessor of R7; X3is a leaving group, X4is remove the trigger group, X5is a leaving group, X6is an activating group, and X7is a leaving group;

and then, if necessary:

i) removing any protective groups;

ii) obtaining a pharmaceutically acceptable salt;

iii) obtaining in vivo hydrolyzable of ester or amide;

iv) optional conversion of the substituent in another optional Deputy.

Specific leaving groups are halogen, for example chlorine, bromine and iodine, sulfonates, such as tosylate, p-bromobenzoic is as ester diarylphosphino acid.

The compounds of formula (IV) can be recovered using such agents as sodium borohydride or cyanhydric sodium. The compounds of formula (IV) can be obtained by reacting the compounds of formula (VII) with the compound of the formula (XV):

< / BR>
where A, R3and R4defined above.

The interaction between the compounds of formulae (VII) and (XV) can occur under standard conditions, which are usually used to obtain the imine (Schiff's base), which can be restored in situ. For example, the imine formation and recovery in situ can be carried out in an inert solvent, such as toluene or tetrahydrofuran, in the presence of a reducing agent, such as Lamborgini sodium (NN3in acidic conditions (Synthesis 135, 1975; Org. Prep. Proceed. Int. 11, 201, 1979).

Compounds of formulas (V) and (VI) can be subjected to interaction under standard conditions, for example in an aprotic solvent such as DMF, in the presence of a weak base at a temperature ranging from room temperature to 180oC. Suitable X are halogen, tosylate, mesilate and triptorelin. In particular, X is chlorine or bromine.

Compounds of formulas (VII) and (VIII) may be subjected to in the and sodium hydride, at a temperature of from 0oWith up to 100oC. Suitable X1are halogen, tosylate, mesilate and triptorelin. In particular, X1is bromine.

The predecessor group, R7is a group which can be converted to R7.

Specifically, X2means cyano, carbarnoyl, alkoxycarbonyl, carboxy and activated carboxypropyl, such as the acid chloride, and activated esters.

Cyano can be converted to tetrazole ring by reacting, for example, with ammonium azide or tin in an aprotic solvent such as DMF, at a temperature of from 100oWith up to 130oC. for More information about the synthesis of tetrazole can be found in the works of S. J. Wittenberger & B. J. Donner JOC, 1993, 58, 4139-4141; B. E. Huff et al., Tet. Lett, 1993, 50, 8011-8014 and J. V. Duncia et al., JOC, 1991, 56, 2395-2400.

Alkoxycarbonyl can be converted into carboxypropyl by acidic or basic hydrolysis. So, for example, the basic hydrolysis can be carried out in an organic solvent such as methanol or tetrahydrofuran (TTF) at a temperature ranging from room temperature to 100oC in the presence of sodium hydroxide or potassium hydroxide.

Acid versatile, in an inert solvent such as dichloromethane.

Alkoxycarbonyl or activated carboxypropyl, such as the acid chloride or activated ester, or acyl group, such as alcoolica group, can be converted to an amide group by reacting with the appropriate amine in an inert solvent, such as DMF or dichloromethane, at a temperature of from 0oWith up to 150oC and preferably at room temperature in the presence of a base such as triethylamine.

Compounds of formula (X) and R7X3can be subjected to interaction in an aprotic solvent such as DMF, in the presence of a base such as sodium carbonate or sodium hydride. Suitable for X3are halogen, tosylate, mesilate and triptorelin, and especially halogen, such as iodine.

The interaction between the compounds of formulas (XI) and (XII) are usually carried out under mild conditions, known as the reaction Mizunami, for example, in the presence of di(C1-4alkyl)isocarboxazide and triphenylphosphine or 11, 11(azodicarbon)dipiperidino and tributylphosphine (Tet. Lett, 34, 1993, 1639-1642) in an inert solvent, such as toluene, benzene, tetrahydrofuran or diethylether CLASS="ptx2">

The interaction between the compounds of formulae (XIII) and (XIV) usually occurs in the presence of a strong base such as sodium hydride, diisopropylamide lithium or LiN(SiMe3)2in DMF or ethereal solvent such as ethyl ether or THF, at temperatures ranging from -78oWith up to room temperature. Suitable X5is, for example, halogen, methanesulfonate or toilet. Examples of activating groups X6are tert-butoxycarbonyl, halogen and TRIFLUOROACETYL.

The interaction between the compounds of formulae (XV) and X7R4can be carried out in an inert organic solvent such as acetone or DMF, at a temperature ranging from room temperature to 60oIn the presence of a weak base. Suitable leaving groups are toilet, mesilate, triptorelin and halogen, for example chlorine or bromine. Alternatively, it may be used interfacial system. X7may be a hydroxy-group, which is activated in situ under the reaction conditions Mizunami (O. Synthesis, 1981, 1).

The compounds of formula (XV), where R6is R1and R7is R2themselves possess analgesic properties.

Compounds of formula (IV), (V) OR4(similar to method 1) from the appropriate starting compounds.

The compounds of formula (IX) can be obtained by methods a), b), C), e), f), g) or h) from the corresponding starting compound in which R6replaced by X2.

The compounds of formula (X) can be obtained by one of the methods a), b), C), d), f), g) or h) from the appropriate starting compounds, where R7represents hydrogen.

The compounds of formula (XII) can be easily obtained from compounds of formula (VII).

Compounds of formula (VI), (VII), (XII) and (XIV) are generally known compounds or they can be obtained by the methods described in the examples or by methods that are typically used to obtain related compounds. Some compounds of formula (VI) in which X is chlorine or bromine, can be obtained by converting the carbonyl group in the ring system in the group of chlorine or bromine by reacting oxocortisol system with gloriouse agent such as sulphonylchloride, trichloride phosphorus, pentachloride phosphorus or P(O)CL3or brainwashin agent such as tribromide phosphorus or P(O)Br3in an inert aprotic solvent.

You can also synthesize some the rigid guide "The Chemistry of Heterocyclic Compounds' E. C. Taylor and A. Veissberger (published by John & Sons) and "Comprehensive Heterocyclic Chemistry", A. P. Katritsky &. C. W. Rees (published by Pergamon Press).

Optional substituents can be converted to other optional substituents. For example, allylthiourea can be oxidized with the formation of alkylsulfonyl or alkylsulfonyl group, the nitro-group can be restored with the formation of an amino group, a hydroxy-group can be alkylated with education metoxygroup or group of bromine can be converted into allylthiourea.

In the compounds of formula (I) and formula (III) and intermediate compounds formed during the formation of compounds of formulas (I) and (III), if necessary, can be entered in different substituents using conventional methods known in the art. So, for example, acyl group or alkyl group may be introduced into an activated benzene ring by reaction Friedel -; formyl group can be introduced by reaction of formirovaniya using titanium tetrachloride and dichlorodifluoro simple ether; the nitro-group can be introduced by reaction of nitration with concentrated nitric and concentrated sulfuric acid, and tx2">

It should be noted that in order to prevent adverse reactions at some stage of the reaction scheme for obtaining compounds of formula (I) may be necessary to protect certain functional groups of intermediate compounds. Then, if protection is no longer needed, at an appropriate stage of the reaction scheme may be implemented to remove protection.

As mentioned above, the compounds of formula (I) are antagonists boleutolyayuschee actions of prostaglandins group E and have the ability to eliminate weak or moderate pain that accompanies, for example, inflammatory diseases such as rheumatoid arthritis or osteoarthritis. Some properties of the compounds of the present invention can be demonstrated by the following tests:

(a) in vitro analysis using ileum of Guinea pigs, which is carried out for the assessment of inhibitory properties of the tested compounds against the G2-induced contractions of the ileum. For this purpose, the terminal ileum is immersed in oxygenated Krebs solution containing indomethacin (4 mg/ml) and atropine (1 μm), and incubated at 37oC; terminal ileum was subjected to the post ileum; then in a solution of Krebs added the test compound (dissolved in dimethyl sulfoxide) and build the curve dose-response relationships for PGE2-induced contraction of the ileum in the presence of the test compound; and then calculate the value of RA2for test compounds;

(b) in vivo analysis on mice carried out for the assessment of inhibitory properties of the tested compounds against the reaction of abdominal contractions induced by intraperitoneal introduction of toxic factors, such as dilute acetic acid or phenylbenzophenone (denoted hereafter (PBQ); however, the specified analysis is performed using the techniques described in European patent application 0218077.

Although the pharmacological properties of the compounds of formula I can vary depending on their structure, but most of the activity of these compounds can be demonstrated in one or two of the above Tests (a) and (b) at the following concentrations or doses:

Test (a): RA2>5,3;

Test (b): ED50in the interval, for example, 0.01 to 100 mg/kg orally.

In test (b) with the introduction of compounds of formula I in doses that are several times higher than their m is ALOS.

Receptors of prostaglandin and, in particular, the receptors for PGE2were tentatively characterized by Kennedy and others (Advances in Prostaglandin, Thromboxane and Leukotriene Research, 1983, 11, 327). Known antagonist of prostaglandin PGE2SC-19220 blocks the effect of PGE2in some tissues, such as the ileum of Guinea pigs or peritoneal dogs, however, in other tissues such as the trachea of cat or in the ileum chicken, this effect is not observed. It was found that tissue which is susceptible to SC-19220-mediated effects have receptors for EP1. On this basis it can be argued that the compounds of the present invention, with activity in test (a), are antagonists EP1.

In accordance with another of its aspects the present invention relates to pharmaceutical compositions containing a compound of the formula (I), or in vivo hydrolyzable ester or amide, or its pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable diluent or carrier.

This composition can be obtained in a form suitable for oral administration, such as tablets, capsules, aqueous or oily solution, suspension or emulsion; and; for intranasal administration, for example, in the form of the drug for inhalation through the nose, sprays or nose drops; for vaginal or rectal administration, for example, in the form of a suppository or rectal aerosol; for administration by inhalation, for example, in the form of fine powder or a liquid aerosol; for sublingual and transbukkalno (through the cheek) the introduction of, for example, in the form of a tablet or capsule; or for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion), for example, in the form of a sterile aqueous or oily solutions or suspensions. Basically, the above compositions can be obtained by standard methods using standard fillers.

The amount of active ingredient (i.e., the compounds of formula (I) or its pharmaceutically acceptable salt), which combine with one or more excipients to produce the desired single dosage form may vary depending on the particular patient being treated, and the route of administration. So, for example, a composition intended for oral administration to a person, usually contains from 0.5 mg to 2 g of active compound, smeshannoj the weight of the entire composition.

In accordance with another aspect of the present invention relates to the compound of formula (I), or in vivo hydrolyzable complex ether or amide, or its pharmaceutically acceptable salt that can be used in therapeutic treatment of animals (including humans).

In accordance with another aspect of the present invention relates to a method for relief of pain in animals (including humans), implying that the animal an effective amount of the compounds of formula I, or in vivo-Gidrodinamika of ester or amide, or its pharmaceutically acceptable salt.

As mentioned above, the compound of formula (I) can be used to eliminate pain, which, for example, are accompanied by inflammatory diseases such as rheumatoid arthritis and osteoarthritis. A daily dose of the compounds of formula I used in therapeutic or prophylactic uses, is usually, for example, from 0.1 mg to 75 mg per kg of body weight and can be introduced, if necessary, in separate doses. For parenteral administration are mainly used lower doses. For example, for intravenous administration can be used, the dose, the component voltage is maintained, for example, from 0.05 mg to 25 mg per kg of body weight.

Although the compounds of formula (I) are usually a therapeutic agent intended for the introduction of warm-blooded animals (including humans), but they can be used in all cases requiring inhibition PGE2in the receptor EP1on the basis of test (a). Thus, these compounds can be used as pharmacological standards for the development of new biological tests and new drugs.

Due to its ability to eliminate the pain of compounds of formula I are effective means for the treatment of certain inflammatory and non-inflammatory diseases which are currently treated with nonsteroidal anti-inflammatory drugs (NSPs), any abscopal effect of cyclooxygenase, such as indomethacin, Ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of compounds of formula I with NSPs can lead to reduction in the number NSPs required to produce a therapeutic effect. This reduces the likelihood of side effects caused NSPs, e.g. which relates to pharmaceutical compositions, containing the compound of formula I, or in vivo hydrolyzable ester or amide, or its pharmaceutically acceptable salt in combination or in a mixture with non-steroidal anti-inflammatory agent and a pharmaceutically acceptable diluent or carrier.

Compounds of the present invention can also be used in combination with other anti-inflammatory drugs, such as inhibitors of the enzyme 5-lipoxygenase (such as described in European patent applications 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662, 0385663, 0385679, 0385680).

The compounds of formula (I) can also be used to treat diseases such as rheumatoid arthritis, when used in combination with anti-arthritis means, such as gold, methotrexate, steroids and penicillamin; and for treatment of diseases such as osteoarthritis, they can be used in combination with steroids.

Compounds of the present invention can be also introduced in degenerative diseases, such as osteoarthritis, in combination with chondroprotective, antidegradation and/or reparative agents such as Diacerhein, hyaluronic acid, such as gualan, rumalon, artear is about, contain one or more other therapeutic agents or prophylactic agents, which are known to have an analgesic effect. For example, in the pharmaceutical compositions of the present invention can also be known opiate pain relievers (such as dextropropoxyphene, Dihydrocodeine or codeine), or antagonists of other mediators of pain or inflammation mediators, such as bradykinin, tachykinin and peptides associated with the gene calcitonin (CGRP), or agonist2-adrenergic receptors agonist GABAB-receptor blocker calcium-channel antagonist SCQB-receptor antagonist neirokinina or antagonist and a modulator of the action of glutamate at the NMDA receptor.

Compounds of the present invention can also be entered when bone diseases such as osteoporosis, in combination with calcitonin and bifosfonatami.

In more detail, the present invention is illustrated in the following, but not limiting of its scope examples, in which, if it is not specifically mentioned:

(i) the evaporation was carried out in a rotary vacuum evaporator, and procedures for the handling was carried out after removal of residual solids uteye;

(iii) the final products of formula I have satisfactory microanalysis data and their structures were largely confirmed by the analyses carried out by NMR and mass spectroscopy.

(iv) the melting temperature is given without amendments, and were identified with the help of automatic special device Mettler SP62 or device using an oil bath, and the melting temperature for the final products were determined after recrystallization from standard organic solvent, such as ethanol, methanol, acetone, ether or hexane, alone or in mixture with each other;

(v) with the following abbreviations:

DMF - N,N-dimethylformamide;

THF - tetrahydrofuran;

DMSO - dimethyl sulfoxide;

TLC is thin layer chromatography;

GHSD - liquid chromatography medium pressure.

