Aromatic compounds and containing pharmaceutical compositions

 

(57) Abstract:

The present invention relates to compounds of formula I where a is optionally substituted phenyl, provided that the group-CH(R3)N(R2)B-R1and OD are in the 1,2-position relative to each other on ring carbon atoms and the ring carbon atom located in anthopology against-OD-linking group (and therefore in the 3-position relative to the-R3NR2-linking group is unsubstituted; represents pyridyl or pyridazinyl; R1located on the ring B in the 1,4-position relative to the-R3NR2-linking group and a is as defined in paragraph 1 of the claims; R2is1-6alkyl; R3represents hydrogen; D is hydrogen, optionally substituted 5-7-membered carbocyclic ring containing one double bond, or D represents a group of the formula (CH2)nCH(R4)C(R5)= C(R6R7where R4represents hydrogen, methyl or ethyl, R5represents hydrogen, methyl, bromine, chlorine, fluorine, R6represents hydrogen, C1-4alkyl, R7represents hydrogen, C1-4alkyl, bromine, chlorine, fluorine,gains are antagonists enhance pain action of prostaglandin E-type. In addition, the invention relates to pharmaceutical compositions for the treatment of pain on the basis of the above compounds and to a method of treating pain using the above compounds. A method of producing compounds of the formula I on the basis of the above compounds and their pharmaceutically acceptable salts or in vivo hydrolyzable esters and intermediate compounds formed in the process of obtaining them. 5 C. and 8 C.p. f-crystals, 6 PL.

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

Compounds of the present invention can be used to eliminate weak or moderate pain associated with joint diseases (such as rheumatoid arthritis and osteo gingivitis), pain associated with burns (including sunburn); for the treatment of bone disease (such as osteoporosis, malignant hypercalcemia, and Paget's disease); for the relief of pain associated with sports herbs and sprains; and to treat any other medical conditions, in which the prostaglandin E-type fully or partially play a pathophysiological role.

Non-steroidal anti-inflammatory drugs (NSPs) and opiates are the main class of drugs that eliminate the weak and moderate pain. 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.

We have discovered a class of compounds that are structurally different from NSPs and opiates, and which can be used to eliminate weak or moderate pain.

Compounds of the present invention may also have anti-inflammatory, antipyretic, and protivoponosnye properties, and are effective in the treatment of other conditions in which the prostaglandin E2(PGE)2fully or partially plays Pato is benzylamino]benzoic acid as an intermediate chemical compounds. In the work Mazumder and others (Biochemistry, 1995, 34, 15111) discloses the compound 4-[2,5-dihydroxy-benzylamino]benzoic acid as inhibitor of the enzyme protein kinase. In the work of H. Chen et al (J. Med. Chem. , 1993, 36, 4094) of the compound 5-[2-hydroxyethylamino]-2-hydroxybenzoic acid and 3-[2,5-dihydroxybenzylamine]benzoic acid are described as inhibitors F-receptorassociated tyrosinekinase activity. In the work of Chin-Yi Hsu and others (J. Biol.Chem., 1991, 266, 21105) discloses the compound 4-[2,5-dihydroxybenzylamine]benzoperoxide as inhibitor ECF-receptor-associated tyrosinekinase activity. In the work of M. Iskander and other (Eur. J. Med. Chem. , 1991, 26, 129) discloses the compound 3-[2-hydroxyethylamino] benzoic acid as an inhibitor of DAWA-aminotransferase. In the description of the patent in the UK 1393727 discloses the compound 4-[2,5-dihydroxybenzylamine] -2-hydroxybenzoic acid, intended for use in the chemical photographic processes. In the work of G. Walker and others (J. Med.Chem., 1966, 9, 624) discloses the compound 4-[2-hydroxyethylamino]-2-hydroxybenzoic acid, but in this work does not indicate any pharmacological activity of the compounds. In Chemical Abstracts, v. 102, abstract 1871, indicates that the compound 4-[2-hydroxyethylamino]benzoic acid is 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 OD are in the 1,2-position relative to one another on ring carbon atoms and the ring atom in anthopology against-OD-linking group (and therefore in the 3-position relative to the-CHR3R2- linking group) is unsubstituted;

B is optionally substituted: phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl, imidazolyl, pyrazinyl, pyridazinyl or pyrimidyl;

R1located on ring B in a 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carboxy1-3alkyl, tetrazolyl, tetrazolyl-C1-3alkyl, tetronic acid, hydroxyamino acid, sulfonic acid; or R1represents a group of formula-CONRaRa1where Rarepresents hydrogen or C1-6alkyl, a Ra1represents hydrogen, C1-6alkyl (optionally substituted with halogen, amino, C1-42-6alkenyl (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 heterocyclyl1-3alkyl, 5 - or 6-membered heteroaryl1-3alkyl, 5 - or 6-membered heterocyclyl, or 5 - or 6-membered heteroaryl; Raand Ra1taken together with the nitrogen atom of amide group with which they are associated (NRaRa1) form amino acid residue or ester, or R1represents a group of formula CONHSO2Rbwhere Rbis1-6alkyl (optionally substituted with halogen, hydroxy, nitro, cyano, amino, C1-4alkylamino, di-C1-4alkylamino, trifluoromethyl, C1-4alkoxy or1-4alkoxycarbonyl)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), 5 - or 6-membered heterocyclyl1-3alkyl, 5 - or 6-membered heteroaryl1-3alkylphenyl1-3alkyl, 5 - or 6-membered heterocyclyl, 5 - or 6-membered heteroaryl, or phenyl; where any heterocyclic or heteroaryl group, Ra1is optionally substituted with halogen, guercilena or heteroaryl group, Rbis optionally substituted with halogen, trifluoromethyl, nitro, hydroxy, amino, cyano, C1-6alkoxy, S(O)RS1-6the alkyl (R=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,1-4-alkoxycarbonyl,1-4alkanoyloxy,1-6alkanoyl, formyl-C1-4the alkyl, hydroxyimino1-6the alkyl, C1-4alkoxyimino1-6the alkyl or C1-6alkylcarboxylic; or R1represents a group of the formula-SO2N(RwithRC1where Rcrepresents hydrogen or C1-4alkyl, a RC1represents hydrogen or C1-4alkyl; or R1represents a group of formula (1A), (1B) or (1C):

< / BR>
< / BR>
where X represents CH or nitrogen, Y is oxygen or sulfur, Y' is oxygen or NRda Z is CH2, NRdor oxygen, provided that the ring is not more than one atom UP>2represents hydrogen, C1-6alkyl, optionally substituted hydroxy group, a cyano group, 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), panels1-3alkyl or pyridyl-C1-3alkyl;

R3represents hydrogen, methyl or ethyl;

D represents hydrogen, optionally substituted 5-7-membered carbocyclic ring containing one double bond, WITH1-3alkyl, substituted optionally substituted 5-7-membered carbocyclic ring containing one double bond, or D represents a group of the formula (CH2)nCH(R4)C(R5)=C(R6R7where

R4represents hydrogen, methyl or ethyl;

R5represents hydrogen, methyl, bromine, chlorine, fluorine or trifluoromethyl;

R6represents hydrogen, C1-4alkyl, bromine, chlorine, fluorine, or trifluoromethyl;

R7represents hydrogen, C1-4alkyl, bromine, chlorine, fluorine, or trifluoromethyl;

n=0 or 1;

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

and S-oxides of serosoderjaschei rings, where chemically possible; and their pharmaceutically acceptable with the slots, 4-[2,5-dihydroxybenzylamine] benzoic acid, 5-[2-hydroxyethylamino]-2-hydroxybenzoic acid, 3-[2,5-dihydroxybenzylamine]benzoic acid, 4-[2,5-dihydroxy-benzylamino] benzoperoxide, 3-[2-hydroxyethylamino] benzoic acid, 4-[2,5-dihydroxybenzylamine]-2-hydroxybenzoic acid, 4-[2-hydroxyethylamino] -2-hydroxybenzoic acid and 4-[2-hydroxyethylamino]benzoic 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 are 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 are selected from nitrogen atoms, oxygen and sulfur.

5-7-membered carbocyclic ring containing one double bond is a monocyclic ring that contains only one double bond.

The particular 5 - or 6-membered monocyclic heteroaryl rings are pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazole sidename heterocyclic ring systems are pyrrolidinyl, pyrrolidyl, imidazolidinyl, pyrazolidine, piperidyl, piperazinil and morpholinyl.

Specific 5-7-membered carbocyclic ring systems, containing one double bond are cyclohexen-3-yl, cyclopenten-2-yl or cyclopenten-3-yl.

Particular substituents for ring carbon atoms in a and heteroaryl or heterocyclic rings are halogen, trifluoromethyl, nitro, hydroxy, amino, C1-4-alkylamino, di-C1-4alkylamino, cyano, C1-6alkoxy, S(O)RS1-6the alkyl (R=0, 1 or 2), C1-6alkyl (optionally substituted by hydroxy, amino, halogen, nitro or cyano), S(O)F3(p=0, 1 or 2), carbarnoyl,1-4allylcarbamate, di-(C1-4alkyl)carbarnoyl,2-6alkenyl,2-6quinil,1-4alkoxycarbonyl,1-4alkanolamine,1-4alkanoyl(N-C1-4alkyl)amino, C1-4alkanesulfonyl, benzosulfimide, aminosulfonyl,1-4-alkylaminocarbonyl, di(C1-4alkyl)aminosulfonyl,1-4alkoxycarbonyl,1-4alkanoyloxy,1-6alkanoyl, formyl-C1-4alkyl, trifter1-3alkylsulfonyl, hydroxyimino1-6alkyl, C1-4alkoxyimino-C1-6alkyl and C1-6alkylborane, he is unsubstituted or substituted WITH1-4the alkyl group.

Particular substituents for ring carbon atoms in b are halogen, trifluoromethyl, nitro, hydroxy, C1-6alkoxy, C1-6alkyl, amino, C1-4alkylamino, di(C1-4alkyl)-amino, cyano, -S(O)p-C1-6the alkyl (R=0, 1 or 2), carbarnoyl,1-4allylcarbamate and di(C1-4alkyl) carbarnoyl.

In the case where the ring atom of nitrogen can be substituted without quaternization, he is unsubstituted or substituted WITH1-4alkyl group.

Particular substituents for 5-7-membered carbocyclic ring containing a double bond (D) are1-4alkyl, C2-4alkenyl,2-4quinil, halogen, hydroxy, amino, C1-4alkylamino: di(C1-4alkyl) amino, cyano, trifluoromethyl, oxo, C1-4alkanoyl, carboxy and carbarnoyl.

The term "alkyl" used in the present description, means alternates with a straight or branched chain, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl; in this case, the functional group on the alkyl chain may be present in any part of this circuit, for example, hydroxyimino-C1-6the alkyl reality of Raand Ra1taken together with the nitrogen atom to which they relate, are the remains ((-NHCH(R)COOH), a natural or synthetic amino acids. Examples of suitable amino acids are glycine, alanine, serine, threonine, phenylalanine, glutamic acid, tyrosine, lysine and dimethylglycine.

Suitable ring systems of formulae (1A), (1B) or (1C) are 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; 3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl; 3-thioxo-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-yl; 3-hydroxy-2-methylpyrazole-5-yl; 3-oxo-2,3-dihydroisoxazole-5-yl; 5-oxo-1,5-dihydroisoxazole-3-yl; and 5-oxo-2,3-dihydropyrazol-3-yl.

Examples1-6alkoxycarbonyl are methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl; examples carboxy1-3the alkyl are carboxymethyl, 2-carboxyethyl, 1-carboxyethyl and 3-carboxypropyl; examples1-6alkoxycarbonyl1-3the alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples tetrazolyl1-3the alkyl are tetrazolyl and 2-Tetra-salatil; examples1-4alkoxy are methoxy, this is a are atenil and PROPYNYL; examples1-4alkanoyl are formyl, acetyl, propionyl, butyryl; examples of halogen are fluorine, chlorine, bromine and iodine; examples1-4alkylamino are methylamino, ethylamino, propylamino, isopropylamino; examples of di(C1-4alkyl)amino are dimethylamino, diethylamino, and ethylmethylamino; examples S(O)RS1-4the alkyl are methylthio, methylsulfinyl, and methylsulphonyl; examples1-4allylcarbamate are methylcarbamoyl and ethylcarbitol; examples of di(C1-4alkyl)carbamoyl are dimethylcarbamoyl, diethylcarbamoyl and ethylmethylamino, examples WITH1-6of alkyl are methyl, ethyl, propyl and isopropyl; examples1-4alkoxycarbonyl are methoxycarbonylamino, ethoxycarbonylethyl; examples1-4-alkanolamine are acetamido, propionamido; examples 1-4alkanoyl(N-C1-4alkyl)amino are N-methylacetamide and N-methylpropionamide; examples1-4alkanesulfonyl are methanesulfonamido, acanalonia; examples1-4alkylaminocarbonyl are methylaminomethyl, and acylaminoalkyl; examples of di(C1-4alkyl)aminosulfonyl are dimethylaminoethanol, diethylaminosulfur the mi formals1-4the alkyl are formylmethyl and 2-formylated; examples hydroxyimino1-6the alkyl are gidroksilaminami and 2-(hydroxyimino)ethyl; examples1-4alkoxyimino1-6the alkyl are methoxyaminomethyl, toksienosti and 2-(methoxyimino)ethyl.

However, it should be noted that if the compounds of formula I have a chiral center, the compounds of the present invention can exist and can be isolated in optically active or racemic form. The present invention includes any optically active or racemic form the compounds of formula I, which has analgesic properties. Synthesis of optically active forms can be made using standard techniques of organic chemistry well known in the art, 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 in the form of geometrical isomers. The present invention includes any geometrical isomer of compounds of formula I, which has analgesic properties.

It should also be noted, che hydrates, 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, if a is optionally substituted: phenyl, naphthyl, thiadiazolyl, thienyl, pyridyl or pyrimidyl.

Preferably, if a is optionally substituted: pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl, or oxazolyl.

Most preferably, if a represents optionally substituted phenyl or thienyl.

More preferably, if a is optionally substituted: pyridyl, phenyl, thienyl, pyridazinyl or thiazolyl.

In particular, a represents optionally substituted phenyl.

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

Particularly preferably, if a is optionally substituted pyridazin-3,6-diyl or pyrid-2,5-diyl.

Particularly preferably, if is pyridazinyl.

If D is hydrogen, p is="ptx2">

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,1-6alkyl-S(O)p1-4alkanesulfonyl, benzosulfimide,1-6alkanoyl,1-4alkoxyimino1-4alkyl, hydroxyimino-C1-4alkyl.

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

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

Preferably, if n=0.

Preferably, if a is unsubstituted or substituted by one Deputy.

More preferably, if a is unsubstituted or substituted by bromine, methanesulfonyl, fluorine, bromine or chlorine.

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

Preferably, if the t is unsubstituted.

Preferably, if R1represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula-CONRaRa1- where Rarepresents hydrogen or C1-6alkyl, a Ra1is1-6alkyl, optionally zamestnani hydroxy group; 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, a Ra1is1-6alkyl, optionally substituted hydroxy, or pyridylmethyl; or R1represents a group of formula CONHSO2Rbwhere Rbis1-6alkyl (optionally substituted by hydroxy or fluorine), phenyl (optionally substituted acetamido), isoxazolyl (optionally substituted with stands), or 1,3,4-thiadiazolyl (optionally substituted acetamido).

Most preferably, if R1represents carboxy, tetrazole or a group of the formula-CONHRBa1, where the uly-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, and Ra1is1-6alkyl, optionally substituted hydroxy, C2-6alkenyl, 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, pyridyl1-3alkyl, or R1represents a group of formula CONHSO2Rbwhere Rbrepresents optionally substituted C1-6alkyl or phenyl.

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

More preferably, if R2represents hydrogen, methyl, ethyl or propyl. Even more preferably, if R2represents hydrogen or ethyl.

Most preferably, if R2represents ethyl.

Preferably, if R3represents hydrogen.

Preferably, if R4represents hydrogen or methyl.

Preferably, if R5represent the er.

Preferably, if R7represents hydrogen or methyl.

Preferably, if a 5-7-membered carbocyclic ring containing one double bond, optionally substituted stands.

More preferably, if a 5-7-membered carbocyclic ring containing one double bond, is unsubstituted.

Preferred D is a 5-6-membered carbocyclic ring containing one double bond (optionally substituted with stands); methyl substituted 5-6-membered carbocyclic ring containing one double bond (optionally substituted with stands); or a group of formula-CH2C(R5)=C(R6R7.

Most preferably, if D represents a group of the formula:

< / BR>
-CH2CH= CH2-CH= CHMe, -CH2CH=C(Me)2, -CH2C(Me)=CHMe, -CH2C(Me)=CHMe, -CH2C(Me)=CH2or-CH2C(Cl)=CH2.

In one aspect of the present invention, D is optionally substituted 5-7-membered carbocyclic ring containing one double bond; C1-3alkyl, substituted 5-7-membered carbocyclic ring; or a group of the formula -(CH2)nHR4C(R5)=C(R6R7.

In other acne formula (II):

< / BR>
where R1, R2and D are defined above, R8represents hydrogen or as defined above for the substituents of the ring carbon atoms in a and b represents phenyl, thienyl, pyridazinyl, pyridyl or thiazolyl.

It should be noted that since the compounds of formula (I) defined above may exist in optically active or racemic forms due to the fact that the compounds of formula (I) contain an asymmetric carbon atom, the definition of the active ingredient of the present invention includes any such optically active or racemic form which possesses analgesic properties. The synthesis of optically active forms can be made by standard methods of organic chemistry well known in the art, for example, by synthesis from optically active starting compounds, or by separation of the racemic form. Similarly, the analgesic properties of the compounds can be assessed using standard laboratory techniques, described below.

In vivo hydrolyzable complex ester compounds of formula (I) containing a carboxy or hydroxy group is, for example, pharmaceutically acceptable ester, colorimetrically acceptable ester, formed from acid (C1-6)alcohol, such as methanol, ethanol, ethylene glycol, propanol or butanol; or a 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 chlorine), (C1-4)alkyl (such as methyl), or (C1-4)alkoxy group (such as ethoxy-group). This term also includes-aryloxyalkyl esters, and the original compounds, 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 with the formation of the original hydroxy group. Premieremrysowa in vivo - hydrolyzable ester with obtaining a hydroxy group, select from alkanoyl, benzoyl, phenylacetyl, substituted benzoyl, substituted phenylacetyl, alkoxycarbonyl (for esters alkalicarbonate acid), dialkylamino and N-(dialkylaminoalkyl)-N-allylcarbamate (for carbamates), dialkylaminoalkyl and carboxyethyl.

Suitable in vivo hydrolyzable by AMICOM the compounds of formula I containing a carboxy group is, for example, N-(C1-6)alkyl or N, N-di-(C1-6)alkylamide, such as N-methyl, N-ethyl-N-propyl-, N,N-di-methyl-, N-ethyl-N-methyl - or N,N-diethylamide.

A suitable pharmaceutically acceptable salt of the compound (I) is, for example, an acid additive salt, compounds of formula I which is sufficiently basic, for example, an acid additive salt formed with an inorganic or organic acid, such as hydrochloric, Hydrobromic, sulfuric, triperoxonane, citric or maleic acid; or, for example, the salt of the compounds of formula (I) which is sufficiently acidic, for example, salt of alkali or alkaline earth metal such as calcium, magnesium or ammonium salt or a salt formed organicheskimim.

In another aspect, the present Serebryanye relates to a method for obtaining compounds of formula (I) or their pharmaceutically acceptable salts, their in vivo hydrolyzable amides or esters; moreover, this method provides for the release of the compounds of formula (III):

< / BR>
where R9is the same as R1or protected R1; R10is the same as R2or protected R2; a R3, R4, n, a, b and D are the same as defined above, with any optional substituents are optionally substituted and contains at least one protective group;

and also, if necessary:

i) obtaining a pharmaceutically acceptable salt;

ii) obtaining in vivo hydrolyzable ether complex or

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 gave near.

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 group (particularly, methyl), (C2-4)Alchemilla group (in particular, allyl), (C1-4)alkoxymethyl group (in particular, methoxymethyl), or tetrahydropyranyl group (in particular, tetrahydropyran-2-yl). Conditions unprotect for 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, sulfuric, phosphoric, or triperoxonane acid; or a fluoride of an alkali metal or ammonium, such as the Jena, for example, by processing (C1-4)alkylsulfides alkali metal, such as titoxd sodium, or, for example, by treatment with 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, by treatment with a suitable acid, such as hydrochloric acid or triperoxonane acid.

Alternatively, a suitable protecting group for a hydroxy group is, for example, acyl group, for example, (C1-4)alcoolica group (in particular, acetyl), or arolina group (in particular, benzoyl). Conditions unprotect for the above-mentioned protective groups can vary depending on the choice of protecting group. So, for example, acyl group, such as alcoolica or arolina group may be removed, for example, by hydrolysis using a base such as alkali metal hydroxide, e.g. lithium hydroxide or sodium.

A suitable protecting group for amino-, imino-, or alkylamino group is, for example, acyl group, such as (Cti, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group), armletaccessory group (in particular, benzyloxycarbonyl group), or arolina group (in particular, benzoline group). Conditions unprotect for 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 a suitable base, such as hydroxide of alkali metal such as lithium hydroxide or sodium. Alternatively, the 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 a carboxy group is, for example, tarifitsiruyutsya group, for example, (C1-4)alkyl group (particularly, a methyl or ethyl group), coloradodog metal, for example, 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 by a method comprising:

a) if B is activated heterocycle, a R10represents hydrogen or C1-6alkyl, the reaction of compounds of formula (IV) with the compound of the formula (V)

< / BR>
X-B-R9(V)

where a, b, R3, R4, R7, R9and n are defined above and X is a leaving group;

b) the reaction of compounds of formula (VI) with the compound of the formula (VII):

R10HN-B-R7, (VI)

< / BR>
C) transformation of X2in R9in the compound of formula (VIII):

< / BR>
d) if R10is not hydrogen, the reaction of compounds of formula R10X3with the compound of the formula (IX):

< / BR>
(e) the reaction of compounds of formula (X) with the compound of the formula (XI)

< / BR>
X4NH-B-R9, (XI)

f) the reaction of compounds of formula (XII) with the compound of the formula (XIII):

< / BR>
X6NH-B-R7, (XIII)

(g) the implementation of9, R10A , b, D and n are defined above;

X and X1are leaving groups, X2is a precursor group, R9; X3is a leaving group; X4is remove the trigger group, X5is a leaving group, X6is an activating group; and X7represents a halogen or an activated hydroxy group; and then, if necessary:

i) removing any protective groups;

ii) obtaining pharmaceutically acceptable salts;

iii) obtaining in vivo hydrolyzable of ester or amide;

iv) the transformation of the optional substituent other optional Deputy.

Specific leaving groups are halogen, for example chlorine, bromine, iodine, sulfonates, for example, tosylate, p-brabanthallen, p-nitrobenzenesulfonate, methanesulfonate and triptorelin, or esters of phosphoric acid, such as ester diarylphosphino acid.

The compound of formula (IV) and the compound of formula (V) can be subjected to reaction under standard conditions, for example, in an aprotic solvent such as dimethylformamide, in the presence of a weak base, at a temperature ranging from room temperature to 180

Compounds of formula (VI) and (VII) may be subjected to reaction in an aprotic solvent such as DMF, in the presence of a base such as potassium carbonate, or 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, R9is a group which can be converted to R9.

Specific X2are cyano, carbarnoyl, alkoxycarbonyl, carboxy and activated carboxy groups, such as anhydrides, and activated esters.

Cyano group can be converted into tetrazole ring by reaction with, for example, ammonium azide or tin azide 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; C. 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 a carboxy group by acid or basic hydrolysis. So, for example, alkaline hydrolysis can be carried out in an organic solvent such as methanol is rockside sodium or potassium hydroxide.

Acid hydrolysis can be carried out, for example, in pure formic acid or pure triperoxonane acid, optionally, in inert solvent such as dichloromethane.

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

Compounds of formulas (IX) and R10X3can be subjected to reaction in an aprotic solvent such as DMF, in the presence of a base such as sodium carbonate or sodium hydride. Suitable groups X3are halogen, tosylate, mesilate and triptorelin, and in particular, halogen, such as iodine.

The reaction between the compounds of formulae (X) and (XI) is usually carried out under mild conditions, known as the reaction Mitsunobu, for example, in the presence of di(C1-4alkyl)isocarboxazide and triphenylphosphine, or 11, 11(Ansol, tetrahydrofuran or diethylether, and in particular toluene. Examples remove the activating groups are tert-butoxycarbonyl and TRIFLUOROACETYL.

The reaction between the compounds of formulas (XII) and (XIII) usually occurs in the presence of a strong base such as sodium hydride, diisopropylamide lithium or LiN(Si3)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 for X6are tert-butoxycarbonyl, halogen and TRIFLUOROACETYL.

Suitable leaving groups for X7are toilet, mesilate, triptorelin and halogen, for example chlorine or bromine. The reaction between the compounds of formulae (XIV) and (XV) can be carried out in an inert organic solvent such as acetone or DMF, at a temperature ranging from room temperature to 60oSince, in the presence of a weak base. For example, if X7is bromine, the reaction between the compound (XIV) and compound (XV) is carried out in DMF at room temperature, in the presence of a base such as potassium carbonate. Alter the I in situ under the reaction conditions Mitsunobu (O. Synthesis, 1981, 1).

The compounds of formula (XIV) where R9is the same as R1, a R10is the same as R2themselves possess analgesic properties.

The compounds of formula (VIII) can be obtained by methods a), b), d), e), f) or g) from the corresponding starting compound in which R9replaced by X2.

The compounds of formula (IX) can be obtained by any of the methods a), b), C), e), p) or g) from the appropriate starting compounds, in which R10represents hydrogen.

The compounds of formula (XI) can be easily obtained from compounds of formula (VI).

The compounds of formula (V), (VI), (XI), (XIII) and (XV) are mostly known, or they can be obtained by the methods used in the Examples or by methods that tend to be used for related compounds. Some compounds of formula (V), where X represents chlorine or bromine, can be obtained by conversion of the oxo-group in the ring system in the group, chlorine or bromine, by reaction oxo-ring system with gloriouse agent such as sulphonylchloride, trichloride phosphorus, pentachloride phosphorus or P(O)C13or brainwashin agent such as tribromide phosphorus elochnye connection and even a secure connection, using first the synthesis of the ring. For help, see the quick guide "Chemistry of Heterocyclic Compounds" by E. C. Taylor & A. Weissberger (published by John Wiley & Sons);Comprehensive Heterocyclic Chemistry", A. R. Katritsky & C. W. Ress (published by Pergamon Press).

Compounds of formula (IV), (VII), (VIII), (IX), (X) and (XII) can be obtained by reaction of compounds of formula (XV) with an appropriate hydroxy-precursor compounds of the formula (IV), (VII), (VIII), (IX), (X), (XII) or (XIV) using the reaction conditions described in method.

(g) Compounds of formula (XV) can be obtained from the appropriate starting materials, form a-CH(R3) N(R10)-B-R9the group, using one of the methods (a)-(f).

The compound of formula (XV) in which R10represents hydrogen, can be obtained by recovering the compounds of formula (XVI):

< / BR>
where R3-R7, R9and n are defined above.

The compounds of formula (XVI) can be recovered using such agents as borohydride sodium or cyanoborohydride sodium. The compounds of formula (XVI) can be obtained by reaction of compounds of formula (VI) with the compound of the formula (XVII):

< / BR>
where R3defined above, and R represents a hydroxy-protective group, followed the Lena in standard conditions, usually used for the formation of imine (Schiff's base), which can be restored in situ. So, for example, education and restoration of the imine in situ can be carried out in an inert solvent, such as toluene or tetrahydrofuran, in the presence of a reducing agent, such as cyanoborohydride sodium (NaCNBH3in acidic conditions (Synthesis 135, 1975; Org. Prep.Proceed.Int. 11, 201, 1979).

Optional substituents can be converted into other optional substituents. For example, allylthiourea can be oxidized with the formation of alkylsulfonyl or alkylsulfonyl group, nitro group can be restored with formation of amino groups, hydroxy group may be alkylated with the formation of the methoxy group, or a group of bromine can be turned into alkylthio group.

If necessary, the compounds of formula (I) and (III) in the intermediate compounds formed during the formation of compounds of formulas (I) and (III) may be introduced for different substituents using standard methods known in the art. So, for example, acyl group or alkyl group may be introduced into an activated benzene ring through reaction Friedel -; formyl of grubego simple ester; the nitro group can be introduced by means of nitration with concentrated nitric acid and concentrated sulfuric acid, and the group of bromine can be introduced by the synthesized using bromine or tribromide Tetra(n-butyl)ammonium.

It should be noted that in order to prevent side 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 can be implemented in the release.

As mentioned above, the compounds of formula (I) are antagonists enhance pain action 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 espido intestine immersed in oxygenated Krebs solution, containing indomethacin (4 mg/ml) and atropine (1 μm), and incubated at 37oC; then the terminal ileum is exposed to a load of 1 g, and build control curve dose-response relationships for GE2-induced contraction of the ileum; and 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 pA2for test compounds;

b) in vivo analysis on mice carried out for the assessment of inhibitory properties of the tested compounds against the response of abdominal contractions induced by intraperitoneal injection of a toxic factor, such as acetic acid or phenylbenzophenone (denoted hereinafter PBQ); however, this analysis was 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, however, in General, the activity of these compounds can be demonstrated in one or two of Visayas> in 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 minimum inhibitory dose any appreciable toxicity or other adverse effects were observed.

The prostaglandin receptors, and in particular, the receptors for G2were tentatively characterized by Kennedy and others (Advances in Prostaglandin, Thromboxane and Leukotriene Research, 1983, 11, 327). Known antagonist of prostaglandin PGE2C-19220 blocks the action of G2in some tissues such as the ileum of Guinea pigs or peritoneal dogs, however, in other tissues, for example, in 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 distinguishing feature, the present invention relates to pharmaceutical compositions containing a compound of the formula (I) or in vivo hydrolyzable ester or amide, or his FA">

This composition can be obtained in a form suitable for oral administration, such as tablets, capsules, aqueous or oily solution, suspension or emulsion; for topical use, for example, in the form of a cream, ointment, gel, aerosol, oil or aqueous solution or suspension; for intranasal, for example, in the form of the drug for inhalation through the nose, mist or drop in the nose; 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., compounds of formula (I) or its pharmaceutically acceptable salt), which combine with one or more fillers for poluchaemogo treatment, and method of treatment. So, for example, a composition intended for oral administration to man, mainly contains from 0.5 mg to 2 g of active compound, mixed with the proper amount of excipients which may vary from about 5 to about 98 wt.% on the total weight of the composition.

In accordance with another of its distinguishing feature, 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 one of its hallmark, 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 hydrolyzable 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, accompanies inflammatory diseases such as rheumatoid arthritis and osteoarthritis. Daily example, from 0.1 mg to 75 mg per kg of body weight, and may be introduced, if necessary, in the form of fractional doses. For parenteral use, mainly lower doses. For example, for intravenous administration may be used dose component, for example, from 0.05 to 30 mg per kg of body weight. Similarly, for the introduction of compounds by inhalation may be used dose component, for example, from 0.05 mg to 25 mg per kg of body weight.

Although the compounds of formula (I), essentially represent a therapeutic agent intended for the introduction of warm-blooded animals (including humans), however, 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, the 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), ingin, sulindac, tolmetin and piroxicam. Co-administration of compounds of formula I with NSPs makes it possible to reduce the number NSPs required to produce a therapeutic effect. At the same time, reduces the likelihood of side effects caused NSPs, for example, gastro-intestinal disorders. Thus, in accordance with another of its distinguishing characteristic is provided a pharmaceutical composition comprising a 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, inhibiting the action of cyclooxygenase and pharmaceutically acceptable diluent or carrier.

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

The compounds of formula (I) can also be used to treat diseases such as rheumatoid arthritis, using them in combination with anti-arthritis means takimag to be used in combination with steroids.

Compounds of the present invention can be also introduced in degenerative diseases, for example, in osteoarthritis, in combination with chondroprotective, antidegradation and/or reparative agents, such as diacerhein, hyaluronic acid, such as hualan (Hyalan), rumalon (Rumalon), arteparon (Arteparon) and glucosamine salts, such as antral (Antril).

Compositions of the present invention may also 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 agonist 2-adrenergic receptors agonist GABAB-receptor blocker calcium-channel antagonist SCQB-receptor antagonist neirokinina, or antagonist and a modulator of the action of the glutamate NMDA receptor. These compositions can be used to eliminate blastoidea of the invention can also be entered in diseases of the bones, 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 by filtration;

(ii) the outputs are given only for illustration and should not be construed as maximum achievable;

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

(iv) the melting temperature is given without amendment, and were identified with the help of automatic special device Mettler SP62 or device using an oil bath; moreover, 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) in this case, we used the following abbreviations:

DMF - N,N-dimethylformamide - liquid chromatography medium pressure.

EXAMPLE 1

2-[N-(5-Bromo-2-(2-chloralose)benzyl)-N-ethylamino]-5-pyridylcarbonyl acid

A solution of methyl 2-[N-(5-bromo-2-(2-chloralose)-benzyl-N-ethylamino] -5-pyridylcarboxylic (comparative example 1) (0.8 g, 2.0 mmol) in methanol (3 ml) and THF (3 ml) was heated with sodium hydroxide (2 N. 5 ml). The reaction mixture was stirred for 18 hours at 40oC. the Solution is evaporated under reduced pressure, and added water. The suspension was acidified with acetic acid and was stirred for 30 minutes. The precipitate was filtered and washed with water, and then dried by air, resulting in the obtained target compound as a white solid (0.7 g).

So pl. 207-209oC.

MS (F+): 425 (M+H)+.

NMR (200 MHz, DMSO-d6) : of 1.13 (t, 3H), 3,61 (kV, 2H), of 4.77 (s, 2H), 4,82 (s, 2H), of 5.55 (d, 1H), USD 5.76 (d, 2H), of 6.65 (d, 1H), 7,15 (m, 2H), 7,41 (DD, 1H), to 8.62 (d, 1H), 12,4 (Shir. s, 1H).

EXAMPLE 2

Compounds shown in table 1, were obtained by the method similar to that described in Example 1.

Notes

a) Compound obtained from the compound of Comparative Example 2.

MS (FAB+): 405 (M+N)+.

Elemental analysis:t, J=7 Hz, 3H), of 1.44 (d, J=6 Hz, 3H), 3,62 (kV, 2H), 4.75 in (m, 3H), 5,22 (m, 2H), 5,95 (m, 1H), 6.42 per (d, J=9 Hz, 1H), 6.75 in (DD, J=3.8 Hz, 1H), 7,13 (m, 1H), 7,26 (m, 1H), 8.0 a (m, 1H), 8,87 (d, J=3 Hz, 1H).

b) Obtained from the compound of Comparative Example 2:

So pl. 167-169oC. MS (FAB+): 405 (M+N)+.

Elemental analysis:

Calculated (%): From 56.3; H 5,22; N 6,91.

Found (%): 56,1; N 5,3; N 6,7.

NMR (mixture of the E+Z) : 1,12 (t, J=7 Hz, 3H), 1,72 (DD, J=6,1 Hz, 3H), 3,6 (kV, J=7 Hz, 2H), 4,55 (d, J=6 Hz, 1,6 N), and 4.68 (m, 2.4 M), of 5.75 (m, 2H), 6,63 (d, J=8 Hz, 1H), 7,0 (m, 2H), 7,38 (DD, J=3, 8 Hz, 1H), 7,86 (DD, J=3.8 Hz, 1H), to 8.62 (d, J=3 Hz, 1H), 12,38 (s, 1H).

(C) Obtained from the compound of Comparative example 2:

So pl. 189-195oC.

MS (FAB+): 405 (M+N)+.

Elemental analysis:

Calculated (%): From 56.3; H 5,22; N 6,91.

Found (%): From 56.3; H 5,3; N 6,6.