EXAMPLE 1

2-[N-(5-Bromo-2-propoxyphenyl)-N-ethylamino]pyridine-5-carboxylic acid

A solution of methyl 2-[N-(5-bromo-2-propoxyphenyl)-N-ethyl-amino]pyridine-5-carboxylate (comparative example 1) (0.12 g, 0.29 mmol) in THF (3 ml) and methanol (3 ml) was treated with an aqueous solution of sodium hydroxide (1 N., 1.8 ml). The reaction mixture was heated to 40oC for 18 h the th product was filtered and got mentioned in the title compound (0.1 g, 88%) as a white solid product.

MS (CI+) : 393/395 (M+N)+.

NMR (200 MHZ, DMSO-d6) : 1,0 (t, J=Hz, 3H); of 1.12 (t, J=Hz, 3H); to 1.75 (m, 2H); 3,6 (kV, J=Hz, 2H); 3,98 (t, J=Hz, 2H); to 4.73 (s, 2H), 6,65 (d, J= Hz, 1H); 7,02 (m, 2H); 7,4 (DD, J=2,9 Hz, 1H); 7,92 (DD, J=2,9 Hz, 1H), and 8.6 (d, J=2 Hz, 1H).

EXAMPLE 2

2-[N-(5-Bromo-2-(methyl)propoxyphenyl)-N-ethylamino] -5-pyridine-carboxylic acid

Specified in the title compound was obtained by the method similar to that described in example 1, except that used the corresponding ester (comparative example 2).

MS (CI+): 407 (M+H)+.

NMR (250 MHZ, DMSO-d6) : 1,0 (d, J=Hz, 6N); of 1.05 (t, J=HZ, 3H); 2,02 (m, 1H); 3,59 (kV, J=Hz, 2H); and 3.8 (d, J=Hz, 2H); 4.75 in (c, 2H); only 6.64 (d, J= Hz, 1H); of 6.96 (d, J=Hz, 1H); 7,05 (d, J=2 Hz, 1H); of 7.36 (DD, J=2,9 Hz, 1H); 7,9 (DD, J=2,9 Hz, 1H); 8,61 (d, J=2 Hz, 1H); 12,35 (Shir. s, 1H).

EXAMPLE 3

6-[N-(5-Bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid

Specified in the title compound was obtained in a manner analogous to the one described in example 1, except that used the corresponding complex butyl ether (comparative example 4).

So pl. 73-80oC.

MS (FAB+): 406 (M+N)+.

NMR (200 MHz, DMSO-d6

EXAMPLE 4

2-[N-(5-Bromo-2-(cyclopentyloxy)benzyl)-N-ethylamino] pyridine-5-carboxylic acid

A solution of methyl 2-[N-(5-bromo-2-(cyclopentyloxy)benzyl)-N-ethylamino]pyridine-5-carboxylate (see comparative example 5) (0,37 g, 0.83 mmol) in THF (4 ml) and methanol (4 ml) was treated with 1 N. aqueous sodium hydroxide solution (4 ml). The reaction mixture was heated at 40oC for 18 hours. The solvent was evaporated under reduced pressure and the residue was acidified using 1 N. acetic acid (4 ml) and left to stir for 2 days. The precipitate was filtered, washed with water and dried in a vacuum at a temperature of 45oWith obtaining specified in the title compound as a white solid (0.32 g, 89%).

MS (ESP+): 433 (M+H)+.

NMR (200 MHz, DMSO-d6) : 1,2 (t, J=Hz, 3H); of 1.35 (m, 2H); was 1.58 (m, 4H); to 1.75 (m, 2H); 2,30 (m, 1H); 3,60 (kV, J=Hz, 2H); 3,9 (d, J=Hz, 2H); 4,74 (s, 2H); of 6.65 (d, J=Hz, 1H); 6,98 (d, J=Hz, 1H); 7,10 (d, J=2 Hz, 1H); 7,88 (DD, J= 2,9 Hz, 1H); 7,92 (d, J=2,9 Hz, 1H); to 8.62 (d, J=2 Hz, 1H), 12,4 (approx. 1H).

EXAMPLE 5

6-[N-(5-Bromo-2-propoxyphenyl)-N-ethylamino] pyridazin-3-carboxylic acid

Specified in the title compound was obtained from butyl 6-[N-(5-bromo-2-propoxyphenyl)-N-ethylamino] pyridazin-3-carboxylate (comparative prints DMSO-d6) : 0,97 (t, J=6,7 Hz, 3H); to 1.16 (t, J=6,7 Hz, 3H); at 1.73 (m, J= 6,7 Hz, 2H); 3,7 (kV, J=6,7 Hz, 2H), 3,98 (t, J=6,7 Hz, 2H); 4,82 (s, 2H); 7.0 d, J=9,3 Hz, 1H); for 7.12 (d, J=9,3 Hz, 1H); 7,17 (d, J=2.0 Hz, 1H); 7,40 (DD, J=2.0 a, 10,0 Hz, 1H); 7,83 (d, J=10.0 Hz, 1H).

EXAMPLE 6

6-[N-(5-Bromo-2-n-butoxybenzoyl)-N-ethylamino] pyridazin-3-carboxylic acid

Specified in the title compound was obtained from butyl 6-[N-(5-bromo-2-n-butoxybenzoyl)-N-ethylamino]pyridazin-3-carboxylate (comparative example 7) by the method similar to that described in example 1.

MS (ESP+): 408/410 (M+N)+.

NMR (200 MHZ, DMSO-d6) : of 0.9 (t, J=6,7 Hz, 3H); 1.14 in (t, J=6,7 Hz, 3H); of 1.40 (m, J=6,7 Hz, 2H); 1,67 (m, J=6,7 Hz, 2H); to 3.67 (q, J=6,7 Hz, 2H); 4,00 (t, J=6,7 Hz, 2H); and 4.8 (s, 2H); 7,0 (d, J=8,3 Hz, 1H); 7,11 (d, J=10.0 Hz, 1H); to 7.15 (d, J=1.7 Hz, 1H); 7,40 (DD, J=1,7, 8,3 Hz, 1H); to 7.84 (d, J=10.0 Hz, 1H).

EXAMPLE 7

[N-(3,6-Dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

A solution of 6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]pyridazin-3-carboxylic acid (example 3) (0,166 g, 0,409 mmol) in DMF (4 ml) was treated with 3,5-dimethyl-4-sulphamethoxazole (0.08 g, 0,455 mmol), dimethylaminopyridine (0.15 g, of 1.23 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.12 g, 0,627 mmol). The reaction mixture was stirred for additional added dimethylaminopyridine (0.05 g, 0,409 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.08 g, 0,418 mmol) and the reaction mixture was stirred for 60 hours at room temperature. The reaction mixture was distributed between water and ethyl acetate. The organic layer was dried (MgSO4) and evaporated and the residue was purified by chromatography (eluent: methanol/dichloromethane/acetic acid) to obtain the specified title compound as a foam (0,073 g).

MS (ESP+): 564 (M+H)+.

NMR (200 MHz, DMSO-d6) : 0,3 (m, 2H); of 0.53 (m, 2H); of 1.55 (m, 4H); 2.40 a (s, 3H); 2,70 (s, 3H); 3,70 (kV, J=Hz, 2H); a 3.87 (d, J=Hz, 2H); is 4.85 (s, 2H); 6,98 (d, J= Hz, 1H); 7,22 (d, J=2 Hz, 1H); from 7.24 (d, J=Hz, 1H); 7,39 (DD, J=2,9 Hz, 1H); 7,83 (d, J=HZ, 1H).

EXAMPLE 8

The compounds presented in the table (see the end of the text), were obtained from the corresponding carboxylic acid and the corresponding sulfonamidnuyu derived in a manner analogous to the one described in example 7.

Notes to table

(a) NMR (200 MHz, DMSO-d6) : 0,97 (d, 6N); to 1.15 (t, 3H); 2,02 (m, 1H); 2.40 a (s, 3H); 2,69 (s, 3H); 3,70 (q, 2H); of 3.80 (d, 2H); is 4.85 (s, 2H); 7.03 is (m, 2H); then 7.20 (d, 1H); 7,27 (DD, 1H); of 7.82 (d, 1H).

Elemental analysis for C23H28ClN5O5S + 0,13 mol of toluene:

The]. (%): C - 53,8; H - 5,5; N - 13,1.

Found (%) of 4.83 (s, 2H);? 7.04 baby mortality (D, J=8gts, 1H); 7,14 (d, J=3 Hz, 1H); 7,28 (DD, J=8, 3 HZ, 1H); EUR 7.57 (d, J=Hz, 1H); with 8.05 (d, J=Hz, 1H); 12,84 (s, 1H).

Elemental analysis for C22H26ClN7O5S2+ 0.1 mol CH2Cl2+ 0,2 mol H2O:

The]. (%): C ACCOUNTS FOR 45.8; H - 4,6; N - 16,9.

Found (%): C Of 45.4; H - 4,5; N - 16,8.

So pl. 240-242oC.

(C) NMR (200 MHz, DMSO-d6) : 1,00 (m, N); to 1.15 (t, 3H); to 1.75 (m, 2H); 2,03 (m, 1H); of 3.45 (t, 2H); 3,70 (q, 2H); 3,81 (d, 2H); a 4.86 (s, 2H); 7.03 is (m, 2H); then 7.20 (d, 1H); 7,27 (DD, 1H); 7,87 (d, 1H).

Elemental analysis for C21H29ClN4O4S:

The]. (%): C - 53,8; H - 6,2; N - 11,9.

Found (Percent): C - 53,9; H - 6,2; N - 11,9.

d) MC (ESP+): 534/536 (MN+).

NMR (200 MHz, DMSO-d6) : of 1.13 (t, 3H); 1,65 (Shir. m); 1,88 (Shir. m, 2H); of 2.38 (s, 3H); in 2.68 (s, 3H); the 3.65 (q, 2H); was 4.76 (s, 2H); is 4.85 (m, 1H); 7,00 (d, 1H); 7.03 is (d, 1H); 7.18 in (d, 1H); from 7.24 (DD, 1H); of 7.82 (d, 1H).

e) MC (ESP+): 507/509 (MN+).

NMR (200 MHz, DMSO-d6) : a 1.11 (t, 3H); 1,60 (Shir. m, 6N); of 1.88 (m, 2H); 3,63 (q, 2H); 4.75 V (s, 2H); is 4.85 (m, 1H); 7,02 (d, 1H); 7,30 (m, 2H); 7,88 (d, 2H); to 8.20 (d, 2H).

f) So pl. 111-113oC.

NMR (MHz, DMSO-d6) : to 0.92 (t, 3H); 1,1 (t, 3H); 1,5-2,2 (m, 8H); to 2.65 (m, 1H); of 3.25 (m, 2H); 3,68 (q, 2H); 3,95 (d, 2H); and 4.8 (s, 2H); 7,0 (m, 2H); to 7.15 (d, 1H); to 7.25 (DD, 1H); of 7.82 (d, 1H).

Elemental analysis for C22H29

g) So pl. 140-142oC.

NMR (MHz, DMSO-d6) : 1,1 (t, 3H); 1,75-2,2 (m, 6N); of 2.25 (s, 3H); to 2.55 (s, 3H); 2,70 (m, 1H); the 3.65 (q, 2H); 4.0 a (d, 2H); 4.75 V (s, 2H); 7,0 (m, 3H); to 7.25 (DD, 1H); 7,8 (d, 1H).

Elemental analysis for C24H28SClN5O5H2O:

The]. (%): C - 52,2; H - 5,4; N - 12,7.

Found (Percent): C - 51,8; H - 5,0; N - 12,5.

EXAMPLE 9

6-[N-(5-Bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid

Butyl-6-[N-(5-bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylate (comparative example 10) (0,22 g, 0.47 mmol) in THF (3 ml) and methanol (3 ml) was treated with 1 N. aqueous sodium hydroxide solution (3 ml) and left for 1.5 hours at room temperature (after which TLC (diethyl ether/hexane 1:1) indicated the absence of ester). The reaction mixture was evaporated to a smaller volume, and treated with a small amount of water and acidified with acetic acid to obtain resin. This resin did not aterials, so it was extracted with ethyl acetate (x2) and the combined extracts were washed with saline, dried (MgSO4) and was evaporated to obtain the resin. The resin was subjected to evaporation of the toluene and dichloromethane to obtain specified in the title compound as a foam (140 mg, 73%).

) : 1,00 (d, J=10Hz, 6N); to 1.16 (t, J=8,3 Hz, 3H); 1.93 and-of 2.15 (m, 1H); 3,69 (kV, J=8,3 Hz, 2H); of 3.80 (d, J=6,67 Hz, 2H); 4,84 (s, 2H); 6,98 (d, J=10Hz, 1H); for 7.12 (m, 2H); 7,40 (DD, J=2, 8,3 Hz, 1H); to 7.84 (d, J=10Hz, 1H).

EXAMPLE 10

6-[N-(5-Chloro-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid

Specified in the title compound was obtained by hydrolysis of butyl-6-[N-(5-chloro-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylate (comparative example 12) in a manner similar to that described in example 1.

NMR (250 MHz, DMSO-d6) : 1,00 (d, 6N); to 1.15 (t, 3H); 2,04 (m, 1H); of 3.69 (q, 2H); of 3.80 (d, 2H); 4,84 (s, 2H); 7.03 is (m, 2H); 7,11 (d, 1H); 7,27 (DD, 1H); 7,83 (d, 1H).

MS (ES+): 362 (M-N)-.

Elemental analysis for C18H22ClN3O3:

The]. (%): C - 59,4; H - 6,1; N - 11,5.

Found (Percent): C - 59,4; H - 5,9; N - 11,4.

So pl. 132-134oC.

MS (CI+): 181 (M+N)+.

EXAMPLE 11

6-[N-(5-Bromo-2-(cyclopropylmethoxy)benzyl)-N-ethyl] pyridazin-3-carboxamid

N-Ethyl-5-bromo-2-(cyclopropylmethoxy)benzylamine (comparative example 13) (12,56 g) was dissolved in N (59 ml) in an argon atmosphere. Was added 6-chloropyridazine-3-carboxamide (6,17 g, 3.9 mmol) and sodium bicarbonate (8,24 g, 98 mmol) and the mixture was heated at 110oWith in 24 hours. Then see what. hydrochloric acid (50 ml). The resulting white precipitate was filtered and washed with ethyl acetate and diethyl ether to obtain specified in the title compound which was dried in a vacuum oven at 55o(11,46 g, 72.1 per cent).