NMR (200 MHz, DMSO-d6) : to 1.14 (t, J=7 Hz, 3H), 1.8 m (s, 3H), 3,63 (kV, J=7 Hz, 2H), of 4.45 (s, 2H), 4,98 (Shir. s, 1H), 5,1 (Shir. s, 1H), only 6.64 (d, J=9 Hz, 1H), 6,9 (d, J=9 Hz, 1H), 7,03 (d, J=3 Hz, 1H), 7,38 (DD, J=3, 8 Hz, 1H), 7,92 [DD, J=8, 3 Hz, 1H), 8,63 (d, J=3 Hz, 1H), 12,35 (Shir. S., 1H).

d) Obtained from the compound of Comparative example 2:

MS (F+): 433 (M+N)+.

NMR (200 MHz, DMSO-d6) : a 1.11 (t, J=7 Hz, 3H), of 1.61 (s, 3H), by 1.68 (s, 3H), 2,41 (kV, J=7 Hz, 2H) and 3.59 (q, J=7 Hz, 2H), 4.00 points (t, J=7 Hz, 2H), 4,7 (s, 2H), >e) Obtained from the compound of Comparative example 2:

MS (F+): 433 (M+Na)+.

NMR (200 MHz, DMSO-d6) : of 1.09 (t, J=7 Hz, 3H), 1,72 (s, 3H), of 1.75 (s, 3H), 3,55 (m, 2H), br4.61 (m, 4H), of 5.55 (m, 1H), 6,4 (d, J=9 Hz, 1H), 7,00 (m, 2H), 7,35 (DD, J=3,9 Hz, 1H), 7,87 (DD, J=3, 9 Hz, 1H), 8,5 (d, J=3 Hz, 1H).

f) Obtained from Comparative example 2:

MS (FAB+): 405 (M+N)+.

NMR (200 MHz, DMSO-d6) : a 1.11 (t, J=7 Hz, 3H) and 3.59 (q, J=7 Hz, 2H), 4.09 to (t, J=6 Hz, 2H), 4,71 (s, 2H), 5,13 (m, 2H), 5,90 (m, 1H), 6,63 (d, J=9 Hz, 1H), 7,03 (m, 2H), 7,37 (DD, J=9 Hz, 2 Hz, 1H), to $ 7.91 (DD, J=2, 9 Hz, 1H), 8,61 (d, J=2 Hz, 1H), 12,37 (W, s, 1H). (2N does not manifest solvent).

(g) Obtained from the compound of Comparative example 2:

So pl. 167oC. MS: 431 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 1.03 (t, J=7 Hz, 3H), of 1.65 (m, 4H) and 1.83 (m, 2H), 3,51 (kV, J=7 Hz, 2H), 4,6 (s, 2H), a 4.86 (m, 1H), USD 5.76 (m, 1H), 5,9 (m, 1H), is 6.54 (d, J=9 Hz, 1H), 7,00 (m, 2H), 7,29 (DD, J=2.5 and 9 Hz, 1H), 7,83 (DD, J=2.3 Hz, 9 Hz, 1H), charged 8.52 (d, 2H).

h) Obtained from the compound of Comparative example 4:

So pl. 94-100oC. MS: 445 (M+N)+.

Elemental analysis:

Calculated (%): 59,3; H 5,7; N 6,3.

Found (%): From 58.8; H 5,7; N 6,0.

NMR (200 MHz, DMSO-d6) : 1,1 (t, J=7 Hz, 3H), 1,7 (m, 6N), of 1.95 (m, 13H), to 3.58 (q, J=7 Hz, 2H), of 4.66 (s, 2H), 4,9 (width, s, 1H), 5.56mm (Shir.s, 1H), 6,62 (d, J=9 Hz, 1H of Example 4:

MS: 485 (M+N)+.

NMR (400 MHz, DMSO-d6) : 1,10 (t, J=7 Hz, 3H), of 1.40 (m, 1H), 1,74 (m, 6N), and 1.9 (m, 1H), 2,07 (m, 1H), measuring 2.20 (m, 1H), 2,35 (m, 1H), 3,62 (kV, J=7 Hz, 2H), 4,77 (m, 5H), of 5.05 (m, 1H), to 5.57 (m, 1H), 6,62 (d, J=9 Hz, 1H), to 7.15 (m, 2H), 7,44 (m, 1H), 7,94 (m, 1H), 8,65 (m, 1H), 12,35 (Shir. s, 1H).

j) Obtained from the compound of Comparative example 4:

So pl. 94-98oC. MS (Χ+): 473 (M+N)-.

Elemental analysis:

Calculated (%): 60,9; N 6,17; N Of 5.92.

Found (%): Of 60.8; H 6,2; N 6,1.

NMR (250 MHz, DMSO-d6) : of 0.95 (s, 3H), 1,0 (s, 3H), 1,1 (t, J=7 Hz, 3H), of 1.45 (m, 1H), 1.69 in (s, 3H), 1.8 m (m, 3H), 3,57 (kV, J=7 Hz, 2H), and 4.68 (s, 2H), 4,93 (Shir. s, 1H), 5,5 (Shir. s, 1H), 6,6 (d, J=9 Hz, 1H),? 7.04 baby mortality (m, 2H), 7,38 (DD, J=2, 9 Hz, 1H), 7,9 (DD, J=2, 9 Hz, 1H), and 8.6 (d, J=2 Hz, 1H).

k) Obtained from the compound of Comparative example 2:

MS (Χ+): 459 (M+H)+.

Elemental analysis:

Calculated (%): 47,0; N And 3.72; N 6,09.

Found (%): From 46.7; H 3,5; N 5,9.

NMR (200 MHz, DMSO-d6) : of 1.13 (t, 3H), 3,6 (kV, 2H), and 4.75 (s, 2H), 5,0 (s, 2H), 6,62 (d, 1H), 7,03 (C.), 7,05 (d, J=10 Hz) and was 7.08 (d, J=2,6 Hz) (combined with 3H), 7,42 (DD, J=2,6, 10 Hz, 1H), to $ 7.91 (DD, J=2,6, 10 Hz, 1H), at 8.60 (d, J=2.5 Hz), 12,35 (Shir. s, 1H).

e) Obtained from the compound of Comparative example 2:

MS (Χ+): 459 (M+N)+.

Elemental analysis (%):

Calculated: 47,0; Is), of 4.75 (s, 2H), 4,9 (s, 1,7 N), 6,63 (d, J=10 Hz), 7,07 (m, 2H), 7,25 (C 0,85 N), and 7.4 (DD, J=2,6, 10 Hz, 1H), to $ 7.91 (DD, J=2,6, 10 Hz, 1H), at 8.60 (d, J= 2.6 Hz), 12,35 (Shir. s, 1H).

m) Obtained from the compound of Comparative Example 6.

n) Obtained from the compound of Comparative example 3.

o) Obtained from the compound of Comparative example 4.

So pl. 122,2-to 124.4oC.

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

NMR (200 MHz, DMSO-d6, HOAc-d4) : of 1.13 (t, J=7 Hz, 3H), at 1.73 (s, 3H), 3,63 (sq , J=7 Hz, 2H), and 4.5 (s, 2H), to 4.81 (s, 2H), is 4.93 (s, 1H), to 5.03 (s, 1H), 6,93 (d, J=9 Hz, 1H), 7,03 (d, J=9 Hz, 1H), was 7.08 (d, J=3 Hz, 1H), 7,33 (DD, J=3, 9 Hz, 1H), 7,8 (d, J=9 Hz, 1H).

p) Obtained from the compound of Comparative example 15:

MS (ESP+): 392/394 (M+N)+.

NMR (250 MHz, DMSO-d6) : to 1.15 (t, 3H), 3,17 (kV, 2H), with 4.64 (m, 2H), a 4.83 (s, 2H), 5.25 in (m, 1H), 5,42 (m, 1H), equal to 6.05 (m, 1H), 7,0 (d, 1H), and 7.1 (m, 2H), 7,40 (DD, 1H), 7,83 (d, 1H).

(g) Obtained from the compound of Comparative example 28:

NMR (200 MHz, DMSO-d6) : to 1.15 (t, 3H), and 1.7 (d, 3H), 3,68 (kV, 2H), of 4.44 (d, 2H), of 4.66 (d, 2H), to 4.81 (s, 2H), 5,55-of 5.75 (m, 1H), 5,74-5,95 (m, 1H), 7,00 (d, 1H),? 7.04 baby mortality-to 7.15 (m, 2H), and 7.4 (DD, 1H), 7,82 (d, 1H).

EXAMPLE 3

6-[N-(5-Bromo-2-(2-chlorpro-2-EN-1-yloxy)benzyl] -N-ethyl-amino] pyridazin-3-carboxylic acid

n-Butyl-6-[N-(5-bromo-2-(2-chlorpro-2-EN-1-yloxy)-benzyl)-N-ethylamino] pyrido what militray 1 N. an aqueous solution of sodium hydroxide. The resulting solution was left for 1.5 hours at ambient temperature and then evaporated to small volume and the precipitate was dissolved in water and acidified with acetic acid to obtain a resinous precipitate. After extraction with methylene chloride, the organic extracts were dried and evaporated with the formation of gums. This substance is triturated with ether and received solid, which was filtered and dried under vacuum, resulting in the obtained target compound in the form of white solid product (0.16 g, 75%). MS: (FAB): 426, 428 (M+N)+.

NMR (200 MHz, DMSO-d6) : to 1.15 (t, J=6.3 Hz, 3H), 3,7 (sq, J=6.3 Hz, 2H), 4,82 (s, 2H), 4,88 (s, 2H), of 5.55 (d, J=1.25 Hz, 1H), of 5.75 (d, J=1.25 Hz, 1H), 7,07 (d, J=9.6 Hz, 1H), 7,12 (d, J=8,3 Hz, 1H), 7,15 (d, J=2.1 Hz, 1H), the 7.43 (DD, J=2,1, 8,3 Hz, 1H), a 7.85 (d, J=9.6 Hz, 1H).

EXAMPLE 4

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

2-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino] pyridine-5-carboxylic acid (Example 7) (1.8 g, 5.1 mmol) in tetrahydrofuran (40 ml) was treated with carbonyl diimidazol (1.8 g, 11 mmol) and was heated under reflux for 4 hours. The mixture was cooled and added to 0,88 M aqueous solution of ammonia (60 ml) and then was stirred for 1 cha is about was diluted with ice/water, was filtered, washed with cold water, and drained the air, resulting in a received target compound as a white solid (1,93 g, 100%). MS (Χ+): 350, 352 (M+N)+.

EXAMPLE 5

5-[2-(N-(5-Bromo-2-(2-chlorpro-2-EN-1-yloxy)benzyl)-N-ethylamino)-5-pyridyl]tetrazol

2-[N-(5-Bromo-2-(2-chlorpro-2-EN-1-yloxy)benzyl)-N-ethylamino)-5-lepirudin (comparative example 8)(0.40 g, 0.96 mmol) in dried molecular sieves N organic (10 ml) was treated with sodium azide (189 mg, 12.9 mmol), and then, the chloride of triethylamine (208 mg, 1,49 mmol) and the mixture was heated at a temperature of 120oC (oil bath) for 8 hours. The red solution was placed in ice water (12 ml), acidified with concentrated hydrochloric acid to pH 1-2, two times were extracted with ethyl acetate, then the combined extracts washed twice with water, dried with magnesium sulfate, and evaporated, resulting in received light red gum (0.45 g). This gum, pre-adsorbed on the layer of silicon dioxide (1.2 g) was purified using GHSD, resulting in the obtained target compound as a colourless gum (135 mg, 31%), which was then utverjdali. MS (ESP+): 449, 451 (M+N)-.

NMR (200 MHz, DMSO-d6) : of 1.16 (t,d, J=2.7 Hz, 1H), 7,42 (DD, J= 2.7, and a 9.3 Hz, 1H), 8,02 (DD, J=2, and 9.3 Hz, 1H), 8,7 (d, J=2 Hz, 1H).

EXAMPLE 6

5-[2-(N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino)-5-pyridyl]tetrazol

2-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] -5-cyanopyridine (comparative example 10) (0.45 g, of 1.16 mmol) in N-organic (12 ml) was treated with sodium azide (228 mg, 3.5 mmol), and then, the chloride of triethylamine (251 mg, 1.8 mmol) and the resulting mixture was heated under stirring at 120oC (oil bath) for 7 hours in an atmosphere of argon balloon. The obtained red solution was poured into ice water (30 ml), acidified, and was twice extracted with ethyl acetate (50 ml). The combined organic extracts washed twice with water, dried with magnesium sulfate, and evaporated resulting received a brown gum. This gum was purified by IHSD and received the target compound in the form of whitish foam (150 mg, 30%).

MS (ESP+): 429, 431 (M+H).

NMR (200 MHz, DMSO-d6) : of 1.27 (t, J=6.25 Hz, 3H), and 1.9 (s, 3H), of 3.73 (q, J=6.25 Hz, 2H), with 4.64 (s, 2H), to 4.87 (s, 2H), 5,08 (s, 1H), 5,2 (s, 1H), 6,91 [d, J= 8,75, 1H), 7,10 (d, J=8,3 Hz, 1H), 7,17 (s, J=2 Hz, 1H), of 7.48 (DD, J=2, 8,3 Hz, 1H), 8,16 (DD, J=2, is 8.75 Hz, 1H), and 8.8 (d, J=2 Hz, 1H).

EXAMPLE 7

2-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-kotelny example 7) (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 the mixture was heated to 40oWith in 24 hours. The solvents are evaporated under reduced pressure and the resulting residue was treated with 1 N. acetic acid (2.7 ml), after which the precipitate was filtered, washed with water, and dried by air, resulting in the obtained target compound (0.17 g, 92%).

MS (FAB+): 351 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 1.12 (t, J=7 Hz, 3H), 3,6 (kV, J=7 Hz, 2H), with 4.64 (s, 2H), 6,6 (d, J=9 Hz, 1H), 6,83 (d, J=9 Hz, 1H), 7,06 (d, J=2 Hz, 1H), 7.23 percent (DD, J= 2, 9 Hz, 1H), 7,92 (DD, J=2,9 Hz, 1H), 8,59 (d, J=2 Hz, 1H).

EXAMPLE 8

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

A solution of butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazin-3-carboxylate (comparative example 11) (0.36 g, 1.0 mmol) in THF (4 ml) and methanol (4 ml) was treated with an aqueous solution of sodium hydroxide (1 n, 4 ml), and kept for one and a half hours at ambient 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 then dried by air, and the received target-soo-d6) : to 1.15 (t, J=6,67 Hz, 3H), 3,68 (kV, J=6,67 Hz, 2H), and 4.75 (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), 7,25 (DD, J=10,00, 2,33 Hz, 1H), 7,83 (d, J=10.00 Hz, 1H).

Example 9

5-[6-(N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino)pyridazinyl]tetrazol

6-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] -3-cyanopyridine (comparative example 13) (0.52 g, of 1.34 mmol) in N-organic (13 ml) was treated with sodium azide (403 mg, 6.1 mmol), and then, the chloride of triethylamine (537 mg, 3.9 mmol), after which the mixture was stirred in an argon atmosphere for 7 hours at 120oC. This mixture was poured into water and acidified to about pH 2. Then, the mixture was twice extracted with ethyl acetate, and the combined organic extracts washed twice with water, dried, and evaporated with the formation of solids. This solid was purified using GHSD, and triturated with a mixture (1:1) diethyl ether/ethyl acetate, resulting in the obtained target compound in the form of a whitish solid (275 mg, 48%).

MS (ESP+): 430, 432 (M+N)+.

NMR (DMSO-d6) : of 1.17 (t, J=8,3 Hz, 3H), 1.77 in (s, 3H), and 3.72 (q, J=8,3 Hz, 2H), 4,55 (s, 2H), around 4.85 (s, 2H), equal to 4.97 (s, 1H), 5,08 (s, 1H), 7,00 (d, J= 10.4 Hz, 1H), 7,22 (d, J= 2.1 Hz, 1H), 7,25 (d, J=10.4 Hz, 1H), 7,40 (DD, J= 10,4, 2.1 Hz, 1H), and 8.0 (d, J=10 the l

The target compound was obtained from the compound of Comparative example 14 in a manner analogous to the one described in Example 9, except that the purification was performed using GHSD, and received a gum, which was utverjdali by evaporation of dichloromethane, which was then triturated, filtered and washed with diethyl ether and ethyl acetate to obtain white solids (yield 43%).

MS (ESP+): 456, 458 (M+N)+.

NMR (DMSO-d6) : to 1.15 (t, J=6,7 Hz, 3H), 1,50-2,08 (Hm, 6N), 3,7 (kV, J= 6,7 Hz, 2H), 4,80 (s, 2H), is 4.93 (m, 1H), 5,70-of 6.02 (m, 2H), 7,10 (d, J=10 Hz, 1H), 7,27 (DD, J=3.3V, 10.00 Hz, 2H), 7,40 (DD, J=8,3, 3.3 Hz, 1H), of 8.00 (d, J=10.0 Hz, 1H).

EXAMPLE 11

N-Propanesulfonyl-6-[N-(5-bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

6-[N-(5-Bromo-2-(2-methylprop-2-enyloxy)benzyl-N-ethylamino] pyridazin-3-carboxylic acid (185 mg, 0.46 mmol) was dissolved in dichloromethane (20 ml) and then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC), dimethylaminopyridine (DMAP) (111 mg, of 0.91 mmol), and propanesulfinamide (68 mg, 0.55 mmol). The resulting mixture was stirred at ambient temperature in an argon atmosphere overnight, after which TLC (25% water/CH3SN) indicated completion of the reaction. The reaction with the/SUB>CL2and then 5% EtOH/A 0.5% AcOH/CH2Cl2was obtained target compound as a transparent oily substance, which was utverjdali by trituration with hexane, and received a colorless powder (110 mg, 47%).

So pl. 113,5oC.

MS: 511 (M+N)+.

Elemental analysis (%):

Calculated: From 49.3; H 5,32; N 11,0.

Found: From 49.1; H 5,3; N 10,6.

NMR (200 MHz, DMSO-d6) : 1,0 (t, 3H), 1,2 (t, 3H), 1.8 m (m, 5H), 3,4 (m, 2H), and 3.7 (q, 2H), 4,55 (s, 2H), 4,90 (s, 2H), 4.95 points (s, 1H), 5,1 (s, 1H) 7,0 (d, 1H), and 7.1 (m, 5H), to 7.4 (m, 1H), 7,9 (d, 1H).

EXAMPLE 12

Compounds shown in table 2, were obtained by the method described in Example 11.

Notes

(a) Obtained from the compound of Example 2:

Yield: 61%, so pl. 162,5oC.

MS: 545 (M+N)+.

Elemental analysis for C24H25BrN4O4S1/2 H2O:

Calculated (%): From 52.0; H 4,69; N 10,1.

Found (%): From 51.7; H 4,4; N 9,8.

NMR (MHz, DMSO-d6) : to 1.15 (t, 3H), 1.8 m (s, 3H), 3,6 (kV, 2H), and 4.5 (s, 2H), and 4.8 (s, 2H), 4,9 (s, 1H), 5,1 (s, 1H), 7,0 (m, 3H), 7,2 (m, 1H), 7.5 (m, 3H), 7.7 (d, 1H), 7,9 (d, 2H).

b) Obtained from the compound of Example 3:

Yield: 61%, so pl. 153,8oC.

MS: 565 (M+N)+.

Elemental analysis (%):

The calc is to 4.8 (s, 2H), and 5.5 (m, 1H), of 5.75 (m, 1H), and 7.1 (m, 3H), 7.5 (m, 4H), of 7.75 (d, 1H), 7,9 (m, 1H).

c) Obtained from the compound of Example 3:

Yield: 30%. So pl. 106,2oC.

MS: 532 (M+N)+.

Elemental analysis (%):

Calculated: From 45.2; H 4,55; N 10,5.

Found: From 45.4; H 4,2; N 10,1.

NMR (MHz, DMSO-d6) : 1,0 (t, 3H), 1,2 (t, 3H), 1,7 (m, 2H), 3,3 (m, 2H), and 3.7 (q, 2H), and 4.8 (s, 2H), 4.95 points (m, 2H), 5,6 (m, 1H), and 5.8 (m, 1H), and 7.1 (m, 3H), 7,45 (m, 1H), and 7.8 (d, 1H).

d) Obtained from the compound of Example 16.1.

Yield: 19%. So pl. of 105.2oWITH

Elemental analysis for C23H29BrN4O4S1,5 H2O (%):

Calculated: Compared To 48.9; H 5,6, N, 9,9.

Found: 49,2; N 5,1; N 9,5.

NMR (MHz, DMSO-d6) : 1,0 (m, 8H), 1.8 m (m, 8H), and 3.7 (q, 2H), and 4.8 (s, 2H), 5,0 (m, 1H), and 5.8 (m, 1H), 6,0 (m, 1H), and 7.1 (m, 3H), of 7.4 (m, 1H), and 7.8 (d, 1H).

e) Obtained from the compound of Example 16.1.

Yield: 28%. So pl. 148,9oC.

Elemental analysis for C25H27BrN4O4S31/2 H2O:

NMR (MHz, DMSO-d6) : 1,1 (t, 3H), 1.8 m (m, 6N), and 3.6 (q, 2H), 4,7 (s, 2H), and 4.8 (m, 2H), 5,7 (m, 1H), 5,9 (m, 1H), and 7.1 (m, 3H), of 7.4 (m, 1H), 7,55 (m, 3H), 7.7 (d, 1H), 7,9 (m, 2H).

f) Obtained from the compound of Example 2:

Yield: 80%. MS (ESP-): 550/552 (M+N)+.

NMR (250 MHz, DMSO-d6) : to 1.14 (t, 3H), and 2.4 (s, 3H),2">

(g) Obtained from the compound of Example 2. Yield: 50%.

MS (ESP-): 596/598 (M+N)+.

NMR (250 MHz, DMSO-d6) : to 1.14 (t, 3H), of 2.23 (s, 3H), 3.46 in (q, 2H), 4,6 (m, 2H), a 4.83 (s, 2H), 5,23 (m, 1H), 5,35 (m, 1H), 6,00 (m, 1H), 7,05 (d, 1H), 7,25 (d, 1H), 7,43 (DD, 1H), EUR 7.57 (d, 1H), with 8.05 (d, 1H), 12,85 (Shir. s, 1H).

EXAMPLE 13

N-Benzazolyl-2-[N-(5-bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridine-5-carboxamide

2-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridine-5-carboxylic acid (200 mg, 0.49 mmol) was dissolved in dichloromethane (20 ml), was added dimethylaminopyridine (120 mg, 0.98 mmol), EDAC (1,41 mg of 0.74 mmol) and benzosulfimide (93 mg, 0.59 mmol). The reaction mixture was stirred overnight in an argon atmosphere at ambient temperature, after which TLC (5% MeOH/CH2Cl2) indicated completion of reaction.

After addition of diluted hydrochloric acid (1 M, 40 ml) and water (40 ml), the reaction mixture was extracted with dichloromethane (390 ml). The combined organic layers were washed with water (40 ml), dried with magnesium sulfate and concentrated by evaporation. In the treatment using IHSD (silica, 2.5% of EtOH/CH2Cl2--> 5% EtOH/CH2Cl2) was obtained transparent oily s in the form of a white powder (26%). So pl. 192,8oC.

MS: 544 (M+N)+, 566 (M+Na)+.

Elemental analysis (%):

Calculated: From 55.2; H To 4.81; N 7,72.

Found: From 55.3; H 5,0; N 7,4.

NMR (MHz, DMSO-d6) : 1,1 (t, 3H), 1.8 m (s, 3H), 3,6 (kV, 2H), 4,55 (s, 2H), and 4.8 (s, 2H), 5,0 (s, 1H), and 6.6 (d, 1H), 7,0 (m, 2H), and 7.3 (DD, 1H), 7,6 (m, 3H), 7,9 (m, 3H), 8,55 (s, 1H).

EXAMPLE 14

Compounds shown in table 3, were obtained by the method similar to that described in Example 13.

Notes

(a) Obtained from the compound of example 2.14. Yield: 36%. So pl. output reached 125.5oC.

MS: 510 (M+H)+, 532 (M+Na)+.

NMR (MHz, DMSO-d6) : 1,0 (t, 3H) and 1.15 (t, 3H), 1,7 (m, 2H), 1.8 m (s, 3H), of 3.45 (m, 2H), 3,6 (m, 2H), 4,55 (s, 2H), and 4.75 (s, 2H), 5,0 (s, 1H), 5,1 (s, 1H), and 6.6 (d, 1H), 7,0 (m, 2H), and 7.4 (m, 1H), 8.0 a (m, 1H), to 8.6 (d, 1H), 11,65 (Shir. S., 1H).

b) Obtained from the compound of Example 1: Yield: 59%. So pl. 192,4oC.

MS: 564 (M+H)+, 586 (M+Na)+.

NMR (MHz, DMSO-d6) : 1,1 (t, 3H), 3,6 (kV, 2H), and 4.75 (s, 2H), of 5.55 (m, 1H), and 5.8 (m, 1H), and 6.6 (d, 1H), 7,05 (m, 2H), 7,6 (m, 3H), or 8.6 (m, 1H), 12,1 (Shir. s, 1H).

(C) Obtained from the compound of example 1. Yield: 56%. So pl. l45,4oC.

MS: 530 (M+N)+, 553 (M+Na)+.

NMR (MHz, DMSO-d6) : 1,0 (t, 3H), 1,2 (t, 3H), 1.8 m (m, 2H), 3,5 (m, 2H), and 3.7 (q, 2H), 4.75 in (d, 4H), of 5.55 (d, 1H), and 5.8 (m, 1 who yl)-N-ethylamino] pyridazin-3-carboxylic acid

6-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]-pyridazin-3-carboxamide (843 mg, 2.4 mmol) was dissolved in DMF (15 ml) over 10 minutes, one drop was added to a suspension of sodium hydride (192 mg, is 2.88 mmol, 60% dispersion in mineral oil) in DMF (15 ml) and tetramethylethylenediamine (TMEDA) (0,72 ml, 8 mmol) in argon atmosphere. The resulting mixture was stirred for one hour and then was added 3-chloro-2-methylprop-1-ene (of 0.47 ml, 5,59 mmol) and the mixture was heated to a temperature of 100oC and kept at this temperature for 16 hours. Then, the mixture was cooled to ambient temperature, poured into water (150 ml) and acidified with acetic acid to pH 5. The aqueous mixture was extracted with ethyl acetate (3120 ml) and the combined organic layers were washed with 50% brine (100 ml), dried with magnesium sulfate, and evaporated, resulting in received light yellow oily substance.

The resulting material was purified using GHSD on silica (50% EtOAc/hexane) and was obtained 6-[N-(5-bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl] -N-ethylamino] -pyridazin-3-carboxamide in the form of a colourless foam (440 mg, 40%). MS: 405 (M+N)+.

NMR (MHz, DMSO-d6) : 1,3 (t, 3H), 1.8 m (s, 3H), and 3.8 (q, 2H), 4,4 (s, 2H), and 4.8 (s, 2H), 5,0 (m, 1H), 5,1 (m, 1H), 5,6 (Shir. s, 1H), 6,9 (m, 2H), 7,1 (l, 3-carboxamide (430 mg, of 1.09 mmol) was dissolved in THF/methanol (30 ml, 1: 1) was added sodium hydroxide solution (2.9 ml, 2 M, 5.8 mmol). The resulting mixture was heated under reflux for 72 hours, then cooled and evaporated. The residue was dissolved in water (25 ml) was added acetic acid to pH 4. The solution was stirred for 16 hours, and then, the colorless precipitate was collected by filtration, washed with water, and dried under vacuum, resulting in the obtained target compound as colorless powder (387 mg, 87%).

MS: 406 (M+N)+.

NMR (MHz, DMSO-d6) : 1,0 (t, 3H), 1,7 (s, 3H), 3,6 (square, 2H), 4,4 (s, 2H), 4,7 (s, 2H), around 4.85 (s, 1H), 5,0 (s, 1H), 6,9 (d, 1H), 7,0 (m, 2H), and 7.3 (m, 1H), 7.7 (d, 1H).

EXAMPLE 16

Compounds shown in table 4, were obtained by the method described in Example 15.

(a) NMR (DMSO-d6) : to 1.15 (t, 3H), 3,6 (kV, 2H), and 4.75 (s, 2H), around 4.85 (s, 2H), and 5.5 (m, 1H), of 5.75 (m, 1H), and 7.1 (m, 3H), of 7.4 (m, 2H), and 7.8 (d, 1H).

b) NMR (DMSO-d6) : 1,1 (t, 3H), 1,7 (m, 3H), 2.0 (m, 3H), and 3.7 (q, 2H), 4,7 (s, 2H), 4,9 (m, 1H), and 5.8 (m, 1H), 6,0 (m, 1H), 7,0 (m, 3H), and 7.3 (m, 1H), and 7.8 (d, 1H).

EXAMPLE 17

N-(3,5-Dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

6-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin and hydrochloride (1-(3-di-methylaminopropyl)-3-ethylcarbodiimide (EDAC) (133 mg, 0.69 mmol), dimethylaminopyridine ((DMAP) (113 mg, of 0.92 mmol), and 3,5-dimethylisoxazol-4-ylsulphonyl (98 mg, 0,56 mmol). The mixture was stirred at ambient temperature in an argon atmosphere for 72 hours, after which TLC (25% water/methanol) indicated that reaction was completed. The reaction mixture was loaded directly on GHSD-column (silica), and the target compound in the form of gum, obtained after elution (first of 2.5% ethanol/dichloromethane, and then with 0.5% acetic acid/2,5% ethanol/dichloromethane), triturated with hexane, and obtained the desired product as a solid (98 mg, 38%).

So pl. 119,8oC.

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

Elemental analysis for C22H26BrN5O5S (%):

Calculated: Compared To 48.9; H With 4.64; N 12,4.

Found: From 48.3; H 4,6; N 12,0.

NMR (250 MHz, DMSO-d6) : to 1.15 (t, J=7 Hz, 3H), 1.8 m (m, 2H), 2,35 (s, 3H), 2,65 (s, 3H), 3,7 (kV, J=7 Hz, 2H), and 4.5 (s, 2H), and 4.8 (s, 2H), 4.95 points (s, 1H), 5,15 (s, 1H), 7,0 (d, J=8.5 Hz, 1H), 7,15 (m, 2H), and 7.4 (DD, J=2,8 Hz, 1H), 7,8 (d, J=8.5 Hz, 1H).

EXAMPLE 18

6-[N-(5-Chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

A mixture of N-ethyl-5-chloro-2-(2-methylprop-2-EN-1-yloxy)-benzylamine (comparative example 16) (13.8 g, 50 mm), 6-Harper the reflux for 16 hours. The mixture was cooled and diluted with water (200 ml), which formed an oily substance, which was left to defend (1 hour). The supernatant was decanted, and the remaining brown gum was dissolved in dichloromethane (250 ml) and washed 2 N. hydrochloric acid (100 ml). The organic layer was suirable on silica (solvent: dichloromethane-isopropanol, 19:1), and then, the desired fractions were collected, combined, and evaporated, resulting in a received target compound in the form of gum (10.5 g, 58%).

MS (ESP+): 361/362 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 1.17 (t, J=7 Hz, 3H), of 1.80 (s, 3H), 3,90 (kV, J= 7 Hz, 2H), 4,55 (s, 2H), around 4.85 (s, 2H), 4,98 (S., 1H), 5,10 (s, 1H), 7,00 (d, J=2 Hz, 1H), 7,05 (d, J=9 Hz, 1H), 7,14 (d, J=9 Hz, 1H), 7,28 (DD, J=2,9 Hz, 1H), 7,47 (S. broad, 1H), 7,87 (d, J=9 Hz, 1H), 8,10 (broad singlet, 1H).

EXAMPLE 19

6-[N-(5-Chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid

A mixture of 6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)-benzyl)-N-ethylamino]pyridazin-3-carboxamide (example 18) (of 10.05 g of 29.3 mol) and liquid caustic soda (40 wt. %, 10 ml, 100 mmol) in ethanol (150 ml) was stirred for 16 hours at reflux. After evaporation of the solvent under reduced pressure, the mod is by Ulfat magnesium, filtered, and evaporated, resulting received a brown gum (10.0 g), which was again dissolved in ether (200 ml) and was slowly led within 12 hours, the resulting target compound as a pale yellow solid (4.6 g, 45%), so pl. 130-131oC.

MS (ESP+): 362/264 (M+N)+.

NMR (200 MHz, DMSO-d6) : 1,17 (t, 7 Hz, 3H), of 1.78 (s, 3H), 3,70 (kV, J= 7 Hz, 2H), 4,55 (s, 2H), around 4.85 (s, 2H), to 4.98 (s, 1H), 5,08 (s, 1H), 7,02 (d, J= 2 Hz, 1H), 7,05 (d, J=8 Hz, 1H), 7,12 (d, J=9 Hz, 1H), 7,27 (DD, J=2, 8 Hz, 1H), 7,83 (d, J=9 Hz, 1H).

EXAMPLE 20

N-(2-(Pyrrolidino)econsultancy)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

A mixture of 6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid (example 19) (2.0 g, 5.5 mmol), 2-(pyrrolidino)etoperidone (20 mmol) and hydrochloride ethyl-dimethylaminopropylamine (7.8 mmol) in dichloromethane (25 ml) containing DMF (5 ml), was stirred at a temperature of 40oC for 16 hours. The mixture was diluted with dichloromethane (50 ml) and water (50 ml), then was stirred for 10 minutes, and the organic layer was separated, washed with water (50 ml) and then dried with anhydrous magnesium sulfate. After chromatography on silica (+N)+.

NMR (200 MHz, DMSO-d6) : of 1.16 (t, J=7 Hz, 3H), of 1.78 (s, 3H), 2.00 (evens Shire. , S., 4H), 3,20 (m, 2H), 3,30 (S. broad, 4H), 3,50 (m, 2H), to 3.67 (q, J=7 Hz, 2H), 4.53-in (s, 2H), to 4.81 (s, 2H), to 4.98 (s, 1H), 5,08 (s, 1H), 6,95-7,25 (m, 4H), of 7.82 (d, J=8 Hz, 1H).

Example 21

N-(2-(Morpholino)ethanesulfonyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy) benzyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound was obtained by reaction of 6-[N-(5-chloro-2-(2-methylprop-2-enyloxy)benzyl)-N-ethylamino pyridazin-3-carboxylic acid (Example 19) and 2-(morpholino)acanalonia the method described in Example 20 (yield: 43%).

MS (ESP+): 538/540 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 1.17 (t, J=7 Hz, 3H), of 1.78 (s, 3H), by 2.55 (m, 4H), 2,87 (t, J=6 Hz, 2H), 3,40 (t, J=6 Hz, 2H), 3,55 (m, 4H), 3,68 (kV, J=7 Hz, 2H), 4.53-in (s, 2H), a 4.83 (s, 2H), equal to 4.97 (s, 1H), 5,08 (s, 1H), 6,97 (d, J= 2 Hz, 1H), 7,03 (d, J=8 Hz, 1H), 7,12 (d, J=8 Hz, 1H), 7,25 (DD, J=2, 8 Hz, 1H), 7,86 (d, J=8 Hz, 1H).

EXAMPLE 22

6-[N-(5-fluoro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxylic acid

The target compound was obtained from the compound of Comparative example 17 in the manner described in Example 1 (yield 74%), so pl. 121-122oC.

MS (ESP+): 344 (M+N)-.

NMR (200 MHz, DMSO-d6) : of 1.18 (t, J=7 Hz, 3H), of 1.80 (s, 3H), 3,70 (kV, J= 7 Hz, 2H), to 4.52 (s, 2H WITH 62.6; N 5,8; N 12,2.

Found %: From 62.7; H 5,9; N 11,9.

EXAMPLE 23

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

The target compound was obtained from the compound of Comparative example 18 in the manner described in Example 1. The product was extracted with dichloromethane, was dried with anhydrous magnesium sulfate, and triturated with ether and hexane (yield: 38%).