NMR (200 MHz, DMSO-d6) : 0,34 (m, 2H); 0,55 (m, 2H); 1,17 (m, 4H); of 3.69 (q, 2H); 3,88 (d, 2H); 4.80 to (s, 2H); of 6.96 (d, 1H); to 7.15 (m, 2H); 7,37 (DD, 1H); 7,42 (Shir. s, 1H); to 7.84 (d, 1H); 8,14 (Shir. s, 1H).

MS (ESP+): 405 (M+N)-.

EXAMPLE 12

5-[6-(N-[5-Bromo-2-(cyclopropylmethoxy)benzyl] -N-ethylamino) pyridazin-3-yl]tetrazole

6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl] -N-ethylamino]-3-lepirudin (comparative example 14) (1.63 g) was dissolved in dimethylacetamide (DMA) (17 ml) in an argon atmosphere. Was added triethylamine hydrochloride (0.87 g, 6.3 mmol) and sodium azide (0,82 g, 12.6 mmol) and the mixture was heated at 95-110oC for 3 hours. Then cooled and distributed between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with 10% 2 N. Hcl, saturated aqueous ammonium chloride (2 x) and brine (x 2), dried over Na2SO4, was filtered and was evaporated. The residue was recrystallized from acetonitrile to obtain specified in the connection header (1,34 g, 74,0%).

NMR (20; ,03 (d, 1H).

Elemental analysis for C18H20BrN7O:

The]. (%): C IS 50.2; H - 4,7; N - 22,8.

Found (%): C Is 50.2; H - 4,8; N - 22,8.

MS (ESP+): 430 (M+N)+.

EXAMPLE 13

5-(6-[N-(5-Chloro-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridazin-3-tetrazol

Specified in the title compound was obtained from 6-[N-(5-chloro-2-(2-methylpropoxy)benzyl)-N-ethylamino] -3-lepirudin (comparative example 15) by the method similar to that described in example 12.

NMR (200 MHz, DMSO-d6) : 0,99 (d, 6N); of 1.18 (t, 3H); 2,04 (m, 1H); and 3.72 (q, 2H); 3,82 (d, 2H); a 4.86 (s, 2H);? 7.04 baby mortality (d, 1H); to 7.09 (d, 1H); 7,27 (m, 2H); 8,03 (d, 1H).

Elemental analysis for C18H22ClN7O:

The]. (%): C AND 55.7; H - 5,7; N - 25,3.

Found (Percent): C - 55,6; H - 5,7; N - 24,9.

MC (ES+): 388 (M+N)+.

So pl. 204-206oC.

EXAMPLE 14

N-Propanesulfonyl-6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl] -N-ethylamino]pyridazin-3-carboxamid

6-[N-(5-Bromo-2-(cyclopropylmethoxy)benzyl] -N-ethylamino] pyridazin-3-carboxylic acid (example 3) (1.0 g, 2,46 mmol) was mixed with propylsulfonyl (0.32 g, 2.6 mmol), 4-(dimethylamino)pyridine (0,90 g, 7,38 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.71 g, 3.7 mmol) in almost actionnow the mixture was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate (x 2). The combined organic extracts washed with 5% 2 n Hcl in a saturated aqueous solution of ammonium chloride, saturated aqueous sodium bicarbonate (×1) and brine (x 1), dried over Na2SO4, was filtered and was evaporated. The residue was purified using liquid chromatography medium pressure (GHSD) using a 2.5% IPA/dichloromethane + 0.2% of acetic acid. The fractions containing specified in the title compound was evaporated and the residue was subjected to co-distillation with toluene, isohexanol and, finally, ether, resulting after drying in a high vacuum there was obtained is listed in the title compound as a white foam (100 g, 79.4 per cent).

NMR (200 MHz, DMSO-d6) : 0,30 (m, 2H); 0,55 (m, 2H); and 1.00 (t, 3H); to 1.16 (m, 4H); to 1.75 (m, 2H); 3.45 points (t, 3H); to 3.73 (q, 2H); a 3.87 (d, J=7.5 Hz, 2H); is 4.85 (s, 2H); 6,97 (d, J=8,3 Hz, 1H); to 7.18 (d, J=3.1 Hz, 1H); from 7.24 (d, J= 8.7 Hz, 1H); 7,39 (DD, J=8,3, 3.1 Hz, 1H); 7,86 (d, J=8.7 Hz, 1H).

Elemental analysis for C21H27BrN4O4S:

The]. (%): C - TO 49.3; H - 5,3; N - 11,0.

Found (Percent): C - 49,7; H - 5,6; N - 10,7.

EXAMPLE 15

6-[N-(5-Bromo-2-(2-hydroxy-3,3,3-cryptocracy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid

Specified in the title compound was obtained from n-butyl ether (comparative example 16) (m, 1H); 4,89 (s, 2H); was 7.08 (m, 3H); to 7.4 (DD, 1H); 7,83 (d, 1H).

MS: 463 (M+N)+.

EXAMPLE 16

5-[6-(N-[2-(Cyclopropylmethoxy)-5-methansulfonate] -N-ethylamino)pyridazin-3-yl]tetrazole

Specified in the title compound was obtained from the corresponding cyanoderivatives (comparative example 17) in a manner similar to that described in example 12, except that the mixture was heated at 85oWith approximately 20 hours and the reaction course was monitored by TLC. Yield: 80%.

NMR (200 MHz, DMSO-d6) : 0,36 (m, 2H); or 0.57 (m, 2H); 1,14-of 1.35 (m, 4H); is 3.08 (s, 3H); of 3.78 (q, 2H); is 4.03 (d, J=6.2 Hz, 2H); is 4.93 (s, 2H); to 7.25 (d, J=8,3 Hz, 1H); to 7.35 (d, J=8,3 Hz, 1H); TO 7.68 (D, J=2.1 Hz, 1H); 7,83 (DD, J=2,1, 8,3 Hz, 1H); WITH 8.05 (D, J=8,3 Hz, 1H).

MS (ESP+): 430 (M+H)+.

EXAMPLE 17

5-[6-(N-[5-Bromo-2-propoxymethyl]-N-ethylamino)pyridazin-3-yl]tetrazole

6-[N-(5-Bromo-2-propoxyphenyl)-N-ethylamino]-3-lepirudin (comparative example 18) (1.0 g, to 2.67 mmol) was dissolved in DMA (15 ml) and treated with sodium azide (520 mg, 8.0 mmol), and then triethylammonium (550 mg, 4.0 mmol) and the mixture was heated for 3 hours at 110oC. the resulting solution was poured into 2M hydrochloric acid (50 ml), extracted with ethyl acetate and dichloromethane (100 ml each) and the combined extracts Fri formation of a solid precipitate, which is triturated in acetonitrile/toluene to obtain specified in the connection header (965 mg, 87%).

MS (ESP+): 418 (M+N)+, 390 (M+H-N2)-.

Elemental analysis for C17H20BrN7O:

Calculated: (%) C To 48.8; H - 4,82; N - 23,4.

Found: (%) C - 49,1; H - 4,7; N - 23,5.

NMR (250 MHz, DMSO-d6) : 0,99 (t, J=Hz, 3H); of 1.17 (t, J=Hz, 3H); 1,72 (m, 2H); and 3.72 (q, J=Hz, 2H); 4,0 (t, J=Hz, 2H); 4,82 (s, 2H), 6,98 (d, J= 8.5 Hz, 1H); 7,22 (d, J=2 Hz, 1H); 7,27 (d, J=8gts, 1H); 7,40 (DD, J=2,8 Hz, 1H); 8,03 (d, J=8.5 Hz, 1H).

EXAMPLE 18

6-(N-[5-Bromo-2-propoxymethyl]-N-ethylamino)pyridazine-3-carboxylic acid

6-[N-(5-Bromo-2-propoxymethyl]-N-ethylamino]-3-cyanopyridine (comparative example 18) (1.5 g, 4 mmol) in ethanol (100 ml) was treated with an aqueous solution of sodium hydroxide (20 ml, 2M, 40 mmol) and heated to 70oC for 16 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in water, acidified with acetic acid and four times were extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over MgSO4and concentrated in vacuum. The resulting resin was ground into the air with obtaining specified in the connection header in the form of a solid product (1.24 g, 79%).

SUB>BrN7O:

Calculated: (%) C - 51,8; H - 5,1; N - 10,7.

Found: (%) C - 51,9; H - 5,3; N - 10,6.

EXAMPLE 19

N-Propyl-6-(N-[5-bromo-2-propoxymethyl] -N-ethylamino) pyridazine-3-carboxamide

6-(N-[5-Bromo-2-propoxymethyl]-N-ethylamino)pyridazine-3-carboxylic acid (example 18) (500 mg, of 1.27 mmol) was dissolved in dichloromethane (50 ml), was added the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC) (365 mg, 2,07 mmol), dimethylaminopyridine (DMAP) (465 mg, 3,81 mmol) and propanesulfinamide (190 mg, 1.54 mmol). The mixture was stirred at room temperature overnight in an argon atmosphere, after which the data TLC (5% methanol/dichloromethane) confirmed the completion of reaction. The reaction mixture was loaded directly on GHSD-column (silica gel) and elution with 5% methanol/dichloromethane got mentioned in the title compound as a foam (380 mg, 60%).

MC (ESP+): 499 (M+H)+.

Elemental analysis for C20H27BrN4O4S:

Calculated: (%) C - 48,1; H - The 5.45; N - 11,2.

Found: (%) C - 48,2; H - 5,8; N - 10,8.

NMR (250 MHz, DMSO-d6) : of 0.95 (m, 6N); of 1.17 (t, J=Hz, 3H); 1,7 (m, 2H); 3,37 (t, J=8gts, 2H); to 3.67 (q, J=Hz, 2H); 3,95 (t, J=Hz, 2H); 4,82 (s, 2H); 6,98 (d, J=8.5 Hz, 1H); FOR 7.12 (D, J=2 Hz, 1H); 7,17 (d, J=8gts, 1H); 7,37 (DD, J=2,8 Hz, 1H); 7,83 (d, J=irydzin-3-carboxamid

6-(N-[5-Bromo-2-propoxymethyl]-N-ethylamino)pyridazine-3-carboxylic acid (example 18) (500 mg, of 1.27 mmol) was dissolved in dichloromethane (50 ml). Added the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC) (365 mg, 2,07 mmol), dimethylaminopyridine (DMAP) (465 mg, 3,81 mmol) and 3,5-dimethyloxazole-4-ylsulphonyl (270 mg, 1.53 mmol). The mixture was stirred at room temperature overnight in an argon atmosphere, after which the data TLC (5% methanol/dichloromethane) confirmed the completion of reaction. The reaction mixture was placed directly on GHSD-column (silica gel) and after elution with 5% methanol/dichloromethane has been specified in the title compound in the form of resin, which was then purified by trituration in ether to obtain the desired product as a solid (180 mg, 33%).

So pl. 122-124oC.

MS (ESP+): 552 (M+N)+.

Elemental analysis for C22H26BrN5O5S 1,1 H2O:

Calculated: (%) C - To 47.8; H - 4,7; N - 12,7.

Found: (%) C - 46,2; H - 4,9; N - 12,2.

NMR (250 MHz, DMSO-d6) : of 0.95 (m, J=Hz, 3H); of 1.12 (t, J=Hz, 3H); 1,72 (m, 2H); and 2.27 (s, 3H); to 2.55 (s, 3H); 3,62 (kV, J=Hz, 2H); 3,95 (t, J=Hz, 2H); 4.72 in (s, 2H); 6,93 (d, J=8.5 Hz, 1H); 6,97 (d, J=8gts, 1H); 7,17 (d, J= 2 Hz, 1H); 7,37 (DD, J=2, 8gts, 1H); to 7.77 (d, J=8.5 Hz, 1H).

oC.

MS (ESP+): 361/363 (M+N)+.

NMR (200 MHz, DMSO-d6) : 0,34 (m, 2H); or 0.57 (m, 2H); to 1.16 (t, J=Hz, 3H); 1,25 (m, 1H); 3,70 (kV, J=Hz, 2H); of 3.78 (d, 2H); to 4.81 (s, 2H); 7,00 (d, J= 8gts, 1H); 7,05 (d, J=2 Hz, 1H); 7,17 (d, J=Hz, 1H); to 7.25 (DD, J=2, 8gts, 1H); 7,45 (Shir. s, 1H); a 7.85 (d, J=Hz, 1H), 8,07 (Shir. s, 1H).

EXAMPLE 22

6-[N-(5-Chloro-2-(cyclopropylmethoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid

Specified in the title compound was obtained as a white powder of 6-[N-(5-chloro-2-(cyclopropylmethoxy)benzyl)-N-ethylamino] pyridazin-3-carboxamide (example 21) in a manner similar to that described in example 26.

Yield: 86%.

So pl. 119-120oC.

MS (ESP+): 362/0 (d, J=Hz, 2H); a 4.83 (s, 2H); 7,02 (d, J= 8gts), was 7.08 (d, J=2 Hz, 1H); 7,14 (d, J=Hz, 1H); 7,26 (DD, J=2, 8gts, 1H); to 7.84 (d, J=Hz, 1H).

Elemental analysis:

Calculated: (%) C - To 59.8; H - 5,6; N - 11,6, Cl 9,8.

Found: (%) C - 59,3; H - 5,6; N - 11,7, Cl 9,9.

EXAMPLE 23

5-[6-(N-[5-Chloro-2-cyclopropylmethoxy]-N-ethylamino) pyridazin-3-yl] tetrazole

Specified in the title compound was obtained from 6-[N-(5-chloro-2-cyclopropylmethoxy] -N-ethylamino] -3-cyanopyridine (comparative example 21) in a manner similar to that described in example 12. Yield: 41%.

So pl. 190-192oC.

MS (ESP+): 386/388 (M+N)+.

NMR (200 MHz, DMSO-d6) : 0,35 (m, 2H); or 0.57 (m, 2H); of 1.20 (t, J=HZ, 3H); of 3.77 (q, J=Hz, 2H); 3,90 (D, J=Hz, 2H); is 4.85 (s, 2H); 7,01 (d, J= 8gts, 1H); 7,14 (d, J=2 Hz, 1H); to 7.25 (DD, J=2,8 Hz, 1H); 7,29 (d, J=8gts, 1H); of 8.04 (d, J=8gts, 1H).