MS (ESP+): 388/390 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 1.13 (t, 3H), of 1.70 (m, 3H), of 1.85 (m, 1H), 2.00 (evens Shire. s, 2H), the 3.65 (q, 2H), and 4.75 (s, 2H), 4,90 (Shir. s, 1H), 5,80 (DD, 1H), 5,94 (dt, 1H),? 7.04 baby mortality (d, 1H), 7,07 (d, 1H), 7,13 (d, 1H), 7,25 (DD, 1H), 7,80 (d, 1H).

EXAMPLE 24

N-(3,5-Dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-chloro-2-(cyclohexen-3-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound was obtained from 6-[N-(5-chloro-2-(cyclohexen-3-yloxy)benzyl-ethylamino-3-pyridazin-3-carboxylic acid (example 23) and 3,5-dimethylisoxazol-4-ylsulphonyl the method described in Example 11 (yield 22%).

MS (ESP+): 546/548 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 1.12 (t, 3H), of 1.20 (m, 3H), of 1.95 (m, 3H), of 2.35 (s, 3H), 2.63 in (s, 3H), of 3.65 (q, 2H), of 4.77 (s, 2H), 4,88 (Shir. s, 1H), 5,77 (DD, 1H), to 5.93 (dt, 1H), 7,02 (d, 1H), 7,10 (d, 1H), 7,12 (d, 1H), 7,25 (DD, 1H), 7,76 (d, 1H).

EXAMPLE 25

5-[6-(N is lexi)benzyl)-N-ethylamino]-3-cyanopyridine] (comparative example 19) in 1-methyl-2-pyrrolidinone (10 ml) was added sodium azide (330 mg, 5.1 mmol) and triethylamine hydrochloride (320 mg, 0.2 mmol), and then, the solution was stirred for 3 hours at 150oC. After adding water (50 ml), the solution was acidified glacial acetic acid to pH 2. The precipitate was isolated, dissolved in dichloromethane, was dried with anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo, resulting in the obtained brown oily substance (140 mg). After trituration with ether was obtained target compound (50 mg, 17%) as crystals.

MS (ESP+): 386/388 (MN+).

NMR (200 MHz, DMSO-d6) : of 1.16 (t, 3H), 1.28 (in s, 3H), 3,71 (kV, 2H), of 4.54 (s, 2H), around 4.85 (s, 2H), equal to 4.97 (2, 1H), 5,08 (s, 1H), 7,05 (m, 2H), 7,27 (m, 2H), 8,02 (d, 1H).

EXAMPLE 26

N-(3-5-Dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)N-ethylamino]-pyridazin-3-carboxamid

The target compound was obtained from 6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid (example 19), (210 mg, of 0.58 mmol) and 3,5-dimethylisoxazol-4-ylsulphonyl the method described in Example 11. The target compound was purified by column chromatography (eluent: 5% propan-2-ol in dichloromethane) (80 mg, 27%).

MS (ESP+): 520/522 (MN+).

NMR (200 MHz, 1H), from 7.24 (DD, 1H), 7,81 (d, 1H).

EXAMPLE 27

N-(Trifloromethyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound was obtained from 6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid (example 19) and triftoratsetofenona the method described in Example 11 (18%).

MS (ESP+): 493/495 (MN+).

NMR (200 MHz, DMSO-d6) : of 1.18 (t, 3H), of 1.80 (s, 3H), of 3.65 (q, 2H), 4,55 (s, 2H), a 4.83 (s, 2H), equal to 4.97 (s, 1H), 5,10 (s, 1H), 6,95 (d, 1H), 7,02 (m, 2H), 7,25 (DD, 1H), 7,80 (d, 1H).

Example 28

N-(2-Carboxyphenyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound was obtained from N-(2-ethoxycarbonylphenyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carboxamide by the method described in Example 1 (19%).

MS (ESP+): 481/483 (MN+).

NMR (200 MHz, DMSO-d6) : of 1.18 (t, 3H), 1,79 (s, 3H), and 3.72 (q, 2H), 4.53-in (s, 2H), 4,88 (s, 2H), equal to 4.97 (s, 1H), 5,08 (s, 1H), 6,98 (d, 1H), 7,03 (d, 1H), 7,20 (m, 3H), a 7.62 (TD, 1H), 7,95 (d, 1H), 8,04 (DD, 1H), 8,81 (d, 1H), 12,86 (s, 1H).

EXAMPLE 29

N-(1-Carboxyethyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound in the form of Kama is xamiga way described in Example 1 (yield: 15%).

MS (ESP+), 433/435 (MN+).

NMR (200 MHz, DMSO-d6) : to 1.15 (t, 3H), of 1.42 (d, 3H), of 1.78 (s, 3H), of 3.69 (q, 2H), 4,45 (dt, 1H), 4,55 (s, 2H), around 4.85 (s, 2H), to 4.98 (s, 1H), 5,10 (s, 1H), 6,97 (d, 1H),? 7.04 baby mortality (d, 1H), 7,17 (d, 1H), 7,83 (d, 1H), 8,73 (d, 1H).

Example 30

N-(-Carboxybenzoyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound was obtained from N-(-methoxycarbonylbenzyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)-benzyl)-N-ethylamino] pyridazin-3-carboxamide by the method described in Example 1 (13%).

MS (ESP+): 495/497 (MN+).

NMR (200 MHz, DMSO-d6) : of 1.17 (t, 3H), 1,24 (s, 3H), 3,70 (kV, 2H), 4.53-in (s, 2H), a 4.83 (s, 2H), equal to 4.97 (s, 1H), 5,08 (s, 1H), of 5.55 (d, 1H), 7,45 (m, N), 7,81 (d, 1H), 8,89 (d, 1H).

EXAMPLE 31

N-(3,5-Dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-chloro-2-allyloxyphenyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound was obtained from the corresponding carboxylic acid by the method described in Example 12, except that the purification was performed by column chromatography in propan-2-Ola, methanoic acid and dichloromethane, and then the connection is triturated with diethyl ether (250 mg, 33%).

MS (ESP+): 506/508.

NMR (250 MHz, DMSO-d 1H), to 6.95 (d, J=2 Hz, 1H), 6,97 (d, J=8 Hz, 1H), 7,03 (d, J=8 Hz, 1H), 7,24 (DD, J=2 Hz, 8 Hz, 1H), 7,79 (d, J=8 Hz, 1H).

EXAMPLE 32

6-[N-(5-Chloro-2-allyloxyphenyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound was obtained by a method similar to that described in Example 18 (4.0 g, 35%).

MS (ESP+): 347/349 (MN+).

NMR (250 MHz, DMSO-d6) : of 1.16 (t, 3H), to 3.67 (q, 2H), with 4.64 (m, 2H), to 4.81 (s, 2H), 5,27 (DD, J=10 Hz, 2 Hz, 1H), 5,42 (DD, J=16 Hz, 2 Hz, 1H), 6,04 (m, 1H), 6,99 (d, J=2 Hz, 1H), 7,05 (d, J=8 Hz, 1H), 7,13 (d, J=9 Hz, 1H), 7,25 (DD, J=2 Hz, 8 Hz, 1H), 7,41 (Shir. s, 1H), 7,82 (d, J=9 Hz, 1H), 8,06 (Shir. s, 1H).

EXAMPLE 33

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

The target compound was obtained from the corresponding amide (example 32) by the method described in Example 19, except that the obtained substance was led from dichloromethane/diethyl ether/hexane, and then triturated with diethyl ether (900 mg, 45%). MS (ESP+): 348/350 (MN+).

NMR (250 MHz, DMSO-d6) : to 1.15 (t, 3H), 3,70 (kV, 2H), 4,63 (m, 2H), a 4.83 (s, 2H), 5,27 (DD, J=10 Hz, 2 Hz, 1H), 5.40 to (DD, J=16 Hz, 2 Hz, 1H), 6,04 (m, 1H), 7,00 (d, J=2 Hz, 1H), 7,05 (d, J=8 Hz, 1H), 7,10 (d, J=8 Hz, 1H), 7,26 (DD, J=2 Hz, 8 Hz, 1H), 7,83 (d, J=8 Hz, 1H).

EXAMPLE 34

N-(4-Methylthiazole-5-ylsulphonyl)-6-[N-(5-bromo-2-(2-methylprop-2-EN-1-roxobel, described in Example 13 (yield: 54%).

So pl. 127,8oC.

MS: 566 (M+N)+, 588 (M+Na)+.

NMR (250 MHz, DMSO-d6) : to 1.15 (t, 3H), 1.8 m (s, 3H), of 2.35 (s, 3H), and 3.7 (q, 2H), and 4.5 (s, 2H) and 4.65 (s, 2H), 4.95 points (s, 1H), of 5.05 (s, 1H), 7,0 (d, 1H), and 7.1 (d, 1H), and 7.3 (d, 1H), and 7.4 (DD, 1H), and 7.8 (d, 1H), 9,25 (s, 1H).

Elemental analysis for C22H24BrN5ABOUT4S2(%):

Calculated: From 46.6; H 4,27; N 12,4.

Found: 46.5; H 4,3; N 12,5.

EXAMPLE 35

5-[6-(N-[5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl] -N-ethylamino)pyridazin-3-yl]-2-thioxo-2,3-dihydro-1,3,4-oxadiazol

6-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carbohydrazide (comparative example 26) (750 mg, 1.78 mmol) was dissolved in THF (25 ml), then was added triethylamine (0,57 ml, 3,91 mmol), and then thiophosgene (0.1 ml, a 1.96 mmol). The solution was stirred at ambient temperature for 3 hours in an argon atmosphere, and then the tetrahydrofuran was removed under vacuum, was added 75 ml of water, and one drop was injected acetic acid to pH 5. The mixture was extracted with ethyl acetate (3200 ml) and the combined organic phases are washed with water and saturated saline solution (100 ml each) and then dried with magnesium sulfate, and concentrated in vacuo, resulting in a received solid foam (230 mg, 28%).

MS: 462 (M+N)+, 484(M+Na)+.

NMR (MHz, DMSO-d6) : of 1.31 (t, 3H), and 1.56 (s, 3H), 3,70 (kV, 2H), 4,55 (s, 2H), around 4.85 (s, 2H), 4.95 points (s, 1H), 5,1 (s, 1H), 7,0 (d, 1H), 7,15 (d, 1H), 7,17 (d, 1H), 7,37 (DD, 1H), 7,82 (d, 1H).

Elemental analysis for C19H20BrN5O2S0,5H2O (%):

Calculated: From 48.4; H 4,5; N 14,9.

Found: From 48.0; H 4,3; N 14,6.

EXAMPLE 36

2-[6-(N-[5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl] -N-ethylamino)pyridazin-3-yl]-1,3,4-oxadiazol

6-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carbohydrazide (comparative example 26) (750 mg, 1.78 mmol) was dissolved in triethylorthoformate (10 ml), and then, the solution was stirred for 5 hours at 170oC. Excess triethylorthoformate was removed in vacuo and the residue was purified by IHSD (dichloromethane/methanol =98:2), which formed the gum (390 mg), which is triturated with ether/hexane and obtained target compound as a solid (160 mg, 21%). So pl. 90-92oWITH

MS: 429 (M+N)+.

NMR (MHz, DMSO-d6) : of 1.12 (t, 3H), of 1.75 (s, 3H), 3,70 (kV, 2H), 4,55 (s, 2H), around 4.85 (s, 2H), 4.95 points (s, 1H), 5,08 (s, 1H), 7,0 (d, 1H), 7,15 (d, 1H), 7.23 percent (d, 1H), 7,42 (DD, 1H), with 8.05 (d, 1H), 9,67 (s, 1H).

Elemental analysis for C19H20BrN5O2(%) the prop-2-EN-1-yloxy)benzyl-N-ethylamino] pyridazin-3-sulfonamide

A mixture of N-ethyl-5-chloro-2-(2-methylprop-2-EN-1-yloxy)-benzylamine (2.76 g, 10 mmol), 3-chloropyridin-6-sulfonamida [Archiv der Pharmazie (1966), 299, 646-650 and European patent 96004] (1.5 g, 7.8 mmol) and ethyldiethanolamine (10 ml, 57 mm) in DMF (50 ml) was stirred at 130oWith over 16 hours at the reflux. After evaporation of the solvent under reduced pressure, the residue was distributed between dichloromethane (100 ml) and water (100 ml). The organic layer was separated, dried with anhydrous magnesium sulfate, filtered, and evaporated with the formation of a brown gum (2.5 g). The obtained brown gum was purified by chromatography on silica, elwira gradient On-->20% ethyl acetate in dichloromethane, resulting in the obtained target compound as a yellow solid (600 mg).

NMR (200 MHz, DMSO-d6) : of 1.17 (t, J=7 Hz, 3H), 1,79 (s, 3H), 3,70 (kV, J=7 Hz, 2H), 4,55 (s, 2H), equal to 4.97 (s, 1H), 5,08 (s, 1H), 7,0-to 7.3 (m, 4H), 7,43 (s, 2H), 7,74 (d, J=8 Hz, 1H);

MS (ESP+): 397/399 (S)MN+.

EXAMPLE 38

5-[6-(N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino)pyridazin-3-yl]-3-hydroxy-2-methylpyrazole

A mixture of ethyl-6-[N-(5-bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxylate (comparative example 29) (1.2 g, 2.5 mmol) and N-methyl-d the Oia of the solvent under reduced pressure, the residue was distributed between 50 ml of dichloromethane and 50 ml of 1 N. hydrochloric acid, and then the organic layer was separated and dried with anhydrous magnesium sulfate. The product was purified by chromatography on silica, elwira methanol (10%) in dichloromethane, and then were led out of utilizaton, resulting in the obtained white powder (500 mg, so pl. 151-152oC.

MS (ESP+): 458/460 (M+N)+(VG).

Analysis (%):

Calculated: 55,0; N 5,3; N 15,3.

Found: From 54.6; H 5,1; N 15,1.

NMR (200 MHz, DMSO-d6) : to 1.15 (t, J=7 Hz, 3H), of 1.80 (s, 3H), to 3.58 (s, 3H), of 3.65 (q, J=7 Hz, 2H), 4,55 (s, 2H), 4,78 (s, 2H), to 4.98 (s, 1H), 5,1 (s, 1H), 5,90 (s, 1H), 6,98 (d, J=8 Hz, 1H), and 7.1 (m, 2H), 7,37 (DD, J=2,8 Hz, 1H), to 7.77 (broad d, J=8 Hz, 1H), 11,05 (S. broad, 1H).

Comparative example 1

Methyl-2-[N-(5-bromo-2-(2-chloralose)benzyl)-N-ethylamino] -5-pyridylcarboxylic

A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-5-pyridylcarboxylic (comparative example 7) (0.73 g, 2 mm) in DMF (12 ml) was treated with K2CO3(0,83 g, 6 mm) and 2,3-dichloro-1-propene (0,490 g, 44 mm). The resulting reaction mixture was stirred at ambient temperature for 48 hours. Then the reaction mixture is evaporated under reduced pressure. The residue was chromatographically (EHI+): 439 (M+N)+.

NMR (200 MHz, CDCl3) : of 1.23 (t, 3H), 3,63 (kV, 2H), a 3.87 (s, 3H), to 4.62 (s, 2H), 4,80 (s, 2H), vs. 5.47 (m, 1H), of 5.55 (m, 1H), 6,45 (d, 1H), 6.75 in (d, 1H), 7,17 (d, 1H), 7,32 (DD, 1H), and 8.0 (DD, 1H), 8,82 (d, 1H).

Comparative example 2

Compounds shown in table 5, were obtained by the method similar to that described in Comparative example 1 using the appropriate alkylating agent (where X represents a leaving group).

Notes:

a: NMR (250 MHz, Dl3) : 1,22 (t, J=7 Hz, 3H), of 1.45 (d, J=6 Hz, 3H), of 3.64 (q, J= 7 Hz, 2H), a 3.87 (s, 3H), amounts to 4.76 (m, 3H), to 5.21 (m, 2H), 5,9 (m, 1H), 6,4 (d, J=8 Hz, 1H), 6.75 in (DD, J=3, 8 Hz, 1H), 7,14 (m, 1H), 7,28 (m, 1H), 7,95 (m, 1H), and 8.8 (d, J=3 Hz, 1H).

b: NMR (250 MHz, CDCl3) : 1,22 (t, J=7 Hz, 3H), of 1.75 (m, 3H), of 3.64 (q, J=7 Hz, 2H), a 3.87 (s, 3H); [4,57 (m) and 4.63 (m) together with 2H]; 4,74 (s, 2H), 5,77 (m, 2H), 6,40 (d, J=8 Hz, 1H), 6.75 in (m, 1H), 7,13 (m, 1H), 7,28 (m, 1H), 7,95 (DD, J=2, 8 Hz, 1H), 8,82 (d, J=2 Hz, 1H).

from: MS (Χ+): 414 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 1.13 (t, J=7 Hz, 3H), 1,79 (s, 3H), 3,63 (kV, J= 7 Hz, 2H), and 3.8 (s, 3H), of 4.54 (s, 2H), equal to 4.97 (Shir. s, 1H), 5,1 (Shir. S., 1H), of 6.68 (d, J=9 Hz, 1H), 7,0 (d, J=8 Hz, 1H), 7,05 (d, J=3 Hz, 1H), 7,38 (DD, J= 9 Hz, 1H), 7,38 (DD, J=9 Hz, 3 Hz), of 7.75 (DD, J=3, 9 Hz, 1H), 8,63 (d, J=3 Hz, 1H).

d: MC (FAB)+: 445 (M+N)+.