Elemental analysis:

Calculated: (%) C - 56,0; H - 5,2; N - 25,4.

Found: (%) C - 55,9; H - 5,3; N - 25,0.

EXAMPLE 24

N-Trifloromethyl-6-[N-(5-chloro-2-cyclopropylmethoxy)-N-ethylamino]pyridazin-3-carboxamid

Specified in the title compound was obtained from 6-[N-(5-chloro-2-cyclopropylmethoxy)-N-ethylamino] pyridazin-3-carboxylic acid (example 22) and triftoratsetofenona manner similar to that described in example 7. Yield: 18%.6
) : 0,35 (m, 2H); or 0.57 (m, 2H); to 1.15 (t, J=Hz, 3H); to 3.67 (q, J=Hz, 2H); 3,88 (d, J=Hz, 2H); 4.80 to (s, 2H); 6,95-7,10 (m, N); from 7.24 (DD, J=2, 8gts, 1H); 7,80 (d, J=8gts, 1H).

EXAMPLE 25

6-[N-(5-Chloro-2-cyclopentadienyl)-N-ethylamine]pyridazin-3-carboxamid

N-Ethyl-5-chloro-2-cyclopentadienide (comparative example 22; used without additional purification) (4,27 g, a 16.8 mmol) in dimethylformamide (25 ml) was then treated with 6-chloropyridazine-3-carboxamide (described in comparative example 3) (3.03 g, 19.2 mmol) and ethyldiethanolamine (5 ml, 29 mmol) and left to boil under reflux at 140oC for 16 hours. Was added water (50 ml) and product was extracted with dichloromethane and ether, dried over anhydrous magnesium sulfate, was filtered and was purified by column chromatography (2% propan-2-ol in dichloromethane) to give 1.44 g of a yellow resin. Rubbing broadcast network specified in the title compound (790 mg, 13%).

MS (ESP+): 375/377 (MN+).

NMR (200 MHz, DMSO-d6) : a 1.08 (t, 3H) and 1.60 (m, 6N); to 1.87 (m, 2H); 3,62 (q, 2H); 4,74 (s, 2H); is 4.85 (m, 1H); 7.03 is (m, 2H); 7,13 (d, 1H); from 7.24 (DD, 1H); 7,42 (Shir. s, 1H); of 7.82 (d, 1H); 8,08 (Shir. s, 1H).

EXAMPLE 26

6-[N-(5-Chloro-2-cyclopentadienyl)-N-ethylamine] pyridazin-3-carboxylic acid

6-[N-(5-Chloro-2-cyclopen 2 N. sodium hydroxide (15 ml) and the solution was heated under reflux at 80oC for 16 hours. After cooling, the solvent was removed in vacuo and added water (100 ml). The solution was acidified glacial acetic acid and is listed in the title compound was extracted with dichloromethane, washed with water (I ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the product recrystallized from dichloromethane, ether and hexane when standing (100 mg, 13%).

MS (ESP+): 376/378 (MN+).

NMR (200 MHz, DMSO-d6, K) : of 0.79 (t, 3H); of 1.62 (m, 6N); of 1.88 (m, 2H); 3.15 in (m, 2H); to 4.38 (s, 2H); 4.80 to (m, 1H); 6,80 (Shir. s, 1H); to 6.95 (d, 1H); 7,22 (DD, 1H); to 7.32 (d, 1H); to 7.93 (d, 1H).

EXAMPLE 27

5-[6-(N-[5-Chloro-2-cyclopentadienyl] -N-ethylamino)pyridazin-3-yl] tetrazole

Specified in the title compound was obtained from 6-(N-[5-chloro-2-cyclopentadienyl] -N-ethylamino)-3-lepirudin (comparative example 23) in a manner similar to that described in example 12, except that the reaction mixture was stirred 9 hours at 150oC, the solution was acidified using 1 N. hydrochloric acid and the product was extracted with dichloromethane (I ml), was purified by column chromatography (10% propan-2-ol, 0.1% of methane acid in dichloromethane)LASS="ptx2">

NMR (200 MHz, DMSO-d6) : to 1.14 (t, 3H) and 1.60 (m, 4H); to 1.70 (m, 2H); of 1.88 (m, 2H); the 3.65 (q, 2H); 4,78 (s, 2H); to 4.87 (m, 1H); 7,02 (d, 1H); 7,13 (d, 1H); 7,28 (m, 2H); 8,03 (d, 1H).

EXAMPLE 28

N-(3,5-Dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

Specified in the title compound was obtained from 6-[N-(5-bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid (example 9) and 3,5-dimethylisoxazol-4-ylsulphonyl manner similar to that described in example 14.

NMR (200 MHz, DMSO-d6) : 0,98 (d, 6N); to 1.15 (t, 3H); 1,95-to 2.06 (m, 1H); of 2.38 (s, 3H); 2,7 (s, 3H); of 3.69 (q, 2H); and 3.8 (d, 2H); is 4.85 (s, 2H); 6,98 (d, 1H); 7,13 (d, 1H); to 7.2 (d, 1H); 7,39 (DD, 1H); 7,8 (d, 1H).

EXAMPLE 29

6-[N-(5-Methanesulfonyl-2-(cyclopropylmethoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid

6-[N-(5-Methanesulfonyl-2-(cyclopropylamino)benzyl)-N-ethylamino]-3-lepirudin (900 mg, 2.3 mmol) in ethanol (30 ml) and water (6 ml) was treated with granular sodium hydroxide (0,93 g, 23 mmol) and the resulting solution was heated at 80oWith overnight (the reaction course was monitored by HPLC). Then the mixture was evaporated to a smaller volume, was added water and the mixture was extracted with ethyl acetate (x 3) (a small number of nerastvorimogo substances are not the ski extracts were washed with saline, was dried and evaporated to remaining resin. The resin was dissolved in dichloromethane and evaporated to obtain specified in the title compound as a foam (0.56 g, 60%).

MS (ESP-): 404 (M-N-).

NMR (200 MHz, DMSO-d6) : 0.3 to 0.4 (m, 2H); of 0.52 to 0.6 (m, 2H); 1,1-1,3 (m + t, 4H); 3,05 (s, 3H); and 3.72 (q, 2H); 4.0 a (d, 2H); to 4.87 (s, 2H); 7.18 in (d, 1H); from 7.24 (d, 1H); 7,58 (d, 1H); 7,8 (DD, 1H); to 7.84 (d, 1H).

EXAMPLE 30

N-(Propanesulfonyl)-6-[N-(5-methanesulfonyl-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

Specified in the title compound was obtained from 6-[N-(5-methanesulfonyl-2-(cyclopropylmethoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid (example 29) in a manner similar to that described in example 14.

MS (ESP+): 511,2 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 0.29 to 0.38 (m, 2H); from 0.5 to 0.62 (m, 2H); and 0.98 (t, 3H); 1,3-1,1 (m + t, 4H); 1,65-to 1.82 (m, 2H);

of 3.05 (s, 3H); 3/43 (t, 2H); 3.75 to (q, 2H); 4.0 a (d, 2H) and 4.9 (s, 2H); 7.23 percent (d, 1H); 7,27 (d, 1H); 7,56 (d, 1H); 7,8 (DD, 1H); a 7.85 (d, 1H).

EXAMPLE 31

N-Propanesulfonyl-6-[N-(5-bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridazin-3-carboxamid

Specified in the title compound was obtained from the corresponding acid (example 9) by the method similar to that described in example 7.

NMR (250 MHz, DMSO-d6) : 1,00 (m, N); to 1.15 (t, 3 which MEASURES 32

N-(3,5-Dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-bromo-2-(3,3,3-Cryptor-2-hydroxypropoxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

Specified in the title compound was obtained from 6-[N-(5-bromo-2-(3,3,3-Cryptor-2-hydroxypropoxy) benzyl)-N-ethyl-amino] pyridazin-3-carboxylic acid (example 15) in a manner similar to that described in example 7.

NMR (250 MHz, DMSO-d6) : to 1.15 (t, 3H); to 2.35 (s, 3H); 2.63 in (s, 3H); 3,68 (q, 2H); 4,2 (m, 2H); however, 4.40 (m, 1H); 4,82 (s, 2H); of 6.65 (d, 1H); 7,05 (m, 2H); to 7.2 (m, 1H); 7,40 (DD, 1H); 7,80 (d, 1H).

MC (ESP+): 622(M+N)+.

EXAMPLE 33

6-[N-(5-Bromo-2-(CYCLOBUTANE)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid

Specified in the title compound was obtained from the corresponding nitrile (comparative example 24) in a manner similar to that described in example 29.

MC (ESP+): 406 (M+H)+.

NMR (250 MHz, DMSO-d6) : to 1.15 (t, 3H); at 1.73 (m, 2H); 2,00 (m, 2H); to 2.42 (m, 2H); of 3.69 (q, 2H); 4.72 in (quintet, 1H); to 4.81 (s, 2H); PC 6.82 (d, 1H); for 7.12 (d, 1H); 7,16 (d, 1H); of 7.36 (DD, 1H); 7,83 (d, 1H).

EXAMPLE 34

5-[6-(N-[5-Bromo-2-(3,3,3-Cryptor-2-hydroxypropoxy)benzyl)-N-ethylamino] pyridazin-3-yl]tetrazole

Specified in the title compound was obtained from the corresponding nitrile (comparative example 25) in a manner similar to that described in example 12.

EXAMPLE 35

2-[N-(5-Bromo-2-cyclopropylmethoxy)-N-ethylamino] pyridine-5-carboxylic acid

2-[N-(5-Bromo-2-cyclopropylmethoxy)-N-ethylamino] -5-lepirudin (comparative example 26) (7.5 g, 19,43 mmol) was dissolved in ethanol (400 ml) was added sodium hydroxide (7.8 g, 174 mmol), then water (80 ml). The mixture was heated under reflux for 16 hours, the ethanol was removed in vacuo and the residue was extracted with ethyl acetate (4x100 ml). The organic extracts were acidified with acetic acid and washed with water (100 ml) to obtain the solid product (6.8 g). This solid product was dissolved in n-butanol (400 ml) was added sodium hydroxide (6.75 g, 169 mmol) and water (80 ml). The mixture was heated under reflux for 72 hours, the butanol was removed under vacuum, was added 100 ml of water and the residue was extracted with ethyl acetate (4x100 ml). The organic extracts were acidified with acetic acid and washed with water (100 ml). The combined aqueous layers were then acidified and extracted with ethyl acetate (4x100 ml) to obtain specified in the connection header in the form of a solid product (2.4 g, 30%).

So pl. 175-177oC.

MS: 404 (M-N)-< / BR>
NMR (MHz, DM is H); 8,58 (d, 1H); 12,30 (s, 1H).

Elemental analysis for C19H21BrN2O3(%):

Calculated: C - 56,3; H - 5,2; N - 6,9.

Found: C - 56,1; H - 5,3; N - 6,8.

EXAMPLE 36

6-[N-(5-Chloro-2-cyclobutanecarbonyl)-N-ethylamino] pyridazin-3-carboxylic acid

Specified in the title compound was obtained by the method similar to that described in example 18, by treating 6-[N-(5-chloro-2-cyclobutanecarbonyl)-N-ethylamino] -3-lepirudin (comparative example 27) (2.3 g, 6,46 mmol), sodium hydroxide (2.6 g, 65 mmol) in water (20 ml) and ethanol (100 ml) to give resin that cures when grinding in ether (1,15 g, 47%).

So pl. 140-142oC.

MS: 374 (M-N)-.

NMR (MHz, DMSO-d6) : 1,1 (t, 3H); 1,95 (m, 6N); 2,70 (m, 1H); 3,68 (q, 2H); 4.0 a (d, 2H); and 4.8 (s, 2H); 7,0 (m, 3H); to 7.25 (DD, 1H); of 7.82 (d, 1H).

Elemental analysis for C19H22ClN3O3(%):

Calculated: C Is 60.5; H - 5,9; N - 11,2.

Found: C Is 60.5; H - 6,0; N - 10,9.

EXAMPLE 37

6-[N-(5-Bromo-2-cyclopropylmethoxy)-N-Propylamine] pyridazin-3-carboxylic acid

Specified in the title compound was obtained from the corresponding complex ester [obtained by the method similar to that described in comparative example 3, with the use of 1. Yield: 20%.

MS (ESP+): 420/422 (MN+).

NMR (200 MHz, DMSO-d6) : 0,25 (m, 2H); or 0.57 (m, 2H); of 0.91 (t, 3H); to 1.21 (m, 1H); to 1.61 (m, 2H); 3,63 (t, 2H); 3,88 (d, 2H); a 4.83 (s, 2H); of 6.96 (d, J= 8gts, 1H); 7,13 (d, J=Hz, 1H); 7,16 (d, J=2 Hz, 1H); 7,38 (DD, J=2 Hz, 8gts, 1H); of 7.82 (d, J=Hz, 1H).

EXAMPLE 38

N-(3,5-Dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-bromo-2-cyclopropylmethoxy)-N-Propylamine]pyridazin-3-carboxamid

Specified in the title compound was obtained from 6-[N-(5-bromo-2-cyclopropylmethoxy)-N-ethylamine] pyridazin-3-carboxylic acid (example 37) in a manner similar to that described in example 7, except that the solvent used dichloromethane and purification on a column was not necessary. Recrystallization (diethyl ether/hexane) gave specified in the title compound (340 mg, 49%).

MS (ESP+): 578/580 (MN+).

NMR (250 MHz, DMSO-d6) : 0,33 (m, 2H); 0,54 (m, 2H); from 0.88 (t, 3H); 1,19 (m, 1H) and 1.60 (m, 2H); 2.40 a (s, 3H); in 2.68 (s, 3H); of 3.60 (t, 2H); a 3.87 (d, 2H); 4,84 (s, 2H); of 6.96 (d, J=8gts, 1H); 7,17 (d, J=2 HZ, 1H); 7.23 percent (d, J=Hz, 1H); 7,38 (DD, J=2 Hz, 8gts, 1H); 7,81 (d, J=Hz, 1H).

EXAMPLE 39

6-[N-(5-Bromo-2-cyclopropylmethoxy)-N-methylamino] pyridazin-3-carboxylic acid

Specified in the title compound was obtained by the method similar to that described in NMR (250 MHz, DMSO-d6) : 0,33 (m, 2H); 0,55 (m, 2H); 1,19 (m, 1H); to 3.38 (d, 2H); a 4.86 (s, 2H); 6,97 (d, J=8gts, 1H); 7,17 (d, J=10Hz, 1H); 7,20 (d, J=2 Hz, 1H); 7,37 (DD, J=8gts, 2 Hz, 1H); to 7.84 (d, J=10Hz).