NMR (200 MHz, DMSO-d6) : 1,1 (t, J=7 Hz, 3H), 1.8 m (m, 6N), to 3.58 (q, J= 7 Hz, 2H), 3,78 (C, e: NMR (250 MHz, DMSO-d6) : of 1.12 (t, J=7 Hz, 3H), 3,60 (kV, J=7 Hz, 2H), of 3.75 (s, 3H), and 4.75 (s, 2H), 4,96 (s, 2H), to 6.67 (d, J=9 Hz, 1H), 7,00 (s, 1H), 7,05 (d, J=8 Hz, 1H), and 7.1 (d, J=3 Hz, 1H), 7,44 (DD, J=3 Hz, 8 Hz, 1H), to 7.93 (DD, J=3 Hz, 8 Hz, 1H), 8,64 (d, J=3 Hz, 1H).

f: NMR (250 MHz, DMSO-d6, E-isomer): 1,12 (J=7 Hz, 3H), 3,6 (kV, J=7 Hz, 2H), 3,76 (s, 3H), and 4.75 (s, 2H), 4,90 (s, 1,6 N), of 6.66 (d, J=9 Hz, 1H), was 7.08 (m, 2H), 7,25 (s, 0.8 H), 7,42 (DD, J=3 Hz, 8 Hz, 1H), to 7.93 (DD, J=3 Hz, 8 Hz), 8,63 (d, J=3 Hz, 1H).

Comparative example 3

Methyl-2-[N-(5-bromo-2-(2-methylbut-2-EN-1-yloxy)benzyl-N-ethylamino] -5-pyridylcarboxylic

A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] -5-pyridylcarboxylic (comparative example 7) (0.4 g, 1.1 mmol) in THF (10 ml) in an argon atmosphere was treated with triphenylphosphine (0.32 g, 1.2 mmol) and diethylazodicarboxylate (0,34 ml of 0.38 g, 2.2 mmol). Then was added a solution of 2-methylbut-2-EN-1-ol (0.14 g, 1.6 mmol) in THF (2 ml). The reaction mixture was stirred at ambient temperature for 60 hours. After that, the reaction mixture is evaporated, and the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was twice extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, and evaporated. The residue was chromatographically (eluent: ethyl acetate) and received the target compound as a pale yellow oil which(t, J=7 Hz, 3H), and 1.63 (d, J=7 Hz, 3H), by 1.68 (s, 3H), 3,6 (kV, J=7 Hz, 2H), 3,79 (s, 3H), of 4.46 (s, 2H), and 4.75 (s, 2H), 5,69 (m, 1H), 6,65 (d, J=9 Hz, 1H), 6,97 (d, J=9 Hz, 1H), 7,03 (DS, J=2 Hz, 1H), 7,35 (DD, J=2, 9 Hz, 1H), to 7.93 (DD, J=2,9 Hz, 1H), 8,63 (d, J=2 Hz, 1H).

Comparative example 4

Compounds shown in table 6, were obtained by the method similar to that described in Comparative example 3 using the corresponding alcohol as the original product.

(a) NMR (250 MHz, DMSO-d6) : 1,1 (t, J=7 Hz, 3H), and 1.63 (d, J=7 Hz, 3H), by 1.68 (s, 3H), 3,6 (kV, J=7 Hz, 2H), 3,79 (s, 3H), of 4.46 (s, 2H), and 4.75 (s, 2H), 5,69 (m, 1H), 6,65 (s, J=9 Hz, 1H), 6,97 (d, J=9 Hz, 1H), 7,03 (s, J=2 Hz, 1H), 7,35 (DD, J=2, 9 Hz, 1H), to 7.93 (DD, J=2, 9 Hz, 1H), 8,63 (d, J=2 Hz, 1H).

b) NMR (250 MHz, DMSO-d6) : of 0.95 (s, 3H), 1,0 (s, 3H), 1,10 (t, J=7 Hz, 3H), of 1.42 (m, 1H), 1,67 (s, 3H), of 1.78 (m, 3H), of 3.56 (q, J=7 Hz, 2H), 3,79 (s, 3H), and 4.68 (s, 2H), 4,93 (Shir. s, 1H), 5,5 (s, 1H), only 6.64 (d, J=9 Hz, 1H), 7,05 (m, 2H), 7,47 (DD, J=2, 9 Hz, 1H), 7,92 (DD, J=2, 9 Hz, 1H), 8,63 (d, J=2 Hz, 1H),

c) NMR (250 MHz, DMSO-d6) : of 1.09 (t, J=7 Hz, 3H), of 1.48 (m, 1H), 1,7 (m, 6N), 1,8-2,4 (m, 4H), of 3.56 (q, J=7 Hz, 2H), 3,79 (s, 3H), of 4.77 (m, 4H), 5,14 (m, 1H), 5,7 (m, 1H), 6,69 (d, J=9 Hz, 1H), 7,15 (m, 2H), 7,44 (m, 1H), 7,94 (m, 1H), 8,65 (m, 1H).

d) MS (ESP+): 434 (M+N)+.

NMR (250 MHz, DMSO-d6) : of 1.16 (t, J=7 Hz, 3H), 1,32 (t, J=7 Hz, 3H), of 1.78 (s, 3H), 3,7 (kV, J=7 Hz, 2H), 4,33 (kV, J=7 Hz, 2H), 4,55 (s, 2H), around 4.85 (s, 2H), to 4.98 (s, 1H), 5,07 (s, 1H), 6,99 (d, J=8 Hz, 1H), tx2">

Comparative example 5

4-Hydroxy-3-methylbut-2-EN

To a suspension of lithium aluminum hydride (0,47 g, 12,4 mm) in tetrahydrofuran (30 ml) at 0oWith solution was added Tihonova acid (1.0 g, 10 mm) in THF (20 ml). The reaction mixture was heated to ambient temperature and was stirred overnight. The reaction was suppressed by adding diluted hydrochloric acid, and then the mixture three times were extracted with ethyl acetate. Thus obtained 4-hydroxy-3-methylbut-2-ene was used in the next stage without purification (0,29 g, 30%).

MS (EI+): 86 (M+).

NMR (250 MHz, DMSO-d6) : of 1.55 (m, 6N), 3,98 (Shir. S., 2H), 4,55 (Shir. s, 1H).

Comparative example 6

Methyl-2-[N-(2-allyloxy-5-bromobenzyl)-N-ethylamino]-5-pyridylcarboxylic

A solution of 5-bromosalicylaldehyde (20,1 g, 100 mm) in DMF (50 ml) was treated with potassium carbonate (20.7 g, 150 mm) and allylbromide (12.7 g, 10.5 mm). The reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was distributed between ethyl acetate and water. The organic phase is four times washed with water and then dried with magnesium sulfate, and evaporated under reduced pressure, resulting in a received 2-allyloxy-5-bromobenzoyl acid in view of the 0 MHz, DMSO-d6) : 4,74 (m, 2H), lower than the 5.37 (m, 2H), 6,1 (m, 1H), 7,20 (d, J=9 Hz, 1H), 7,76 (m, 2H), 10,3 (s, 1H).

A solution of 2-allyloxy-5-bromobenzaldehyde (5,27 g, 21.9 mmol) was treated with sodium borohydride (0,145 g 10,9 mm). The reaction mixture was stirred at ambient temperature for 2.5 hours, and then added water, and the solvent was removed under reduced pressure. The residue was acidified to pH 1 and extracted twice with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, and evaporated, resulting in a received 2-allyloxy-5-bromobenzoyl alcohol (5,12 g, 96%) as a white solid.

MS (EI+): 242 (M+).

NMR (250 MHz, DMSO-d6) : 4,5 (s, 2H), 4,55 (m, 2H), 5,15 (Shir. s, 1H), 5,3 (m, 2H), 6,02 (m, 1H), 6,9 (d, J=9 Hz, 1H), 7,35 (DD, J=2 Hz, 9 Hz, 1H), 7,47 (d, J=2 Hz, 1H).

A solution of 2-allyloxy-5-bromobenzylamine alcohol (5,12 g, 21,1 mm) in dichloromethane (25 ml) was treated with triphenylphosphine (x 6.15 g, 23.5 mm) and tetrabromomethane (8,67 g, 26,13 mm). The reaction mixture was stirred at ambient temperature overnight. The solvent is evaporated under reduced pressure, and thus obtained 2-allyloxy-5-bromobenzylamine used in the next stage without purification.

Sodium hydride (60%, 0,909 g, 22.7 mm) three R is etilkarbitola (as 4.02 g, 22.3 mm), the reaction mixture was stirred at ambient temperature for 1 hour. After adding a solution of 2-allyloxy-5-bromobenzylamine (21,1 mm), the reaction mixture was stirred for 23 hours at ambient temperature. The reaction is extinguished by water, and the mixture was extracted with ethyl acetate. The organic layer was three times washed with water, dried with magnesium sulfate, and evaporated. After chromatography (eluent: ethyl acetate/hexane) was obtained methyl 2-[N-(2-allyloxy-5-bromobenzyl)-N-ethylamino] -5-pyridylcarboxylic in the form of a dark yellow oily substance, which is used in the subsequent stage without further purification.

Comparative example 7

Methyl-2-[N-(5-bromo-2-hydroxybenzyl)-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 is hermetically closed in the autoclave and heated to 170oC for 6 hours. The reaction mixture is evaporated, partially neutralized with concentrated hydrochloric acid, and the pH is brought to 5 by adding glacial acetic acid. The solid product was filtered and dried under vacuum for 18 hours, resulting in the received 6-(ethylamino)nicotinic kislota,3 (kV, J=7 Hz, 2H), 6,45 (d, J=9 Hz, 1H), 7,25 (Shir. so, 1H), 7,78 (DD, J=2, 9 Hz, 1H), 8,54 (d, J=2 Hz, 1H), 11,6 (Shir. s, 1H).

A suspension of 6-(ethylamino)nicotinic acid (50 g, 0.3 mol) in methanol (500 ml) was treated with concentrated sulfuric acid (30 ml). The reaction mixture was heated under reflux for 18 hours. Then the reaction mixture is evaporated, poured into ice water (1 liter), and brought to pH 8 by adding solid sodium bicarbonate (foaming). The aqueous mixture was extracted with ethyl acetate (3300 ml) and the organic layers were combined, dried with magnesium sulfate, and evaporated, resulting in a received methyl-6-(ethylamino)nicotinate in the form of a whitish solid product (45,5 g, 84%).

MS (Χ+): 181 (M+N)+.

NMR (200 MHz, DMSO-d6) : to 1.14 (t, J=7 Hz, 3H), 3,3 (kV, J=7 Hz, 2H), 3,76 (s, 3H), 6,46 (d, J=9 Hz, 1H), 7,39 (Shir. so, 1H), 7,80 (DD, J=3, 9 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 at ambient temperature for 18 hours and then was diluted with ethyl acetate, and filtered. The filtrate was washed with hydrochloric acid (0.05 M), saturated aqueous solution of the residue triturated with hexane/ethyl ether. The product was filtered and obtained 2-benzyloxy-5-bromobenzaldehyde in the form of a white solid (15,8 g, 90%), so pl. 70-72oC.

MS (Χ+): 291 (M+N)+.

NMR (200 MHz, DMSO-d6) : 5,38 (s, 2H), 7.5 (m, 6N), and 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 increased to 33oC. After one hour, the reaction mixture is evaporated, and the residue was dissolved in ethyl acetate and poured into a mixture of ice water (200 ml) and In HCl (25 ml). The organic layer was separated and then washed with an aqueous solution of sodium bicarbonate, and saline. After drying with sodium sulfate and evaporation was obtained 2-benzyloxy-5-bromobenzoyl alcohol as a pale yellow oily substance (14,85 g, quantitative yield).

MS (Χ+): 292 (M+).

NMR (200 MHz, DMSO-d6) : to 4.52 (d, J=5 Hz, 2H), 5,12 (s, 2H), 5,17 (t, J=5 Hz, 1H), 6,98 (d, J=9 Hz, 1H), and 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 Then added drop by drop a solution of RVG3(13,68 g, 50 IMO the temperature of the environment and was stirred for 1 hour. The reaction mixture was filtered through silicagel (200 g). Then the silica gel was washed with ethyl ether to remove all products. The filtrate was washed with water (1150 ml), aqueous saturated sodium bicarbonate solution (1150 ml), and brine (11150 ml). The organic layer was dried with sodium sulfate and evaporated, resulting in the obtained 2-benzyloxy-5-bromobenzylamine in the form of a light yellow oily substance (15.2 g, 85%) which crystallized on standing. MS (EI+): 354 (M+).

NMR (200 MHz, DMSO-d6) : the 4.65 (s, 2H), and 5.2 (s, 2H), 7,05 (d, J=9 Hz, 1H), and 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 0oAnd was treated with sodium hydride (60%, 75 mmol). The reaction mixture was stirred for one hour and the solution was added 2-benzyloxy-5-bromobenzylamine (25 g, of 70.2 mmol) in DMF (50 ml). The reaction mixture was heated to ambient temperature and was stirred for 18 hours. The reaction was completed by adding water, and the mixture three times were extracted with ethyl acetate. The organic layers were combined, washed with water and brine (twice), and then dried with magnesium sulfate, and evaporated with the formation of white solids. In Mino]pyridine-5-carboxylate (22,7 g, 71%).

MS (Χ+): 455/457 (M+N)+.

NMR (200 MHz, DMSO-d6) : 1,1 (t, J=7 Hz, 3H), 3,5 (kV, J=7 Hz, 2H), of 3.78 (s, 3H), 4,77 (c, 2H), by 5.18 (s, 2H), 6,65 (d, J=9 Hz, 1H), was 7.08 (m, 2H), and 7.4 (m, 6N), and 7.9 (DD, J=2, 9 Hz, 1H), to 8.62 (d, 1H).

A solution of methyl 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino] -5-pyridylcarboxylic (10.0 g, 22 mm) in dichloromethane (150 ml) was treated with complex dimethyl sulfide-trichloride Bora (40 ml, 2 M, 80 mm). The reaction mixture was stirred at ambient temperature for 48 hours. After adding saturated sodium bicarbonate solution, the layers were separated. The aqueous layer was washed with dichloromethane. The organic layers were combined, dried with magnesium sulfate, and evaporated, resulting in a received whitish solid. This is a whitish solid was subjected to chromatography (eluent: ethyl acetate/hexane) and received the target connection (of 6.02 g, 75%).

MS (Χ+): 365 (M+N)+.

NMR (250 MHz, DMSO-d6) : to 1.14 (t, J=7 Hz, 3H), 3,61 (kV, J=7 Hz, 2H), of 3.78 (s, 3H), of 4.66 (s, 2H), 6,65 (d, J=9 Hz, 1H), 6,8 (d, J=9 Hz, 1H), 7,02 (d, J=2 Hz, 1H), 7,2 (DD, J=2, 9 Hz, 1H), to 7.93 (DD, J=2, 9 Hz, 1H), 8,64 (d, J=2 Hz, 1H), 10,13 (s, 1H).

Comparative example 8

2-[N-(5-Bromo-2-(2-chlorpro-2-EN-1-yloxy)benzyl)-N-ethylamino]-5-lepirudin

2-[N-(5-Bromo-2-hydroxybenzyl)config solution was treated with pyridine (0,46 ml, 0,46 g, 5.7 mmol) and triperoxonane anhydride (0.9 ml, 1.35 g, 6.4 mmol) at ambient temperature (weak exothermic reaction). After the appearance of a yellow solid substance was dissolved in tetrahydrofuran. The resulting solution was left overnight at ambient temperature and then was added pyridine (0,46 ml, 5.7 mmol) and TFAA (of 0.90 ml, 6.4 mmol), after which, the reaction mixture was again passed during the night. The resulting mixture was evaporated to a smaller volume and added a saturated solution of sodium bicarbonate. Then the mixture was stirred at ambient temperature for 30 minutes, then evaporated to a smaller volume, and the resulting white precipitate was filtered, washed with water, and dried by air, resulting in a received 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] -5-lepirudin in the form of a white solid (1.0 g, 100%).

MS (Χ+): 332, 334 (M+N)+.

Cyano-compound from the previous stage (0.52 g, 1.56 mmol) in dimethylacetamide (10 ml) was subjected to reaction with potassium carbonate (650 mg, 4.7 mmol), and then 2,3-dichloro-1-propene (0,32 ml, 384 mg, 3,47 mmol). The resulting mixture was stirred at ambient temperature overnight, and evaporated to dryness and then the residue pre-treatment in the form of a white gum (0.4 g, 63%).

MS (ESP+): 406, 408 (M+N)+.

Comparative example 9

n-Butyl-6-[N-(5-bromo-2-(2-chlorpro-2-EN-1-yloxy)benzyl]-N-ethylamino]pyridazin-3-carboxylate

n-Butyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] -pyridazin-3-carboxylate (compare. example 11) (0.28 g, 0.69 mmol) in DMF (4 ml) was treated with potassium carbonate (2.05 mmol), and then 2,3-dichloroprop-1-Yong (168 mg, 140 μl, 1.4 mmol) and the reaction mixture was left for the weekend for mixing at ambient temperature. Then the reaction mixture is evaporated to dryness and the residue was absorbed on silica (1.5 g), and purified using GHSD with obtaining the target compound as a colourless gum (0.24 g, 72%).

MS (Χ+): 482, 484 (M+N)+.

Comparative example 10

2-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] -5-cyanopyridine

2-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxamide (example 4) (1,93 g, 5.5 mmol) suspended in THF (30 ml) and treated with pyridine (1,15 g of 14.25 mmol, 1,15 ml), and then triperoxonane anhydride (3.4 g, 16 mmol), with stirring at ambient temperature. After dissolving the white solid was observed weak exothermic reaction. The resulting solution acadeny aqueous solution of sodium bicarbonate, and the mixture was stirred for 30 minutes at ambient temperature. Then the mixture is again evaporated to small volume and precipitated white solid was filtered, washed with water, and dried in vacuum (1.68 g). The solid product was purified using GHSD on silicon dioxide, resulting in a received 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] -5-lepirudin in the form of a white solid (1,15 g, 63%).

MS (Χ+): 332, 334 (M+N)+.

Cyano-compound from the previous stage (0.52 g, 1.56 mmol) in dimethylacetamide (10 ml) was treated with potassium carbonate (0.65 g, 4.7 mmol) and then 3-chloro-2-methylprop-1-Yong, and the mixture was stirred for 48 hours at ambient temperature. The mixture is then evaporated to dryness, and the residue was applied directly on a column with silica, then purified by IHSD, resulting in a received 2-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] -5-lepirudin (0.45 g, 75%), which was then led.

MS (ESP+): 386, 388 (M+H)+.