EXAMPLE 40

N-(3,5-Dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-bromo-2-cyclopropylmethoxy)-N-methylamino]pyridazin-3-carboxamid

Specified in the title compound was obtained from the corresponding carboxylic acid by a method similar to that described in example 38.

MS (ESP+): 550/552 (MN+).

NMR (250 MHz, DMSO-d6) : 0,30 (m, 2H); 0,52 (m, 2H); to 1.16 (m, 1H); 2,39 (s, 3H); 2,69 (s, 3H); up 3.22 (s, 3H); of 3.85 (d, 2H); by 5.87 (s, 2H); to 6.95 (d, J= 8gts, 1H); 7,20 (d, J=2 Hz, 1H); 7,27 (d, 1H); 7,39 (DD, J=2 Hz, 8gts, 1H); to 7.84 (d, 1H).

Comparative example 1

Methyl-2-[N-(5-bromo-2-propoxyphenyl)-N-ethylamino]pyridine-5-carboxylate

6-Chloronicotinic acid (100 g, was 0.63 mol) was treated with ethylamine (70% in water, 500 ml). The reaction mixture was loaded into the autoclave was tightly closed and heated at 170oC for 6 hours. The reaction mixture was evaporated and partially neutralized with concentrated HCl and was set to pH 5 with glacial acetic acid. The solid product was filtered and dried under vacuum for 18 hours to obtain 6-(ethylamino)nicotinic acid (87,8 g, yield 84%).

MS (CI+): DD, J=2, GC, 1H); 8,54 (d, J=2 Hz, 1H); 11,6 (Shir. s, 1H).

A suspension of 6-(ethylamino)nicotinic acid (50 g, 0.3 mmol) in methanol (500 ml) was treated with concentrated H2SO4(30 ml). The reaction mixture was heated under reflux for 18 hours. Then the reaction mixture was evaporated, poured into ice water (1 l) and was set to pH 8 with solid sodium bicarbonate (foaming). The aqueous mixture was extracted with ethyl acetate (CH ml) and the organic layers were combined, dried (MgSO4) and was evaporated to obtain methyl-6-(ethylamino)-nicotinate as not quite white solid product (45,5 g, 84%).

NMR (200 MHz, DMSO-d6) : to 1.14 (t, J=Hz, 3H); 3,3 (kV, J=Hz, 2H); 3,76 (s, 3H); 6,46 (d, J=Hz, 1H); 7,39 (Shir. t, 1H); 7,80 (DD, J=3, Hz, 1H); 8,56 (d, J=3 Hz, 1H).

A solution of 5-bromosalicylaldehyde (12.0 g, 59,7 mmol) in DMF (50 ml) was treated with K2CO3(16.5 g, 120 mmol) and benzylbromide (11.2 g, 65,6 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate and filtered. The filtrate is washed with Hcl (0.05 M), saturated aqueous sodium bicarbonate and saline. The organic phase was dried (Na2SO4) and was evaporated, the residue triturated in hexane/diethyl EPE is square 70-72oC.

MS (CI+): 291 (M+H)+.

NMR (200 MHz, DMSO-d6) : 5,38 (s, 2H); 7.5 (m, 6N); to 7.9 (m, 2H); 10,41 (s, 1H).

A suspension of 2-benzyloxy-5-bromobenzaldehyde (14.5 g, a 50.2 mmol) in absolute ethanol (250 ml) was treated with sodium borohydride (2.6 g, to 68.8 mmol). The reaction mixture was stirred and the temperature was slowly raised to 33oC. After 1 hour the reaction mixture was evaporated and the residue was dissolved in ethyl acetate and poured into a mixture of ice water (200 ml) and 1 N. Hcl (25 ml). The organic layer was separated, washed with an aqueous solution of sodium bicarbonate, saline, dried (Na2SO4) and was evaporated to obtain 2-benzyloxy-5-bromobenzylamine alcohol in the form of a pale yellow oil (14,85 g, quantitative yield).

MS (CI+): 292 (M+).

NMR (200 MHz, DMSO-d6) : to 4.52 (d, J=5Hz, 2H); 5,12 (s, 2H); 5.17 to (t, J= 5Hz, 1H); 6,98 (d, J=Hz, 1H); to 7.4 (m, 6N); 7.5 (d, 2H, 1H).

A solution of 2-benzyloxy-5-bromobenzylamine alcohol (14,75 g of 50.2 mmol) in anhydrous ethyl ether (150 ml) was cooled to 4oC. was Added dropwise a solution of RVG3(13,68 g, 50 mmol) in anhydrous ether (40 ml), keeping the temperature below 10oC. the Reaction mixture was allowed to warm to room temperature and was stirred during the of all products. The filtrate was washed with water (I ml), saturated aqueous sodium hydrogen carbonate (g ml) and brine (CH ml). The organic layer was dried (Na2SO4) and was evaporated to obtain 2-benzyloxy-5-bromobenzylamine (15.2 g, 85%) as a pale yellow oil, which crystallizes upon standing.

MC (EI+): 354 (M+).

NMR (200 MHz, DMSO-d6) : the 4.65 (s, 2H); and 5.2 (s, 2H); 7,05 (D, J=HZ, 1H); to 7.4 (m, 6N); 7,66 (d, J=3 Hz, 1H).

A solution of methyl-6-ethylaminoethanol (15.2 g, 84,4 mmol) in DMF (50 ml) was cooled to a temperature of 0oAnd was treated with sodium hydride (60%, 75 mmol). The reaction mixture was stirred 1 hour and the solution was added 2-benzyloxy-5-bromobenzylamine (25 g, of 70.2 mmol) in DMF (50 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. The reaction mixture was extinguished with water and was extracted with ethyl acetate (three times). The organic layers were combined, washed with water and brine twice, dried (MgSO4) and was evaporated to obtain a white solid product. Recrystallization from ethyl acetate/hexane gave methyl 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridine-5-carboxylate (22,7 g, 71%).

MC (CI+): 455/457 (M+N)+.

NMR (200 MHz, D is, N); to 8.62 (d, 1H).

A solution of methyl 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethyl-amino]pyridine-5-carboxylate (10.0 g, 22 mol) in dichloromethane (950 ml) was treated with complex dimethylsulfide boron (40 ml, 2M, 80 mmol). The reaction mixture was stirred at room temperature for 48 hours. Was added a saturated aqueous solution of sodium bicarbonate and the layers were washed with dichloromethane. The organic layers were combined, dried (MgSO4) and was evaporated to obtain not just the white solid product, which was subjected to chromatography (eluent: ethyl acetate/hexane) to obtain methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethyl-amino]pyridine-5-carboxylate (of 6.02 g, 75%).

MS (CI+): 365 (M+H)+.

NMR (250 MHz, DMSO-d6) : to 1.14 (t, J=Hz, 3H); 3,61 (kV, J=Hz, 2H); of 3.78 (s, 3H); of 4.66 (s, 2H); of 6.65 (d, J=Hz, 1H); 6.8 cm (d, J=Hz, 1H); 7,02 (D, J=2 Hz, 1H); 7,2 (DD, J=2, GC, 1H); to 7.93 (DD, J=2, GC, 1H); 8,64 (d, J= 2 Hz, 1H); 10, 13 (s, 1H).

1-Bromopropane (0.12 g, 0.69 mmol) was treated with a solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] -5-pyridylcarboxylic (0.2 g, 0.55 mmol) in DMF (4 ml). To this solution was added potassium carbonate (230 mg, 1.7 mmol) and the reaction mixture was stirred for 18 hours. The solvent was evaporated and the residue was treated with water (4 ml) and was extracted with acetat/hexane) to obtain specified in the title compounds as a pale yellow oil (0,122 g, 54%), which was used in the next stage without additional purification.

Comparative example 2

Methyl-2-[N-(5-bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridine-5-carboxylate

A solution of methyl 2-[N-(5-bromo-2-(hydroxybenzyl)-N-ethylamino] pyridine-5-carboxylate (comparative example 1, paragraph 7) (0.5 g, 1.37 mmol) in THF (15 ml) was treated with triphenylphosphine (0.39 g, 1,49 mmol) and diabetesdiabetes. The reaction mixture was stirred for five minutes at room temperature and then was added isobutyl alcohol (0.152 g, of 2.06 mmol). Then the reaction mixture was stirred for 18 hours at room temperature, was distributed between ethyl acetate and water and the aqueous layer washed with ethyl acetate (x 2). The organic layers were combined, washed with water and brine, dried (MgSO4) and was evaporated. The residue was subjected to chromatographicaliy (eluent: ethyl acetate/hexane) to obtain the specified title compound (0.35 g, 60%) as not quite white solid product.

MS (CI+): 421 (M+H)+.

NMR (250 MHz, DMSO-d6) : 1,0 (d, J=Hz, 3H); of 1.12 (t, J=Hz, 6N); 2,04 (m, 1H); 3,6 (kV, J=Hz, 2H); of 3.78 (s, 3H); of 3.80 (s, 2H); 4.75 V (s, 2H); 6,66 (d, J= Hz, 1H); 6,97 (d, J=Hz, 1H); 7,05 (d, J=2 Hz, 1H); 7,37 (DD, J=2, GC, 1H); to 7.93 (DD, J=2, GC, 1H); 8,73 rboxylic

A solution of 6-oxo-1,6-dihydropyridin-3-carboxylic acid (British patent 856409) (52 g, 0.33 mmol) in n-Vias (80 ml) and butanol (80 ml) was treated with concentrated sulfuric acid (5 ml). The mixture was heated to trap Dean-stark. After 5 hours the formation of water ceased. The reaction mixture was allowed to cool to room temperature and after standing overnight the precipitate was filtered off, washed with diethyl ether and dried to obtain butyl-6-oxo-1,6-dihydropyridin-3-carboxylate in the form of a white solid product (55,2 g, 85%), so pl. 81-83oC.

The solution of the above butyl ether (55,2 g, 0.28 mol) in acetonitrile (220 ml) was carefully added to l3(55,2 ml of 0.60 mol). The resulting solution was stirred at 100oC for 2 hours. The reaction mixture was cooled and evaporated under reduced pressure. The residue was dissolved in dichloromethane (280 ml) and added to a cold stirred solution of sodium carbonate (55 g) in water (280 ml). The resulting mixture was stirred until the complete termination of allocation of gas bubbles, and then the layers were separated and the organic layer was dried (gS4) and was filtered through a pad of silica gel. The solution was evaporated to obtain butyl-6-chloropyridazine-3-carboxylate as a pale pink solid fuel is THF (375 ml) was treated with methanolic ammonia (feast upon., 80 ml). The reaction mixture was left to stand overnight at room temperature. The precipitate was filtered and dried to obtain 6-chloropyridazine-3-carboxamide in the form of a solid pink product (18.2 g, 49%). [Additional product can be obtained by evaporation of the filtrate (under reduced pressure) and the handling balance THF (100 ml) methanolic ammonia (40 ml). The product was isolated as above, getting a pink solid product (17,4 g). Total output (35,6 g, 95%)].

A suspension of 6-chloropyridazine-3-carboxamide (28.5 g, 0.18 mol) in methanol (200 ml) was treated with aqueous solution of ethylamine (70% solution, 77 ml). The reaction mixture was heated under reflux for 3.5 hours. The reaction mixture was allowed to cool to room temperature and left overnight. The precipitate was filtered and washed with a small volume of water and dried to obtain 6-(ethylamino)pyridazine-3-carboxamide in the form of a pink solid product in (8.9 g). [The filtrate was evaporated to small volume, diluted with cold water (100 ml) and additional amounts of the desired solid product was filtered, washed with water and dried (12.8 g). Total output (21,7 g, 72%)].

A solution of 6-(ethylamino)pyridazine-3-carboxamide (21,7 g, 0,131 mol) in n-butanol (109 ml is Uchenie 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in water with ice (400 ml) and neutralized with solid sodium bicarbonate with stirring. The oily precipitate was extracted with dichloromethane (250 ml) containing methanol (50 ml). The extracts were dried (gS4) and was evaporated (in vacuo) to give a slightly viscous solid product, which was recrystallized from ethyl acetate (~ 250 ml) to give butyl-6-(ethylamino)pyridazine-3-carboxylate in the form of not-quite-white solid product (22,0 g, 75%).

Suspension butyl ester previous stage (21 g, 0,094 mol) in acetic acid (400 ml) was treated with 4-Bromphenol (65,5 g, 0,378 mol) and paraformaldehyde (3,15 g, 0,105 mol). The reaction mixture was heated at 100oWith over 4.5 hours and was added another portion of paraformaldehyde (6.3 g, 0.21 mol) and the reaction mixture was heated at 100oC for 16 hours. The reaction mixture is painted in a dark color was evaporated and obtained dark oil. The chromatography was carried out (eluent: diethyl ether/hexane) gave fast moving products in the form of a brown oil. This oil was dissolved in ethyl acetate (~ 70 ml) and left to stand overnight at room temperature to obtain a white solid precipitate, cotrimazine-3-carboxylate in the form of the product (12.3 g, 32%).

Comparative example 4

Butyl-6-[N-(5-bromo-2-cyclopropylmethoxy)-N-ethylamino] pyridazin-3-carboxylate

A solution of n-butyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] pyridazin-3-carboxylate (comparative example 3) (0,286 g, 0.69 mmol) in DMF (3.5 ml) was treated with bromelicola (0.1 g, 0.78 mmol) and potassium carbonate (0,473 g, 3.4 mmol). The reaction mixture was allowed to mix at room temperature for 60 hours. The solvent was evaporated under reduced pressure (vacuum pump) and the residue was distributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2x10 ml). The organic layers were combined, dried (MgSO4) and was evaporated. The residue was purified by chromatography (eluent: ethyl acetate/hexane) and got mentioned in the title compound as a pale yellow oil (0.3 g, 94%).

MS (ESP+): 462 (M+N)+.

NMR (200 MHz, DMSO-d6) : 0,32 (m, 2H); 0,55 (m, 2H); of 0.93 (t, J=Hz, 3H); to 1.15 (m, 4H); to 1.42 (m, 2H); 1,7 (m, 2H); 3,7 (kV, J=Hz, 2H); to 3.89 (d, J= Hz, 2H); 4,3 (t, J=Hz, 2H); 4,84 (s, 2H); 6,98 (d, J=8gts, 1H); to 7.15 (m, 2H); 7,4 (DD, J=3,9 Hz); of 7.82 (d, J=8gts, 1H).

Comparative example 5

Methyl-2-[N-(5-bromo-2-(cyclopentyloxy)benzyl)-N-ethylamino] pyridine-5-carboxylate

Specified in the header with the 1, paragraph 7), using cyclopentylmethyl instead of isobutyl alcohol (yield: 60%).

MC (ESP+): 447 (M+N)+.

NMR (200 MHz, DMSO-d6) : a 1.11 (t, J=Hz, 3H); of 1.35 (m, 2H); was 1.58 (m, 4H); 1,77 m, 2H); 2,3 (m, 1H); 3,6 (kV, J=Hz, 2H); 3,79 (s, 3H); 3,9 (d, J= Hz, 2H); 4.75 V (s, 2H); of 6.68 (d, J=Hz, 1H); 6.8 cm (d, J=Hz, 1H); 7,07 (d, J= 2 Hz, 1H); 7,38 (DD, J=2, GC, 1H); 7,94 (DD, J=2, GC, 1H); 8,65 (d, J=2H, 1H).

Comparative example 6

Butyl-6-[N-(5-bromo-2-propoxyphenyl)-N-ethylamino]pyridazin-3-carboxylate

Specified in the title compound was obtained by reacting 1-iodopropane with butyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazin-3-carboxylate (comparative example 3) in a manner similar to that described in comparative example 4.

MC (ESP1+): 450/452 (M+N)+.

Comparative example 7

Butyl-6-[N-(5-bromo-2-butoxybenzoyl)-N-ethylamino]pyridazin-3-carboxylate

Specified in the title compound was obtained by reacting 1-iodobutane with butyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazin-3-carboxylate by the method similar to that described in comparative example 4.

MC (ESP+): 464/466 (M+H)+.

Comparative example 8

6-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]pyridazin-3-carboxylic acid the(0.36 g, 1.0 mmol) in THF (4 ml) and methanol (4 ml) was treated with 1 N. aqueous sodium hydroxide solution (4 ml) and kept for 1.5 hours at room temperature. The reaction mixture was evaporated to small volume, diluted with water and acidified with acetic acid. After incubation for 18 hours, the precipitate was filtered, washed with water and ether and dried (gSO4) obtaining specified in the title compound as a white solid (0.26 g, 71%).

MS (ESP+): 352/354 (M+N)+.

NMR (200 MHz, DMSO-d6) : to 1.15 (t, J=6,67 Hz, 3H); 3,68 (kV, J=6,67 Hz, 2H); 4.75 V (s, 2H); 6,83 (d, J=8.34 per Hz, 1H); 7,10 (d, J=8.34 per Hz, 1H); 7,13 (d, J=2,33 Hz, 1H); to 7.25 (DD, J=10,00, 2,33 Hz, 1H); 7,83 (d, J=10.00 Hz, 1H).

Comparative example 9

2-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylic acid

A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] pyridine-5-carboxylate (see comparative example 1) (10.2 g, 0.55 mmol) in THF (3 ml) and methanol (5 ml) was treated with 1 N. aqueous sodium hydroxide solution (2.7 ml) and was heated to 40oWith in 24 hours. The solvent was evaporated under reduced pressure, the residue was treated with 1 N. acetic acid (2.7 ml) and the precipitate was filtered, washed with water and dried with air to obtain specified in the header of the 3H); 3,6 (kV, J=Hz, 2H); with 4.64 (s, 2H); 6,6 (d, J=Hz, 1H); 6,83 (d, J=Hz, 1H); 7,06 (d, J=2 Hz, 1H); 7.23 percent (DD, J=2, GC, 1H); 7,92 (DD, J=2, GC, 1H); 8,59 (d, J=2 Hz, 1H).

Comparative example 10

Butyl-6-[N-(5-bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylate

Butyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] pyridine-3-carboxylate (see comparative example 3) (1.12 g, was 2.76 mmol) in dimethylformamide (16 ml) was treated with potassium carbonate, and then 1-bromo-2-methylpropanol (0.16 ml, 770 mg, 5.6 mmol) and was stirred over night at room temperature. TLC indicated that the reaction was not completed, and the reaction mixture was added an additional amount of potassium carbonate (1.12 g) and 1-bromo-2-methylpropane. The resulting mixture was stirred at room temperature for 2 days. Then the mixture was evaporated to a smaller volume and the residue was purified directly by IHSD obtaining specified in the title compounds as a colourless resin. Yield: 98% (1.26 g).

NMR (250 MHz, DMSO-d6) : 0,90 (m, N); to 1.15 (t, 3H); to 1.42 (m, 2H); to 1.70 (m, 2H); 2,03 (m, 1H); to 3.73 (q, 2H); of 3.80 (d, 1H); to 4.28 (t, 2H); 4,82 (s, 2H); 6,97 (d, 1H); and 7.1 (m, 2H); 7,38 (DD, 1H); 7,81 (d, 1H).

Comparative example 11

Butyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazin-3-carboxylate

Specified in the header link is positive example 3 except that the reaction mixture was added 0.4 equivalent triperoxonane acid.

NMR (250 MHz, DMSO-d6) : of 0.94 (t, 3H); of 1.17 (t, 3H); USD 1.43 (m, 2H); to 1.70 (m, 2H); 3,7 (q, 2H); to 4.28 (t, 2H); 4.75 V (s, 2H); 6,85 (d, 1H); 6,97 (d, 1H); and 7.1 (m, 2H); of 7.82 (d, 1H); 10,1 (Shir. s, 1H).

Comparative example 12

Butyl-6-[N-(5-bromo-2-(2-methoxypropane)benzyl)-N-ethylamino] pyridazin-3-carboxylate

Specified in the title compound was obtained by reacting butyl-6-[N-(5-chloro-hydroxybenzyl)-N-ethylamino] pyridazin-3-carboxylate (comparative example 11) and 1-bromo-2-methylpropane manner similar to that described in comparative example 4.

NMR (200 MHZ, DMSO-d6) : of 0.95 (m, N); to 1.15 (t, 3H); USD 1.43 (m, 2H); to 1.70 (m, 2H); 2,03 (m, 1H); 3,68 (q, 2H); of 3.80 (d, 2H); to 4.28 (t, 2H); a 4.83 (s, 2H); 6,99 (d, 1H);? 7.04 baby mortality (d, 1H); 7,10 (d, 1H); 7,26 (DD, 1H); 7,83 (d, 1H).

MS (ES+): 420 (M+N)+.

Comparative example 13

N-Ethyl-5-bromo-2-(cyclopropylmethoxy)benzylamine

1-Methyl-2-pyrrolidinone (90 ml) (N) was added anhydrous potassium carbonate (of 27.6 g, 0.2 mol) in argon atmosphere. To stir the mixture portions was added 5-bromosalicylaldehyde (20,1 ml, 0.1 mol) and the mixture was stirred for 10 minutes. Bromelicola (14.4 ml, 0.15 mol) was dissolved in N and was added on ka for 3 hours, and then raised to 70oC for 1 hour and then cooled to 35oC. ethylamine Hydrochloride (13,85 g to 0.17 mol) was dissolved in methanol (60 ml) was added to the mixture, which was then heated at a temperature of 35-40oC for 3 hours and stirred overnight to cool to room temperature). Then the reaction mixture was cooled on ice. To this reaction mixture was added dropwise sodium borohydride (5,3 g, 0.14 mol), dissolved in N (58 ml) [bubbling gas and the heating of the 15oS], and the mixture was heated at 40-45oC for 2 hours. To this mixture was added dropwise 2 N. hydrochloric acid (250 ml) while maintaining the temperature below 30oC. the resulting mixture was transferred into a separating funnel and was extracted with ethyl acetate (x 2). The combined organic layers were washed with 20% brine/water (x 3) and brine (x 1), dried over Na2SO4, was filtered and was evaporated. The residue was dissolved in ethyl acetate (100 ml) and cooled on ice. Then stir the solution was barbotirovany gaseous hydrogen chloride. Specified in the title compound in the form of cleaners containing hydrochloride salt was besieged, was filtered, washed with ethyl acetate (x 2) and dried in high vacuum (12,6 g, 28 7,53 (DD, J= 8,0, 2,9 Hz, 1H); 7,73 (d, J=2,9 Hz, 1H); 9,25 (Shir. s, 2H).

MS (ESP+): 284 (M+N)+.

Comparative example 14

6-[N-(5-Bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]-3-lepirudin

6-[N-(5-Bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino] pyridazin-3-carboxamide (example 11) (2,03 g) suspended in pyridine (25 ml) and cooled in an argon atmosphere at 4oC. To the suspension was added dropwise methanesulfonanilide (4.6 ml, 59.5 mmol) (reaction with evolution of heat to -8oWith), and then pyridine (20 ml). The reaction mixture was heated and stirred over night. After removal of the pyridine under reduced pressure, the residue was distributed between ethyl acetate and 1 N. hydrochloric acid. The organic layer was washed with 50% of 1 N. Hcl/saturated aqueous ammonium chloride (x 1), saturated aqueous sodium bicarbonate (×1) and brine (x 1), dried over Na2SO4, was filtered and was evaporated. The residue was purified by column chromatography (eluent: 2.5% ethyl acetate/dichloromethane), and the fractions containing specified in the header of the product was evaporated to a resin (1.65 g, 85.0 per cent).

NMR (200 MHz, DMSO-d6) : 0,30 (m, 2H); 0,54 (m, 2H); to 1.15 (m, 4H); of 3.69 (q, 2H); of 3.85 (d, 2H); 4.80 to (s, 2H); to 6.95 (d, 1H); 7,20 (m, 2H); 7,38 (DD, 1H); 7,80 (d, 1H).

SAMINA]-3-lepirudin

6-[N-(5-Chloro-2-(2-methylpropoxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid (example 10) (2.0 g) was dissolved in pyridine (30 ml) in an argon atmosphere and cooled to 4oC. was Added methanesulfonamide (0.75 ml, 9.7 mmol), the mixture was stirred for 1.5 hours at a temperature of 4oWith and received a dark purple solution. In the solution for 2 minutes was barbotirovany gaseous ammonia (warming to +15oWith) and got a dark red solution which was then evaporated under reduced pressure. The residue was dissolved in pyridine (30 ml) and cooled in a stream of argon to 4oC. After adding dropwise methanesulfonanilide (5.1 ml, 66 mmol) (warming up to 10o(C) the obtained brown suspension was stirred over night at room temperature. Then the brown solution was evaporated and the residue was distributed between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with 10% 2 N. Hcl/saturated aqueous ammonium chloride (×2), saturated aqueous sodium bicarbonate (×1) and brine (x 1), dried over Na2SO4, was filtered and was evaporated. Specified in title product was isolated using column chromatography using as e is H); 2,00 (m, 1H); to 3.67 (q, 2H); 3,79 (d, 2H); is 4.85 (s, 2H); 7,05 (m, 2H); 7,19 (d, 1H); 7.29 trend (DD, 1H); to 7.84 (d, 1H).

MS (ES+): 345(M+N)+.

Comparative example 16

n-Butyl-6-[N-(5-bromo-2-(2-hydroxy-3,3,3-cryptocracy) benzyl)-N-ethylamino]pyridazin-3-carboxylate

Specified in the title compound was obtained by reacting 3-bromo-1,1,1-tryptophan-2-ol and butyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] pyridazin-3-carboxylate by the method similar to that described in comparative example 4.

NMR (250 MHz, DMSO-d6) : of 0.95 (t, 3H); to 1.15 (t, 3H); to 1.42 (m, 2H); by 1.68 (m, 2H); 3,7 (q, 2H); 4,20 (m, 4H); was 4.42 (m, 1H); of 4.83 (s, 2H); of 6.65 (d, 1H); and 7.1 (m, 3H); 7,42 (DD, 1H); 7,63 (d, 1H).

Comparative example 17

6-[N-(2-(Cyclopropylmethoxy)-5-methanesulfonylaminoethyl)-N-ethylamino] -3-lepirudin

4-Methylmercaptopurine (8,96 g, 64 mmol) suspended in toluene (80 ml) was added to a solution of magnesium methylate in methanol (5.5 ml, 8%, up 41.4 mmol) and the reaction mixture was stirred for 1 hour at reflux. Then the yellow solution was treated with toluene (80 ml) and the reaction mixture kept methanol until a temperature of the reaction mixture of approximately 95oS. had Formed a small amount of solid precipitate. To a mixture of dargon when heated under reflux (temperature must be at least 95oC). The reaction mixture containing a small amount of solid product was cooled and treated 2 N. sulfuric acid (80 ml), toluene (80 ml) was stirred for 15 minutes and separated. The organic layer was washed with water (x 3), dried and evaporated to a residue in the form of an orange oil (9.6 g). This oil was purified using GHSD using 5% ether/isohexane, obtaining 2-hydroxy-5-methylthiazolidine (3.3 grams).

NMR (200 MHz, DMSO-d6) : of 2.45 (s, 3H); 6,98 (d, J=Hz, 1H); of 7.48 (DD, J=2,3, 9.0 Hz, 1H); at 7.55 (d, J=2.3 Hz, 1H); of 10.25 (s, 1H); 10,67 (s, 1H).

MS (CI+): 168 (M+).

2-Hydroxy-5-methylthiazolidine alkilirovanie bromelicola manner similar to that described in comparative example 4, to obtain the 2-cyclopropylmethoxy-5-methylthiazolidine.

NMR (200 MHz, DMSO-d6) : 0,36 (m, 2H); 0,6 (m, 2H); 1.26 in (m, 1H); to 2.46 (s, 3H); 4,0 (d, J=of 8.25 Hz, 2H); 7,2 (d, J=9,2 Hz, 1H); 7,52 to 7.62 (m, 2H); 10,38 (s, 1H).

MS (CI+): (M+N)+223,3.

N-Ethyl-2-cyclopropylmethoxy-5-methylthiophenethylamine was obtained by reductive amination of 2-cyclopropyl-methoxy-5-methylthiophenethylamine manner similar to that described in comparative example 19 (1).

NMR (200 MHz, DMSO-d6) : 0,32 (m, 2H); 0,5 kg, 1H); to 7.25 (d, J=2.5 Hz, 1H).

MS (ESP+): 252,4 (M+N)+.

N-Ethyl-2-cyclopropylmethoxy-5-methylthiophenethylamine were subjected to interaction with 3-chloro-6-lepirudin (obtained in comparative example 18) in a manner similar to that described in example 11, which was obtained 6-[N-(2-cyclopropylmethoxy)-5-methylthiophenyl)-N-ethylamino]-3-lepirudin.