NMR (200 MHz, DMSO-d6) : to 1.15 (t, 3H), 1,76 (width, C., 3H), 3,68 (Shir. kV, 2H), 4.53-in (s, 2H), around 4.85 (s, 2H), equal to 4.97 (s, 1H), is 5.06 (s, 1H), 7,0 (d, 1H), 7,18 (m, 2H), and 7.4 (DD, 1H), 7,83 (d, 1H).

Sravnitelny example 11

Butyl-6-[N-(5-bromo-2-hydrox is the emer 13, paragraph 1-3) (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. Then the reaction mixture was cooled to ambient temperature and kept overnight. The precipitate was filtered off, washed with a small volume of water, and drained, resulting in the received 6-(ethylamino)pyridin-3-carboxamide in the form of a pink solid (8,9 g). [Filtrates evaporated to small volume and then diluted with cold water (100 ml), and the additional amount of the desired solids were filtered off, washed with water, and drained (12.8 g). Full output (21,7 g, 72%)].

A solution of 6-(ethylamino) pyridazine-3-carboxamide (21,7 g, 0,131 mol) in n-butanol (109 ml) and F3Et2O (54 ml) was heated in the condenser with air cooling (evaporation Et2O) at 120oC for 18 hours. The reaction mixture is 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 with magnesium sulfate and evaporated in vacuo, resulting in Ali butyl-6-(ethylamino)pyridazine-3-carboxylate in the form of a whitish solid (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 then added an additional 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, evaporated, and received a dark oily substance. After chromatography (eluent: diethyl ether/hexane) received other party products in the form of a brown oily substance. The oily substance was dissolved in ethyl acetate (about 70 ml) and left overnight at ambient temperature, resulting in the formed white solid precipitate. This precipitate was filtered and washed with ethyl acetate, and then dried off, and got the desired product, namely, butyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazin-3-carboxylate (12.3 g, 32%).

Comparative example 12

Butyl-6-[N-(5-bromo-2-(2-chlorpro-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxylate

Butyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] -pyridazin-3-carboxylate (comparative example 0 ál, 1.4 mmol) and the mixture was left for the weekend for mixing at ambient temperature. The resulting mixture was evaporated in vacuum to dryness and then the residue pre-absorbed on 1.5 g of silicon dioxide, purified using GHSD, and received the target compound as a colourless gum (0.24 g, 72%).

MS (Χ+): 482, 484 (M+N)+.

Comparative example 13

6-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] -3-cyanopyridine

1. A mixture of 6-oxo-1,6-dihydropyridin-3-carboxylic acid (117, 24 d) [Cm. British patent 856409], n-butyl acetate (293 ml), n-butanol (410 ml) and concentrated sulfuric acid (5,9 ml) was heated under reflux for one hour. After evaporation of the solvent, the residue was washed with n-butyl acetate, and received n-butyl-6-oxo-1,6-dihydropyridin-3-carboxylate (yield of 79.6%, to 130.6 g), so pl. 79-80oC.

NMR (DMSO-d6) : of 0.93 (t, 3H, J=7.5 Hz), of 1.40 (sextet, 2H, J=7.5 Hz), 1,67 (m, 2H), 4,28 (t, 2H, J=6.5 Hz), of 6.96 (d, 1H, J=10 Hz), 7,83 (d, 1H, J= 10 Hz), 13.56MHz (S. broad, 1H).

2. To a mixture of phosphorus oxychloride (20 ml) and acetonitrile (40 ml), heated under reflux, was added a solution of n-butyl-6-oxo-1,6-dihydropyridin-3-carboxylate (20 g) in acetonitrile (80 ml). The reactions is the solution TO2CO3(87,8 g) in water (600 l) with vigorous stirring. The obtained product was filtered off, washed with water and dried at 60oWith obtaining n-butyl-6-chloropyridazine-3-carboxylate (17.5 g, yield 80%), melting point: 110-111oC.

NMR (CDl3) : 1,99 (t, 3H, J=7.5 Hz), to 1.48 (sextet, 2H, J=7.5 Hz), of 1.84 (m, 2H), 4,49 (t, 2H, J=6.5 Hz), 7,71 (d, 1H, J=8,3 Hz), 8,18 (d, 1H, J=8,3 Hz).

3. It cooled in an ice bath to a solution of n-butyl-6-chloropyridazine-3-carboxylate (40 g) in methanol (280 ml) was added excess amount of ammonia gas. The resulting mixture was stirred at ambient temperature for 4 hours, and then the residue was filtered off, washed with methanol (20 ml), and dried off, resulting in the received 6-chloropyridazine-3-carboxamide (28,0,5 g, 95.5 percent), so pl. 243-245oC.

NMR (DMSO-d6) : of 7.96 (broad, 1H), 8,07 (d, 1H, J=8,3 Hz), by 8.22 (d, 1H, J=8,3 Hz), charged 8.52 (S. broad, 1H).

4. To a mixture of 5-bromo-2-hydroxybenzaldehyde (100,5 g) and K2CO3(207,5 g) in 1-methyl-2-pyrrolidinone (500 ml) at 30oC for one hour drop added benzylbromide (71,4 ml). The mixture was stirred for 3 hours at 35-40oC. To the mixture over 30 minutes at 35oWith solution was added ethylamine hydrochloride (57,1 g) Metalli solution of sodium borohydride (26.5 g) in 1-methyl-2-pyrrolidinone (300 ml) at 35-40oC, and the mixture was stirred for 2 hours at 40-45oC. Then the mixture was cooled (10oC), diluted with ethyl acetate (200 ml), and acidified 2 N. Hcl (3500 ml). The precipitate was filtered off, washed with toluene and 40-60% petroleum ether, and then dried in vacuum at 60oC. the Residue was purified by stirring in a mixture of acetonitrile (140 ml) and toluene (700 ml) at 80oC for 30 minutes followed by cooling to 10oAnd filtering the product. Thus was obtained cleaners containing hydrochloride salt of N-ethyl-N-(2-benzyloxy-5-bromobenzyl) amine (13,6 g, yield: 76.7 per cent).

NMR (DMSO-d6) : of 1.20 (t, 3H, J=7,3 Hz), of 2.97 (q, 2H, J=7,3 Hz), 4,13 (s, 2H), 5,20 (s, 2H), 7,15 (d, 1H, J=8,3 Hz), 7,22-of 7.60 (m, 6N), of 7.70 (d, 1H, J=2.5 Hz), 8,68 (S. broad, 1H).

5. A mixture of cleaners containing hydrochloride salt of N-ethyl-N-(2-benzyloxy-5-bromobenzyl)amine (87 g), 6-chloropyridazine-3-carboxamide (35 g), and NaHC3(41 g) in 1-methyl-2-pyrrolidinone was heated for 24 hours at 115oWith, and then was cooled to 20oWith, and added to water (1100 ml) with vigorous stirring while maintaining the temperature below 30oC with external cooling. After adding ethyl acetate (725 ml), the mixture was stirred at 20oC for 2 hours. The precipitate was filtered, dried, washed with 40 to 60%-naml)-N-ethylamino] pyridazin-3-carboxamide (83 g, yield: 84.7 per cent), so pl. 171-172oC.

NMR (DMSO-d6) : of 1.12 (t, 3H, J=7.0 Hz), 3,66 (square, 2H, J=7.0 Hz), 3,66 (q, 2H, J=7.0 Hz), is 4.85 (s, 2H), 5,19 (s, 2H), 7,07-7,16 (m, 3H), 7,30-7,51 (m, 7H), 7,79 (d, 1H, J=9 Hz, 8,10 (S. broad, 1H).

6. 6-[N-(2-Benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazin-3-carboxamide (3,24 g, 7,3 mmol) in dichloromethane (50 ml) was treated with complex dimethyl sulfide-trichloride Bora (18.5 ml, 2 M solution) in dichloromethane (37 mmol) and the solution was stirred at ambient temperature for 6 days. Then the mixture was carefully treated with excess aqueous sodium bicarbonate solution to pH 9. After addition of dichloromethane, the organic and aqueous layers were separated, and the aqueous layer washed with dichloromethane. The combined organic extracts were washed with saline, then was dried and evaporated, resulting in a formed adhesive solid. This substance was treated with diethyl ether (30 ml) and methanol (3 ml), and then left overnight at ambient temperature. The obtained solid substance was filtered off, washed with diethyl ether, and dried under vacuum, resulting in the received 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazin-3-carboxamide (1,34 g, yield: 52%).

The phenol from the previous stage (1.73 g, 4.9 mmol) eh). After the mixture has acquired a green tint, it was left overnight at ambient temperature. The mixture is then evaporated to obtain a gum which was treated with excess aqueous sodium bicarbonate solution, and was stirred at ambient temperature for approximately 30 minutes. The obtained red solid was filtered, washed with water, and dried in vacuum (1.8 g), and then the residue was purified by IHSD to obtain 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-3-lepirudin (white solid; 0.87 g, 53%).

MS (ESP+): 333, 335 (M+N)+.

The product obtained in the previous stage) (0.52 g, 1.56 mmol) in dimethylacetamide (10 ml) was treated with potassium carbonate (0.65 g, 4.7 mmol) and then 3-chloro-2-methylpropene (340 μl, 314 mg, 3,47 mm) and the mixture was stirred over night at ambient temperature.

Then, the mixture is evaporated in vacuo, and the residue pre-absorbed onto silica, and purified using GHSD, and received 6-[N-(5-bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]3-lepirudin.

MS (ESP+): 387, 389 (M+N)-.

Comparative example 14

6-[N-(5-Bromo-2-(cyclohex-2-enyloxy)benzyl)-N-ethylamino]3-tianpin is that together 3-chloro-2-methylpropene used 3-bromocyclohexene. The compound obtained was a light yellow gum (97%).

MS (ESP+): 413, 415 (M+N)-.

Comparative example 15

Ethyl-6-[N-(5-bromo-2-allyloxyphenyl)-N-ethylamino] pyridazin-3-carboxylic acid

The target compound was obtained from ethyl-6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] pyridazin-3-carboxylate (example 8) by the method described in comparative example 3.

NMR (250 MHz, DMSO-d6) : to 1.15 (t, 3H), 1.33 (t, 3H), of 3.69 (q, 2H), 4,84 (kV, 2H), 4,62 (Shir. D., 2H), 4,84 (s, 2H), 5,27 (m, 1H), 5,91 (m, 1H), 6,04 (m, 1H), 7,00 (d, 1H), and 7.1 (m, 2H), and 7.4 (DD, 1H), 7,83 (d, 1H).

Comparative example 16

N-Ethyl-5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzylamine

A mixture of 5-chlorosalicylaldehyde (25,0 g, 0.16 mol), anhydrous potassium carbonate (70,0 g, 0.5 mol), metallicgold (27,0, ml, 0.27 mol) and N-methylpyrrolidinone (250 ml) was stirred at the reflux at 60-70oC for 16 hours. Then the mixture was cooled to 20oC and carefully treated with a solution of ethylamine hydrochloride (40,0 g, 0.49 mol) in 200 ml of methanol (observe the formation of foam). After termination of the addition, the mixture was stirred for one hour at 20oC and then was treated with portions of sodium borohydride (4.6 g, 0.12 mol) and a small aliquot (approximately 10 ml) EF is h" was decomposed by careful addition of 6 N. HCl (200 ml), cooling if necessary. The mixture was stirred for 1 hour at a temperature of 20oWith, and then podslushivaet 2 N. sodium hydroxide (NaOH) to pH 10, and extracted with dichloromethane (3250 ml). The combined organic extracts were washed with water (3250 ml), dried with anhydrous magnesium sulfate, filtered, and evaporated with the formation of a brown oily substance, which was dissolved in isopropanol (200 ml). To the solution under stirring was added concentrated hydrochloric acid (36 wt.%/about., 10 ml) and the solution was cooled at 5oC for 2 hours, resulting in the formed needle crystals. This substance was filtered, washed with isopropanol and ether, and has been the target connection, namely, a salt of hydrochloric acid (18.0 g, 41%), so pl. 135-136oC.

MS (Χ+): 240/242 (M+N)+.

NMR (200 MHz, DMSO-d6) : a 1.25 (t, J=6 Hz, 3H), of 1.80 (s, 3H), 2,93 (kV, J= 6 Hz, 2H), 4,07 (s, 2H), of 4.54 (s, 2H), equal to 4.97 (s, 1H), 5,08 (S, 1H), 7,07 (d, J= 8 Hz, 1H), 7,40 (DD, J=8 Hz, J=2 Hz, 1H), of 7.70 (d, J=2 Hz, 1H), for 9.47 (s, 2H).

Analysis (%):

Calculated: From 56.5; H 6,9; N 5,1; Cl 25,7.

Found: 56, 7mm; N 6,9; 5,0 N; Cl 25,5.

Comparative example 17

Butyl-6-[N-(5-fluoro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-ka is,8 mmol) and para-formaldehyde (1.7 g, a 56.6 mmol) in TFA (100 ml) was stirred for one hour at a temperature of 50-60oTo a clear solution is formed. This solution was cooled to ambient temperature and was treated with 4-tortenelem (5.6 g, 50.0 mmol) and then stirred for 16 hours and evaporated under reduced pressure. The residue was distributed between ice and water (200 g) and dichloromethane (200 ml) and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, and evaporated with the formation of a yellow gum. After chromatography on silica (eluent: 10% ether in dichloromethane) was obtained solid substance, which was led from the ether, and received butyl-6-[N-(5-fluoro-2-hydroxybenzyl)-N-ethylamino] pyridazin-3-carboxylate in the form of a pale pink needle-like crystals (2.2 g).

MS (ESP+): 348 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 0.93 (t, J=7 Hz, 3H), of 1.27 (t, J=7 Hz, 3H), USD 1.43 (m, 2H), 1.70 to (m, 2H), and 3.72 (q, J=7 Hz, 2H), 4,30 (t, J=7 Hz, 2H), of 4.77 (s, 2H), 6.73 x-of 7.90 (m, 3H), 7,10 (d, J=8 Hz, 1H), 7,83 (d, J=8 Hz, 1H), 9,83 (s, 1H).

The target compound was obtained from butyl 6-[N-(5-fluoro-2-hydroxybenzyl)-N-ethylamino] pyridazin-3-carboxylate by the method described in Comparative example 1 (yield: 95%).

NMR (200 MHz, CDCl, 1H), 5,10 (s, 1H), to 6.67 (d, J=8 Hz), 7,83 (d, J=8 Hz, 1H).

Comparative example 18

Butyl-6-[N-(5-chloro-2-(cyclohexen-3-yloxy)benzyl)-N-ethylamino] pyridazin-3-carboxylate

The target compound was obtained from butyl 6-[N-(5-chloro-2-hydroxybenzyl)-N-ethylamino] pyridazin-3-carboxylate (comparative example 20) by the method described in comparative example 1, except that the reaction mixture was left at 80 hours at 50oWith, as eluent used in chromatography, represented 10% diethyl ether/dichloromethane.

MS (ESP+): 444/446 (M+N)+.

NMR (200 MHz, DMSO-d6) : and 0.98 (t, 3H) and 1.15 (t, 3H), of 1.45 (m, 2H), 1.70 to (m, 5H), 1,90 (m, 1H), 2,04 (m, 2H), 3,66 (kV, 2H), 4,30 (t, 2H), of 4.77 (s, 2H), 4,93 (Shir. s, 1H), of 5.83 (DD, 1H), 5,95 (dt, 1H), 7,05 (d, 1H), was 7.08 (d, 1H), 7,13 (d, 1H), 7,26 (DD, 1H), 7,82 (d, 1H).

Comparative example 19

6-[N-(5-Chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] -3-lepirudin

To a solution of 6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] -pyridazin-3-carboxamide (example 18) (210 mg, 0.6 mmol) in pyridine (10 ml) at 0oWith added methanesulfonamide (0.5 ml, 0.6 mmol) and the mixture was left to stir for 60 hours (slowly bringing to the ambient temperature as melting ice). The solution was poured into 2 N. hydrochloric to the NYM magnesium sulfate, and the solvent was removed in vacuo, resulting in a received target compound as a brown gum (260 mg), which was used without further purification.

Comparative example 20

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

The target compound was obtained from butyl-6-(ethylamino)-pyridazin-3-carboxylate and 4-chlorophenol by the method described in comparative example 1, 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), 1.70 to (m, 2H), and 3.7 (q, 2H), 4,28 (t, 2H), and 4.75 (s, 2H), 6,85 (d, 1H), 6,97 (d, 1H), and 7.1 (m, 2H), 7,82 (d, 1H), 10,1 (Shir. s, 1H).

Comparative example 21

N-(2-Ethoxycarbonylphenyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound was obtained from 6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid (example 19) by the method described in Example 11.

MS (ESP+): 495/497 (MN+).

NMR (200 MHz, DMSO-d6) : of 1.24 (t, 3H), of 1.78 (s, 3H), of 3.73 (q, 2H), 3,90 (s, 3H), 4,55 (s, 2H), 4,88 (s, 2H), equal to 4.97 (s, 1H), 5,10 (s, 1H), 6,97 (d, 1H), 7,07 (d, 1H), 7,22 (m, 3H), 7,68 (TD, 1H), of 7.97 (d, 1H), 8,04 (DD, 1H), 8,83 (d, 1H).

Against the Jn-3-carboxamid

The target compound was obtained from 6-[N-(5-chloro-2-(2-methylprop-2-enyloxy)-benzyl)-N-ethylamino]pyridazin-3-carboxylic acid (example 19) by the method described in Example 11, except that the target compound was not purified by column chromatography.

MS (ESP+): 447/449 (MN+).

NMR (200 MHz, DMSO-d6) : of 1.16 (t, 3H), USD 1.43 (d, 3H), of 1.78 (s, 3H), of 3.65 (s, 3H), 3,71 (kV, 2H), 4,55 (m, 1H), 4,56 (s, 2H), around 4.85 (s, 2H), equal to 4.97 (s, 1H), 5,08 (s, 1H), 7,00 (d, 1H), 7,05 (d, 1H), 7,16 (d, 1H), 7,26 (DD, 1H), of 7.82 (d, 1H), 8,95 (d, 1H).

Comparative example 23

N(-Methoxycarbonylbenzyl)-6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino]pyridazin-3-carboxamid

The target compound was obtained from 6-[N-(5-chloro-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid (example 19) by the method described in Example 11, and was purified by column chromatography (eluent: 2% iPrOH in dichloromethane).