NMR (200 MHz, DMSO-d6) : 0,28 (m, 2H); 0,52 (m, 2H); 1,20-1,08 (m, 4H); to 2.35 (s, 3H); 3,70 (q, 2H); of 3.84 (d, J=8,3 Hz, 2H); and 4.8 (s, 2H); to 6.95 (d, J= 8,3 Hz, 1H); 7.03 is (d, J=2.1 Hz, 1H); 7,19 (DD, J=10,4, 2,1 Hz, 2H); 7,8 (d, J= 10.4 Hz).

MS (ESP+): 355 (M+N)+.

6-[N-(2-Cyclopropylmethoxy-5-methylthiophenyl)-N-ethylamino] -3-lepirudin (201 mg, or 0.57 mmol) in dichloromethane (5 ml) was cooled on ice to approximately -10oAnd was treated with 50% m-chloroperbenzoic acid (196 mg, or 0.57 mmol). The reaction mixture was stirred for 1 hour at a temperature of from -10oWith 0oWith, then was diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate (×2). The organic extracts were dried and evaporated with the formation of a pale brown foam (180 mg). Foam (180 mg, 0.49 mmol) in dichloromethane (5 ml) was cooled to -10oC, was treated with m-chloroperbenzoic acid (170 mg, 0.49 mmol) and re is on, the mixture was extracted with aqueous saturated sodium bicarbonate solution (×2), dried and evaporated to obtain foam, which was purified using GHSD using 2:1 ethyl acetate/hexane as eluent, to obtain specified in the header of the product (100 mg, 53%).

NMR (200 MHz, DMSO-d6) : 0,32 (m, 2H); 0,54 (m, 2H); 1,27-1,08 (m, 4H); is 3.08 (s, 3H); 3,7 (q, 2H); 3,98 (d, J=8,3 Hz, 2H); 4,88 (s, 2H); 7,22 (d, J= 10.4 Hz, 1H); 7,26 (d, J=10.4 Hz, 1H); to 7.61 (d, J=2.1 Hz, 1H); to 7.77 for 7.78 (m, J= of 10.21 Hz, 2H).

MS (ESP+): (M+N)+387,2.

Comparative example 18

6-[N-(5-Bromo-2-propoxyphenyl)-N-ethylamino]-3-lepirudin

(1) a Mixture of 6-chloropyridazine-3-carboxamide (described in comparative example 3) (15 g, 95.5 mmol) and pyridine (22,6 g, 23.1 ml, 286,6 mmol) suspended in dichloromethane and cooled to -30oC in argon atmosphere. To a stirred mixture was added dropwise TFW, maintaining an internal temperature below -20oC. the Reaction mixture was stirred for 19.5 hours to warm to room temperature. The mixture was poured into water (500 ml) and washed with water (I ml) up until the aqueous phase is acquired light yellow tint. The organic phase was dried over gSO4was filtered through a pad of silica gel (diameter 50 mm, depth 30 mm) and koncentrirebuli-chloro-6-lepirudin in the form of a colourless solid (5,25 g, 59%).

MS (EI+): 139 (M+).

NMR (250 MHz, CDCl3) : 7,71 (d, J=8gts, 1H); 7,83 (d, J=8 Hz, 1H).

(2) a Solution of 5-bromosalicylaldehyde (20 g, 100 mmol) in NM (100 ml) was treated with K2CO3(up 41.4 g, 300 mmol) for 30 minutes at a temperature of 40oC. was Added n-propyliodide (25,5 g, 150 mmol) and the reaction mixture was stirred for 19 hours at 40oC. was Added a solution of ethylamine hydrochloride (11,41 g, 140 mmol) in ethanol (50 ml), the mixture was stirred for further 3 hours at 40oC and then for 1 hour was added dropwise a solution of sodium borohydride (5,292 g, 140 mmol) in NM (20 ml). (Caution: there is a large amount of foam). The reaction mixture was stirred for 19 hours at 40oC, cooled to room temperature and was added 5M hydrochloric acid (500 ml). Then the solution was treated with 5M solution of sodium hydroxide to pH 14 and extracted with ethyl acetate (CH ml). The combined organic phases were washed with water (I ml), dried over potassium carbonate, and after the solution was passed dry Hcl gas. Suspension was concentrated in vacuo and received a yellow solid product which was recrystallized from acetonitrile/toluene, the result of which was obtained the hydrochloride of N-ethyl-2-propoxy-5-brombenzene : 1,02 (t, J=Hz, 3H); 1,25 (t, J=Hz, 3H); of 1.80 (m, 2H); of 3.77 (q, J=Hz, 2H); to 3.92 (t, J=Hz, 2H); 4.80 to (Shir. s, 2H); to 6.67 (d, J= 8.5 Hz, 1H); 6.75 in (d, J=Hz, 1H); for 7.12 (d, J=2 Hz, 1H); 7,34 (DD, J=8, 2 Hz, 1H); 7,38 (d, J=8.5 Hz, 1H).

(3) N-Ethyl-2-propoxy-5-bromobenzylamine hydrochloride 2 (of 5.17 g, a 16.8 mmol) and 3-chloro-6-lepirudin (2.65 g, a 16.8 mmol) was dissolved in N (25 ml) was added sodium bicarbonate (3,54 g, 42.1 mmol). The resulting mixture was heated at 110oC in argon atmosphere for 7.5 hours, then allowed to cool to room temperature. The mixture was poured into ethyl acetate (200 ml), washed with water (I ml) and brine (200 ml), the organic phase was dried over MgSO4and concentrated in vacuum. The residue was purified using IHSD (20% ethyl acetate/hexane) and then was led from ether/hexane to obtain specified in the header of the product (4,80 g, 76%).

MC (ESP): 272 (MN+), 227 (M-EtNH2)+.

NMR (250 MHz, DMSO-d6) : 0,99 (t, J=Hz, 3H); 1.26 in (t, J=Hz, 3H); of 1.78 (m, 2H); 2,92 (kV, J=Hz, 2H); 3,95 (t, J=Hz, 2H); was 4.02 (s, 2H); 7,02 (d, J=8gts, 1H); 7,52 (DD, J=8,2 Hz, 1H); of 7.75 (d, J=2 Hz, 1H); to 9.32 (Shir. s, 2H).

Comparative example 19

6-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]-3-lepirudin

(1) a Solution of 5-bromosalicylaldehyde (20,1 g, 0.1 mmol) in THF (150 ml) was treated with a solution of ethylamine in methanol (2M, 70 ml, 0.14 mm the portions bath was added sodium borohydride (5.3g, 0.14 mmol). The reaction mixture was stirred over night at room temperature. Added water and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, the organic layer was dried over MgSO4and acidified with gaseous Hcl. Hydrochloride, N-ethyl-5-bromo-2-hydroxybenzylidene was collected by filtration and obtained white solid product (17,53 g, 66%).

NMR (250 MHz, DMSO-d6) : of 1.23 (t, 3H); to 2.94 (q, 2H); 4,60 (t, 2H); of 6.96 (d, 1H); 7,37 (DD, 1H); 7,63 (d, 1H); 9,02 (Shir. s, 1H); 10,59 (s, 1H).

MS (ESP+): 230/232 (M+N)+.

(2) Specified in the title compound was obtained by reacting the hydrochloride of N-ethyl-5-bromo-2-hydroxybenzylidene with 3-chloro-6-lepirudin manner similar to that described in comparative example 18, except that in chromatography as eluent used 2% diethyl ether/dichloromethane (yield: 50%).

NMR (250 MHz, DMSO-d6) : to 1.15 (t, 3H); of 8.37 (q, 2H); 4.75 V (s, 2H); for 6.81 (d, 1H); 7,07 (d, 1H); to 7.15 (d, 1H); to 7.25 (DD, 1H); of 7.82 (d, 1H); 10,12 (Shir. s, 1H).

Comparative example 20

N-Ethyl-5-chloro-2-(cyclopropylmethoxy)benzylamine

Specified in the title compound was obtained by reacting 5-chloro-2-hydroxybenzaldehyde with brometalia is S="ptx2">

NMR (200 MHz, Dl3) : 0,34 (m, 2H); 0,63 (m, 2H); of 1.13 (t, J=Hz, N); of 1.26 (m, 1H); to 2.65 (q, J=Hz, 2H); of 3.78 (d, 2H); of 3.80 (d, 2H); 6,72 (d, J=8gts, 1H); 7,13 (DD, J=2, 8gts, 1H); 7,21 (d, J=2 Hz, 1H).

Comparative example 21

6-[N-(5-Chloro-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]-3-lepirudin

To a stirred mixture of 6-[N-(5-Chloro-2-(cyclopropylmethoxy) benzyl)-N-ethylamino]pyridazin-3-carboxamide (3.5 g, 9.7 mmol) in pyridine (120 ml) at a temperature of 20oC for 20 minutes was added dropwise methanesulfonanilide (10.0 ml, 124 mmol). The resulting mixture was stirred at a temperature of 20oWith over 60 hours and poured into ice (300 g), was added 10 N. hydrochloric acid (100 ml) and the mixture vigorously stirred, and then was extracted with ether (500 ml). The organic layer is washed with 1 N. hydrochloric acid (500 ml), dried over anhydrous magnesium sulfate and evaporated, resulting in the received specified in the header of the product in the form of a light brown resin (3,3 g, 99%).

MS (ESP+): 343/345 (M+N)+.

NMR (200 MHz, CDCl3) : 0,32 (m, 2H); of 0.60 (m, 2H); of 1.20 (m, 1H); 1,25 (t, J= Hz, 3H); 3,82 (d, 2H); 3,85 (kV, J=Hz, 2H); is 4.85 (s, 2H); is 6.78 (d, J= 8gts, 1H); 7,06 (d, J=8gts, 1H); to 7.09 (d, J=2 Hz, 1H); 7,22 (DD, J=2, 8gts, 1H); 7,52 (d, J=8gts, 1H).

Comparative example 22

N-Ethyl-5-chloro-2-(cyclopentyloxy)benzo is l) was added anhydrous potassium carbonate (23,4 g, 169 mmol) and the solution was stirred for 16 hours at 50oC. Inorganic solid substance was extracted, and the solvent was removed in vacuum. The resulting product was extracted with dichloromethane from water (200 ml) and the organic layer was sequentially dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The dissolved product was purified on a column of silica gel by washing with dichloromethane and 2 N. a solution of sodium hydroxide (3100 ml), which was obtained 5-chloro-2-cyclopentanecarboxaldehyde (19, 22 the g, 66%).

MC (CI+): 225/227 (MN+).

NMR (200 MHz, DMSO-d6) : of 1.80 (m, 8H); to 4.98 (m, 1H); from 7.24 (d, J=8gts, 1H); 7,58 (d, J=2 Hz, 1H); a 7.62 (DD, J=2,8 Hz, 1H); 10,28 (s, 1H).

5-Chloro-2-cyclopentanecarboxaldehyde (a 9.35 g of 41.6 mmol) and ethylamine hydrochloride (18.6 g, 229 mmol) in methanol (100 ml) was stirred for 30 minutes at room temperature, and then added Lamborghini sodium (5.6 g, 88 mmol) and the reaction mixture was heated under reflux at 70oWith over 70 hours with periodic acidification with glacial acetic acid to pH 6. Was added dropwise normal hydrochloric acid (100 ml) and the resulting mixture was podslushivaet 2 n solution of sodium hydroxide to a pH of 11, about the anhydrous magnesium sulfate, was filtered and the solvent was removed to obtain specified in the title compound (8.5 g, 80%).

Comparative example 23

6-(N-[5-Chloro-2-(cyclopentyloxy)benzyl]-N-ethylamino)-3-lepirudin

Specified in the title compound was obtained by reacting the compound of comparative example 22 3-chloro-6-lepirudin (comparative example 18 (1)) in a manner similar to that described in comparative example 18 (3).

Comparative example 24

6-(N-[5-Bromo-2-(cyclobutylamine)benzyl]-N-ethylamino)-3-lepirudin

Specified in the title compound was obtained by alkylation of the corresponding nitrile (comparative example 18) bromocyclobutane, using a method similar to that described in comparative example 4, except that the reaction mixture was stirred for 10 days at room temperature.

MS (ESP+): 387 (M+N)+.

NMR (250 MHz, DMSO-d6) : to 1.14 (t, 3H); at 1.73 (m, 2H); to 1.98 (m, 2H); 2.40 a (m, 2H); 3,68 (q, 2H); 4.72 in (quintet, 1H); to 4.81 (s, 2H); PC 6.82 (d, 1H); to 7.2 (m, 2H); 7,37 (DD, 1H); 7,83 (d, 1H).

Comparative example 25

6-[N-(5-Bromo-2-(3,3,3-Cryptor-2-hydroxypropoxy)benzyl] -N-ethylamino)-3-lepirudin

Specified in the title compound was obtained by vzaimodei described in comparative example 4.

MS (ESP+): 445 (M+N)+.

NMR (250 MHz, DMSO-d6) : to 1.15 (t, 3H); 3,68 (q, 2H); 4.16 the (m, 1H); 4.25 in (m, 1H); 4,4 (m, 1H); is 4.85 (s, 2H); of 6.65 (d, 1H); 7,14 (m, 3H); the 7.43 (DD, 1H); 7,83 (d, 1H).

Comparative example 26

2-[N-(5-Bromo-2-cyclopropylmethoxy)-N-ethylamino]-5-lepirudin

Specified in the title compound was obtained by reacting N-ethyl-5-bromo-2-cyclopropylacetylene (comparative example 13) with 2-chloro-5-lepirudin manner similar to that described in comparative example 18.

MS: 386 (M+H)+.

NMR (MHZ, DMSO-d6) : 0,33 (m, 2H); 0,55 (m 6,70 (d, 1H); to 6.95 (d, 1H); 7,05 (d, 1H); to 7.35 (DD, 1H); of 7.75 (DD, 1H); to 8.45 (d, 1H).

Comparative example 27

6-[N-(5-Chloro-2-cyclobutylmethyl]-N-ethylamino)-3-lepirudin

Cyclobutylmethyl (5 g, 58 mmol) was dissolved in dichloromethane (150 ml) and cooled in an ice water bath. To the solution was added triethylamine (10.5 ml, of 75.6 mmol) and then was added dropwise a solution of tosylchloramide (13.3 g, 69,8 mmol) in dichloromethane (50 ml). After removal of the cooling bath the mixture was allowed to warm to room temperature over 16 hours. The mixture was washed with water (I ml), dried (MgSO4) and concentrated in vacuum to obtain tosilata of cyclobutanone in>5-Chlorosalicylaldehyde (7.7 g, 49.4 mmol) was dissolved in DMF (20 ml) with potassium carbonate (7.5 g, 54.1 mmol) and tosylate of cyclobutanone (13 g, 54.1 mmol). The mixture was stirred for 16 hours in an argon atmosphere at 50oC. was Poured into water (500 ml), extracted with ethyl acetate (4x100 ml) and the combined organic fractions washed with 1M sodium hydroxide solution (100 ml), water (100 ml), saturated brine (100 ml), dried (MgSO4) and concentrated in vacuo, resulting in a received 5-chloro-2-(cyclobutylmethyl)benzaldehyde as a brown oil (13 g), which was used without further purification.

MS: 225 (M+N)+.

5-Chloro-2-(cyclobutylmethyl)benzaldehyde (13 g) was dissolved in DMF (100 ml) was added potassium carbonate (16 g, 116 mmol) and ethylamine hydrochloride (9.5 g, 117 mmol). The mixture was heated for 1 hour at 40oC, then cooled in an ice water bath and was added dropwise a solution of sodium borohydride (4.3 g, 116 mmol) in minimum amount of DMF. After complete addition, the cooling bath was removed and the reaction mixture was heated at 40oC for 16 hours. The reaction mixture was cooled to room temperature and carefully added 5M hydrochloric acid up until the pH of the mixture is by ethyl acetate (CH ml), the combined organic fractions were washed with water (100 ml), saturated brine (100 ml), dried (MgSO4) and concentrated in vacuo to obtain an oil (15 g). This oil was purified using IHSD (5% methanol/dichloromethane) was obtained N-ethyl-5-chloro-2-(cyclobutylmethyl)benzylamine resin that solidifies upon standing (2.1 g, 17%).

MS: 254 (M+N)+.

NMR (MHz, DMSO-d6) : of 1.05 (t, 3H); 1,95 (m, 6N); of 2.50 (m, 1H); to 2.75 (q, 2H); the 3.65 (s, 2H); to 3.92 (d, 2H); to 6.95 (d, 1H); 7,20 (DD, 1H); 7,28 (d, 1H).

N-Ethyl-5-chloro-2-(cyclobutylmethyl)benzylamine (2.1 g, 8.3 mmol) was subjected to binding assays with 3-chloro-5-lepirudin (1.3 g, 8.25 mmol) with sodium bicarbonate (0.71 g, to 8.45 mmol) in NM (10 ml) in a manner similar to that described in comparative example 18. Specified in the title compound was purified by IHSD (dichloromethane, 1% Meon/dichloromethane) (2.3 g, 78%) to obtain the solid product.

MS: 357 (M+N)+.

NMR (MHz, DMSO-d6) : 1,1 (t, 3H); 1,95 (m, 6N); 2,60 (m, 1H); the 3.65 (q, 2H); 3,95 (d, 2H); and 4.8 (s, 2H); to 6.95 (d, 1H); 7,00 (d, 1H); 7.18 in (d, 1H); 7,26 (DD, 1H); of 7.82 (d, 1H).

Comparative example 28

N-Ethyl-5-bromo-2-(cyclopropylmethoxy)benzylamine

To 5-bromosalicylaldehyde (15.0 g, 74 mmol) in dimethylformamide was added betw the owls at the 50oC. Then was added Propylamine (26.5 g, 450 mmol) and the solution was left to mix at room temperature for 2 hours, after which was added diethyl ether (50 ml) and sodium borohydride (2.6 g, 68 mmol) and the solution was kept for 1 hour. After adding dropwise 6 N. hydrochloric acid (150 ml) the solution was left to stir for 16 hours. The admixture was extracted with diethyl ether (200 ml x 2), the solution was podslushivaet liquid caustic soda and the product was extracted with diethyl ether (250 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuum to obtain specified in the title compound (4.8 g, 22%).

MS (EI+): 298/300 (MN+).

NMR (200 MHz, DMSO-d6) : 0,34 (m, 2H); of 0.56 (m, 2H); from 0.88 (t, 3H); 1,22 (m, 1H); of 1.44 (m, 2H); 2,47 (t, 2H); 3,66 (s, 2H); 3,82 (d, 2H); 6,86 (d, J= 8gts, 1H); 7,31 (DD, J=2 Hz, 8gts, 1H); 7,46 (d, J=2 Hz, 1H).

1. Aromatic compounds of the formula I

< / BR>
where a is optionally substituted phenyl, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring atom of the ring, in anthopology towards OR4-joined the group (and, sledovatel objazatelnye the substituents of the carbon atoms of the ring are selected from halogen, trifloromethyl, nitro, hydroxy, amino, C1-4alkylamino, dis1-4alkylamino, cyano, C1-6alkoxy, C1-6S(O)p(p = 0, 1 or 2), C1-6the alkyl (optionally substituted by hydroxy, amino, halogen, nitro or cyano), CF3S(O)p(p = 0, 1 or 2), carbamoyl,1-4allylcarbamate, di(C1-4alkyl)carbamoyl,2-6alkenyl,2-6the quinil,1-4alkoxycarbonyl,1-4alkanolamine,1-4alkanoyl(N-C1-4alkyl)-amino, C1-4alkanesulfonyl, benzosulfimide, aminosulfonyl,1-4alkylaminocarbonyl,1-4alkanolamines, di(C1-4alkyl)aminosulfonyl,1-4alkoxycarbonyl,1-4alkanoyloxy,1-6alkanoyl, formals1-4of alkyl, trifter1-3alkyl-sulfonyl, hydroxyimino1-6of alkyl, C1-4alkoxyimino1-6the alkyl and C1-6alkylcarboxylic;

In - pyridyl or pyridazinyl;

R1located on the ring In the 1,3 - or 1,4-position relative to the-CHR3NR2-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula NRaRa1where Rais hydrogen or C1-6alkyl and R1-6
the alkyl or C1-4alkanolamines;

R2- C1-6alkyl;

R3is hydrogen;

R4- C1-4alkyl, C3-7cycloalkyl1-3alkyl or C3-7cycloalkyl where specified WITH1-6alkyl optionally substituted by a hydroxy-group or halogen,

or their pharmaceutically acceptable salt or in vivo hydrolyzable ester, where or in vivo hydrolyzable ester of carboxypropyl selected from pharmaceutically acceptable complex ester formed WITH1-6alcohol, phenol or benzyl alcohol, substituted phenol or benzyl alcohol, where the Deputy is1-4alkyl or C1-4alkoxy; or-aryloxyalkyl complex ether;

in vivo hydrolyzable ester of the hydroxy-group is selected from alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to obtain esters of alkalicarbonate), dialkylamino and N-(dialkylaminoalkyl)-N-allylcarbamate (to get carbamates), dialkylaminoalkyl and carboxyethyl; and with the exception of 2-[2-methoxybenzylamine] pyridine-5-carboxylic acid.

Boxy, tetrazolyl or a group of the formula-ONHRA1where RA1- C1-4alkyl or a group of the formula-CONHSO2Rbwhere Rb- C1-4alkyl, 3,5-dimethylisoxazol-4-yl or 5-acetamido-1,3,4-thiadiazole-2-yl.

4. The compound according to any one of paragraphs. 1-3, where a is substituted by halogen, nitro, trifluoromethyl, cyano, amino, C1-6alkoxy, carbamoyl,1-4allylcarbamate, di(C1-4alkyl)carbamoyl,1-4alkanolamine,1-6S(O)pWITH1-4alkanesulfonyl, benzosulfimide,1-6alkanoyl,1-4alkoxyimino1-4the alkyl or hydroxyimino1-4the alkyl.

5. The compound according to any one of paragraphs. 1-4, where R4- C1-4alkyl, C3-6cycloalkylation,3-6cycloalkyl where specified WITH1-4alkyl optionally substituted by a hydroxy-group or halogen.

6. Connection on p. 1, representing 6-[N-(5-chloro-2-salutogenesis)-N-ethylamino] -N-(3,5-dimethylisoxazol-4-ylsulphonyl)-pyridazin-3-carboxamide, or N-propanesulfonyl-6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino] pyridazin-3-carboxamide, or its pharmaceutically acceptable salt.

7. Connection on p. 1, representing 6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl)-N-Atila the IDF.

8. Pharmaceutical composition for the treatment of pain, which contains an effective amount of a compound according to any one of paragraphs. 1-7 and a pharmaceutically acceptable carrier.

9. The way to eliminate pain by injecting the patient an effective amount of the compounds of formula (I) PP. 1-7.

10. The method of obtaining aromatic compounds of the formula I under item 1, in which R1-carboxy, carbarnoyl, or a group of the formula-ONRaRA1or formula CONHSO2R6where Rand, RA1and Rbhave the values listed in paragraph 1, or pharmaceutically acceptable salt or in vivo hydrolyzable esters defined in paragraph 1, characterized in that the compound of formula III

< / BR>
in which R6means secured carboxypropyl;

R7matter listed for R2in paragraph 1 of the formula;

R3, R4, A and b have the values listed in paragraph 1,

remove carboxyamide group to obtain the compounds of formula I, where R1- carboxy, followed, if necessary, converting the compounds obtained into a compound of formula I, where R1- carbarnoyl, or group-NRandRA1or group NHSO2R6and convert it to think>/P>11. Aromatic compounds of the formula III

< / BR>
where R6means carboxypropyl protected tarifitsiruemih1-4alkyl group;

R7matter listed for R2in paragraph 1 of the formula;

R3, R4, A and b have the values listed in paragraph 1.

Priority points and features:

20.06.1995 on PP. 1-4 for compounds where R4- unsubstituted WITH1-6alkyl; p. 5, where R4- unsubstituted WITH1-4alkyl; p. 8, wherein the pharmaceutical composition contains the above compounds; p. 9 where to use these connections, and p. 10 the method of obtaining these compounds;

25.01.1996 on PP. 1-4 for compounds where R4- C1-6alkyl, substituted hydroxy and halogen, or WITH3-7cycloalkyl; p. 5, where R4- C1-4alkyl, substituted hydroxy and halogen, or WITH3-6cycloalkyl; p. 8, wherein the pharmaceutical composition contains these compounds; p. 9 using these compounds and p. 10 in obtaining these compounds;

17.06.1996 (on the date of filing of application PCT/GB 96/01442) PP. 1-4 for compounds where R4- C3-7cycloalkyl1-3alkyl; p. 5, where R4- C3-6cycloalkenyl; PP. 6 and 7 p. 8, wherein the pharmaceutical composition contains the

 

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The invention relates to a method for the preparations of thiazolidinediones of the formula III, where a denotes CH=CH or S, W is O; X Is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl; Y is CH or N; R is naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine; R1is hydrogen, C1-C6alkyl and n = 1-3, by restoring the compounds of formula IV metal aluminum in proton solvent

The invention relates to a new, more thermodynamically stable crystalline form of the hydrochloride of (R)-(-)-2-{N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}-chroman

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

The invention relates to a medicinal product on the basis of derivatives of thiazole or thiadiazole of the formula I, where a denotes a linear or branched C1-C18-alkylenes group which may contain at least one group selected from the group consisting of: O, S, NR3, СОNR3, NR3CO, COO, OCO or double or triple bond; In denotes the radical of the formula II, R1denotes H, halogen JV CO2R2, NR2R3, OR SIG3, CF3or C1-C8-alkyl, which is unsubstituted or substituted HE OS1-C8-alkyl or halogen; R2denotes H, C1-C8-alkyl, which is unsubstituted or substituted HE OS1-C8-alkyl or halogen, or phenyl-C1-C8-alkyl; R3has the meanings given for R2or indicate СОR2or CO2R2; X represents N or CR4where R4denotes H, C1-C8-alkyl, which is not substituted or is substituted by IT, OS1-C8-alkyl or halogen, or denotes phenyl which is not substituted or substituted with halogen, CF3C1-C8-alkyl or C1-C8-alkoxy; Ar denotes phenyl, pyridyl, pyrimidyl or triazinyl,

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to a method for Cefotaxime formula I by reacting acetone compounds of the formula II with the compound of the formula III and subsequent, if necessary, converting the compounds of formula I in the presence of a source of sodium ions in a mixture of acetone and water in the sodium salt of Cefotaxime in the form of rounded agglomerates with a bulk density of 0.2-0.6 g/ml or in the form of needle-shaped crystals

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

The invention relates to new heterocyclic compounds with valuable biological properties, in particular derived dioxide benzothiazine, the pharmaceutical compositions based on them having inhibitory receptor endothelin activity, and to a method of inhibiting endothelin receptor

The invention relates to a new method of obtaining isoxazolidinone the compounds of formula (II) in which R represents an optionally substituted aromatic hydrocarbon group or its salt, by reacting the compounds of formula (1) or its salt with the compound of the formula (2) in the presence of an inorganic base in an aqueous solvent with getting aspartates the compounds of formula (3), which interacts with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula (4), to which is added p-toluensulfonate acid to obtain oxazolidinedione derivative of the formula (5)which then restores the tetrahydrofuran in the presence of NaBH4and methanol to obtain oxazolidinones the compounds of formula (6) and its further interaction with methylchloride in the presence of triethylamine to obtain methanesulfonate derivative of the formula (7), which interacts with the compound of the formula (8) in the presence of potassium carbonate to obtain benzylidene derivative of the formula (9), which is further restored in an atmosphere of hydrogen for the floor is warping with obtaining the compounds of formula (11)

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to derivatives of N-sulfanilimide formula I, where R1and R2denote hydrogen, halogen, C1-4alkyl, C1-4alkoxycarbonyl or phenyl which can be substituted one to three times, equal or different residues from the group comprising halogen, C1-4alkyl, trifluoromethyl; R3- halogen, cyano, trifluoromethyl; R4- 4-isoxazolyl, pyrazolyl, which may be substituted with halogen, C1-4the alkyl, amino group, cycloalkyl, as well as their acid-salt additive

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

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

- aminohydroxylation and carboxylic acid" target="_blank">

The invention relates to new compounds of General formula I, where Q, A, R1n, m are listed in the value formula

The invention relates to new derivatives of benzimidazole of formula 1, where R1represents hydrogen or hydrocarbon group with a short chain, R2- CH2HE, COOH, СООR34,4-dimethyl-2-oxazoline
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