MS: (ESP+): 509/511 (MN+).

NMR (200 MHz, DMSO-d6) : to 1.15 (t, 3H), of 1.78 (s, 3H), to 3.67 (s, 3H), of 3.69 (q, 2H), 4.53-in (s, 2H), 4,84 (s, 2H), equal to 4.97 (s, 1H), 5,08 (s, 1H), 5,69 (d, 1H), 6,97 (d, 1H),? 7.04 baby mortality (d, N), 7,17 (d, 1H), 7,25 (DD, 1H), 7,38 (m, 1H), 7,83 (d, 1H), 9,03 (d, 1H).

Comparative example 24

N-Ethyl-5-chloro-2-allyloxymethyl

The target compound was obtained SPO is malformed, and as the alkylating agent instead of metallicgold used allylbromide. Also, the product was isolated as free base, and not in the form of a hydrochloric salt. Yield: 67% (14.8 g). MS (Χ+): 226/228 (MN+).

NMR (250 MHz, DMSO-d6) : the 1.04 (t, 3H), 2.57 m (q, 2H), 3,68 (s, 2H), 4,58 (m, 2H), from 5.29 (DD, J=10 Hz, 2 Hz, 1H), 5.40 to (DD, J=16 Hz, 2 Hz, 1H), 6,04 (m, 1H), 6,95 (d, J=8 Hz, 1H), 7,19 (DD, J=8 Hz, 2 Hz, 1H), 7,38 (d, J= 2 Hz, 1H).

Comparative example 25

4-Methylthiazole-5-ylsulphonyl

2-Acetylamino-4-methylthiazole-5-ylsulphonyl (100 mg) was dissolved in hydrazine hydrate (1.1 ml) and the solution was stirred at ambient temperature for 2 hours. After adding water (20 ml), the mixture was extracted with ethyl acetate (550 ml). The combined organic extracts evaporated, and subjected to azeotropic distillation with toluene, and purified using IHSD (silica; 5% ethanol in dichloromethane), which was obtained 2-amino-4-methylthiazole-5-ylsulphonyl in the form of a waxy solid (170 mg, 46%).

MS: 192 (M+N)+.

NMR (MHz, DMSO-d6) : 2,3 (s, 3H), 7,25 (Shir. s, 2H), and 7.4 (Shir. s, 2H).

A solution of 2-amino-4-methylthiazole-5-ralfinamide (150 mg, 0.78 mmol) in THF (5.5 ml) for 30 minutes drop by drop in heating the reflux for 3 hours, and then added an additional portion amilnitrita (0.5 ml) and the reaction mixture was heated for another 16 hours. After that, the mixture was cooled, evaporated to dryness, and the residue was purified using IHSD (5-10% ethanol in dichloromethane), resulting in a received target compound as a light brown waxy solid (40 mg, 29%).

MS: 179 (M+N)+.

NMR (MHz, DMSO-d6) : 2,6 (s, 3H), and 7.8 (d, 2H), 9,1 (W, s, 1H).

Comparative example 26

6-[N-(5-Bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carbohydrazide

Butyl-6-[N-(5-bromo-2-(2-methylprop-2-EN-1-yloxy)-benzyl)-N-ethylamino]pyridazin-3-carboxylate (comparative example 4) (4.3 g, 9.3 mmol) was dissolved in ethanol (170 ml) was added hydrazine hydrate (17 ml, 330 mmol) and the mixture was heated under reflux for 16 hours. After removal of solvent in vacuo, the residue was treated with ethyl acetate and water (200 ml each). The organic phase was separated, and the aqueous phase re-extracted with ethyl acetate (2200 ml). The combined organic phases were dried with magnesium sulfate and concentrated in vacuo, resulting in a received target compound in the form of an oily substance, which was led when defending (3,66 g, 94, ,85 (lat. C., 2N), to 4.52 (s, 2H), 4,82 (s, 2H), equal to 4.97 (s, 1H), 5,08 (s, 1H), 6,97 (d, 1H), and 7.1 (m, 2H), 7,37 (DD, 1H), to 7.77 (d, 1H), and 9.8 (s, 1H).

Comparative example 27

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

6-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]pyridazin-3-carboxylic acid (example 8) (6.5 g) suspended in ethanol (30 ml) and carefully treated with concentrated sulfuric acid (1.5 ml). The reaction mixture was heated under reflux overnight, and then the organic solvent is evaporated. The residue was distributed between ethyl acetate and water and the organic phase was dried with magnesium sulfate and evaporated, resulting in a received target connection (5,86 g) as a brown solid.

MS (ESP+): 380 (M+N)+.

NMR (200 MHz, DMSO-d6) : of 1.16 (t, 3H), of 1.33 (t, 3H), and 3.7 (q, 2H), 4,35 (kV, 2H), amounts to 4.76 (s, 2H), 6,8 (d, 1H), and 7.1 (m, 2H), 7,26 (DD, 1H), 7,83 (d, 1H), 10,19 (Shir. s, 1H).

Comparative example 28

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

The target compound was obtained from butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino] pyridazin-3-carboxylate by the method described in Comparative example 9 (mixture of E:Z = 2:1).

NMR (200 MHz, DMSO-d6)d, 1H), 7,13 (d, 1H), and 7.4 (DD, 1H), 7,82 (d, 1H).

Comparative example 29

Ethyl-6-[N-5-bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino)pyridazine-3-carboxylate

A mixture of 6-[N-(5-bromo-2-(2-methylprop-2-EN-1-yloxy)benzyl)-N-ethylamino] pyridazin-3-carboxylic acid (example 2, compound 15), (2.1 g, 5.2 mmol) and carbonyldiimidazole (1.0 g, 5.9 mmol) was stirred in dry THF (25 ml) in an argon atmosphere for one hour at a temperature of 40-50oC. the resulting solution was added to the magnesium enolate derived from a mixture of ethylmalonate potassium (1.1 g, 6.5 mmol), triethylamine (1.2 ml, 8.6 mmol) and anhydrous magnesium chloride (0.7 g, 7.4 mmol) in acetonitrile (40 ml), and then the mixture was stirred at a temperature of 20-25oC for 2 hours in argon atmosphere.

The resulting mixture was stirred for 16 hours at 25oC, was heated under reflux for 30 minutes and then cooled and evaporated under reduced pressure. The residue was distributed between dichloromethane (100 ml) and 2 N. Hcl (100 ml). The organic layer was separated, dried with anhydrous magnesium sulfate, and filtered through a layer of silicon dioxide, while washing with ether. The combined filtrates evaporated and obtained target compound as a colourless gum (1.2 g).

1-4alkylamino, dis1-4alkylamino, cyano, C1-6alkoxy, S(O)pWITH1-6the alkyl (R= 0, 1 or 2), C1-6alkyl (optionally substituted by hydroxy-, amino-, halogen-, nitro-, cyano groups), S(O)pCF3(p= 0, 1 or 2), carbarnoyl,1-4allylcarbamate, di(C1-4alkyl)carbarnoyl,2-6alkenyl,2-6quinil,1-4alkoxycarbonyl,1-4alkanolamine,1-4alkanoyl(N-C1-4alkyl)amino, C1-4alkanesulfonyl, benzosulfimide, aminosulfonyl,1-4alkylaminocarbonyl, di(C1-4alkyl) aminosulfonyl, C1-4alkoxycarbonyl,1-4alkanoyloxy, C1-6alkanoyl, formals1-4alkyl, drifters1-3alkylsulfonyl, hydroxyimino1-6alkyl, C1-4alkoxyimino1-6alkyl and C1-6alkylcarboxylic; provided that the group-CH(R3)N(R2)B-R1and OD are in the 1,2-position relative to one another on ring carbon atoms and the ring atom in anthopology against-OD-linking group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted;

In represents pyridyl, pyridazin and represents carboxy, carboxy1-3alkyl, tetrazolyl, tetrazolyl1-3alkyl, or R1represents a group of formula-CONRaRa1where Rarepresents hydrogen or C1-6alkyl, a Ra1represents hydrogen, C1-6alkyl, carboxyphenyl, or Ra1and Rataken together with the nitrogen atom of amide group with which they are associated (NRaRa1) form amino acid residue, such as glycine, alanine, phenylalanine or phenylglycine; or R1represents a group of formula CONHSO2Rbwhere Rbrepresents C1-6alkyl, optionally substituted with halogen, hydroxy, nitro, cyano, amino, C1-4alkylamino, di-C1-4alkylamino, trifluoromethyl, C1-4alkoxy or1-4alkoxycarbonyl, 5 - or 6-membered heterocyclyl, 5 - or 6-membered heterocyclic1-3alkyl, where heterocyclyl means pyrrolidinyl or morpholinyl heteroaryl1-3alkyl, heteroaryl where heteroaryl means isoxazolyl, thiazolyl or thiadiazolyl, phenyl or phenyl-C1-3alkyl, each heteroaryl group, Rboptionally substituted C1-4alkanolamine or C1-6alkyl group; or R1represents a group of the formula-SO2N(Rc)(Rc1), where Rrepresents a group of formula (1A), (1B) or (1C):

< / BR>
< / BR>
where Y is sulfur;

Rdrepresents hydrogen or C1-4alkyl;

R2represents C1-6alkyl;

R3represents hydrogen;

D represents hydrogen, optionally substituted 5-7-membered carbocyclic ring containing one double bond, where the above optional substituents D include C1-4alkyl, C2-4alkenyl, C2-4quinil, halogen, hydroxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano, trifluoromethyl, oxo, C1-4alkanoyl, carboxy and carbarnoyl, or D represents a group of the formula

(CH2)nCH(R4) (R5)=C(R6R7,

where R4represents hydrogen, methyl or ethyl;

R5represents hydrogen, methyl, bromine, chlorine, fluorine;

R6represents hydrogen, C1-4alkyl;

R7represents hydrogen, C1-4alkyl, bromine, chlorine, fluorine;

n=0 or 1,

or their pharmaceutically acceptable salt or in vivo hydrolyzable ester, where in vivo hydrolyzable ester of carboxy - or hydroxy-group is chosen from pharmaceutically acceptable ester formed by C1-6alcohol, phenol or benzyl alcohol, SRAM; in vivo hydrolyzable ester of a hydroxy-group selected from alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (giving alkalicarbonate esters), dialkylaminoalkyl and carboxyethyl.

2. Connection on p. 1, characterized in that it R2represents methyl, ethyl or propyl.

3. The compound according to any one of paragraphs.1 and 2, characterized in that it R1represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula-CONRaRa1where Rarepresents hydrogen or C1-6alkyl, a Ra1represents C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rbrepresents optionally substituted C1-6alkyl, phenyl, or heteroaryl where these optional substituents defined above.

4. The compound according to any one of paragraphs.1-3, characterized in that it R1represents carboxy, tetrazolyl, or a group of the formula-CONHRa1where Ra1represents C1-4alkyl, or R1represents a group of formula CONHSO2Rbwhere Rbrepresents C1-4alkyl, 3,5-dimethylisoxazol-4-yl or 5-acetamido-1,3,4-thiazole-2-yl.

5. The connection on either the si, carbamoyl, C1-4allylcarbamate, di(C1-4alkyl)carbamoyl, C1-4alkanolamine, C1-6S(O)p-, C1-6alkanesulfonyl, benzosulfimide, C1-6alkanoyl, C1-6alkoxyimino1-4the alkyl or hydroxyimino1-4the alkyl.

6. The compound according to any one of paragraphs. 1-5, characterized in that it D represents hydrogen.

7. The compound according to any one of paragraphs. 1-6, characterized in that it D is a 5-6-membered carbocyclic ring containing one double bond (optionally substituted with stands), or a group of formula-CH2C(R5)= C(R6R7where R5, R6and R7are as they were defined in paragraph 1.

8. Connection on p. 1, characterized in that is any of the compounds described in examples 1-38, or its pharmaceutically acceptable salt.

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

10. The method of treatment of pain, wherein introducing an effective amount of the compounds of formula (1) defined in the PP.1-8, to a patient in need of pain.

is the formula CONRaRa1or a group of the formula CONHSO2Rbwhere Ra, Ra1, Rbhave the meanings given in paragraph 1, and R2, R3, n, a, b, and D are as defined above, or its pharmaceutically acceptable salt or in vivo hydrolyzable esters, characterized in that exercise, the release of the protective group in the compound of formula III

< / BR>
where R9is a protected carboxy;

R10is the same as R2defined in paragraph 1, and R3, n, a, b, and D are as defined in paragraph 1, to obtain the compounds of formula I, where R1represents carboxy, followed, if necessary, conversion of the compounds obtained in the compound of formula I, where R1represents a group of the formula CONRaRa1or a group of the formula CONHSO2Rbwhere Ra, Ra1, Rbhave the above values and/or their pharmaceutically acceptable salt or in vivo hydrolyzable ester.

12. Aromatic compounds of the formula III

< / BR>
where R9means carboxypropyl protected etherification C1-4alkyl group, R10matter listed for R2in paragraph 1 of the formula, and R3A , b, D are the values of casilino/pyridazin-3-carboxylic acid, or its pharmaceutically acceptable salt or in vivo hydrolyzable ester.

Priority points:

20.06.1995 - p. 1 (with the exception of compounds where RA1is carboxyphenyl, RA1and Randtaken together with the nitrogen atom of amide groups form a specified amino acid residue, Rbrepresents C1-6alkyl, substituted amino, C1-4alkylamino, di-C1-4alkylamino, R1- a group of SO2N(RwithRC1or a group of formula (IA), (IB), (IC), D represents an optionally substituted 5-7-membered carbocyclic ring containing one double bond, R4is ethyl, R5- bromine, fluorine, R6- C1-4alkyl, R7- C1-4alkyl, bromine, chlorine, fluorine), p. 2, p. 3 (with the exception of compounds where Rboptionally substituted C1-6alkyl), p. 5, the pharmaceutical composition under item 9, which contains these compounds, and a method of pain relief on p. 10 where the use of these compounds, the method according to p. 11 (except for the producing compounds of formula I, where RA1or RA1and Rand, Rband D have the above values);

25.01.1996 - p. 1 for compounds where D represents hydrogen, optionally substituted 5-7-membered carbocyclic ring containing the Ohm, chlorine, fluorine, p. 6, PP.9-11 (where use and get these connections);

17.06.1996 - p. 1, where RA1is carboxyphenyl, or RA1and Randtaken together with the nitrogen atom of amide groups form a specified amino acid residue, Rbrepresents C1-6alkyl, substituted amino, C1-4alkylamino, di-C1-4alkylamino, R1- a group of SO2N(RwithRC1where Rwithand RC1have the meanings given in paragraph 1, or R1the group of formula (IA), (IB), (IC), PP.4, 7, 8 and PP.9-11 (where use and get these connections), PP.12-13.

 

Same patents:

The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH

The invention relates to the derivatives of pyrrolidine formula I

< / BR>
where R1- H, C1-C6alkyl; phenyl, possibly substituted; biphenyl, possibly substituted; 1H, 5H - pyrido [3,2,1-ij] chinolin; phenyl WITH1-C6alkyl, optionally substituted; biphenyl WITH1-C6alkyl, optionally substituted; biphenylcarboxylic; terphenyl; naphthyl, optionally substituted; Z denotes-S-, -O-, -och2-, -N(R16), where R16- H, C1-C6alkyl, C3-C8cycloalkyl1-C6alkyl, panels1-C6alkyl, a chemical bond; X1means-CO-, -(CH2)r-CO-N(R17), where R17means H, C1-C6alkyl (where r = 0 or 1), -CH2NHSO2-, -(CH2)s-N (R18)-CO- (where R18- N, s=1-3), - CH2NHCОСН2O-, -CH2N (R19Of PINES = CH- (where R19- H, -CH2OCH2-, -CH2-N (R20)-CH2- (where R20- H, C1-C6alkyl, C1-C6alkylsulphonyl, phenylcarbinol)1-C5alkylen,2-C4albaniles, a chemical bond; X2- phenylene, optionally substituted hydroxy, theoffender, purandar, piperidinyl,< / BR>
< / BR>
< / BR>
R2and R3each - H; and R4- phenyl, possibly substituted with halogen; R5- phenyl, possibly substituted; a cycle of G is phenyl,3-C7cycloalkyl, pyridyl, thienyl; loop J is phenyl; L is phenyl; p=0-2;----- means the presence or absence of chemical bonding;displays a CIS - or TRANS-configuration D relative to E; provided that X1means-CH2NHCО-, X2means 1,4-phenylene and X3means a chemical bond or a C1-C5alkylen, when the carbon atom bound CD and adjacent carbon atom in the cycle are connected by a simple relation and V1does not mean a chemical bond, when X1means-CH2O-; and pharmaceutically acceptable salt or hydrate of the compound

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

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 СОNRaRa1where 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; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH

The invention relates to new isoxazol derivative of formula 1, where D represents hydrogen; one of a and b is a group (1) -E-N= C(NR25R26)NR27R28; E represents a direct link or alkilinity group; R25and R26each represents, independently, hydrogen; C1-4-alkyl; -(CH2)n-CO2R32, n is an integer of 1-3, and R32represents hydrogen, C1-4-alkyl; -(CH2)m-CO2R35m is 2 or 3 and R35represents hydrogen, C1-4-alkyl; -(CH2)mHE, m defined above, or -(CH2)n-C(O)R36n is defined above and R3represents hydrogen, C1-4-alkyl; and t

The invention relates to substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

The invention relates to new derivatives of kalaidjieva, fungicides, method of combating fungal diseases of crops and intermediate compounds for obtaining

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to new derivatives of benzoxazinone General formula (I), where R1means N or carboxyethyl, R2represents hydrogen or alkyl, and R3is a different derivatively of amino acids, dipeptides and hydrazones acid groups, respectively, their conjugates with active substances, such as residues from a number of penicillin

The invention relates to compounds: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl] methyl]-N,3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide and their pharmaceutically acceptable salts, such as lithium, sodium or potassium salt or a salt with a base, which is an organic amine

The invention relates to new substituted pyrazolylborate General formula (I) in which R1-R6have the meanings given in the description of the invention
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