Condensed 5-membered heterocyclic compounds or their salts are active in the inhibition of aggregation

 

(57) Abstract:

Usage: as drugs active on the inhibition of aggregation. The inventive condensed 5-membered heterocycles f ly (1) with certain literal values active in the inhibition of aggregation. table 1. (I).

The invention relates to new chemical compounds with valuable pharmacological properties, namely, condensed the five-membered heterocycles of General formula

(1) where R1the atom of hydrogen, fluorine, chlorine or bromine, alkyl-, aralkyl-, aryl-, heteroaryl-, R3O-, (R3)2N-, R4CO - NR3-, alkylsulfonyl - NR3-, arylsulfonyl - NR3-, R3S-, R3SO, R3S2O-, or R5group, and R3is a hydrogen atom, an alkyl group containing from 1 to 6 carbon atoms, aryl, heteroaryl, kalkilya, carboxialkilnuyu or alkoxycarbonylmethyl group;

R4a hydrogen atom, alkyl or CNS group containing 1-6 carbon atoms, aryl, heteroaryl or kalkilya group containing 1-6 carbon atoms in the alkyl part;

R5azetidinone, pyrolidine, hexamethyleneimino or heptathlete oxygen, sulfenyl-, sulfinil or sulfonylureas or aminogroups, which can be substituted for R3, R4CO4, alkylsulfonyl or arylsulfonyl, and R3and R4have the above values.

X atom oxygen, sulfur or nitrogen or the group NR2and

R2a hydrogen atom, a linear or branched alkyl group containing 1-15 carbon atoms, linear or branched alkenylphenol and alkylamino group containing 3-10 carbon atoms, and a double and a triple bond may not be directly connected to the nitrogen atom, cycloalkyl or cycloalkenyl group containing 3-7 carbon atoms in cycloalkyl parts, aryl or heteroaryl group, alkyl group containing 2-6 carbon atoms, which, starting from a position to the nitrogen atom-NR2groups, substituted R3O-, (R3)2N-, R4CO-NR3-, alkylsulfonyl-NR3-, aryl - sulfonyl-NR3- alkylsulfanyl, alkylsulfonyl-, alkylsulfonyl - or R5groups;

or an alkyl group containing 1-6 carbon atoms, which is substituted by one or two aryl groups, heteroaryl group, groups of R6OCO-, (R3)2NCO-, R5CO-, R3and R5have the above meanings and R6means hydrogen, an alkyl group containing 1-6 carbon atoms, cycloalkyl group containing 5-7 carbon atoms, or aracelio group

Y NO-group, nitrogen atom, or unsubstituted or substituted alkyl group methine group;

Z1, Z2, Z3, Z4that may be the same or different represent methine groups, carbon atoms, aminogroup or nitrogen atoms, and at least one of the residues Z1-Z4must contain a carbon atom, and one or two adjacent to the nitrogen atom of the methine group may be substituted by carbonyl groups,

Z5and Z6mean carbon atoms or one of the residues Z5or Z6means a nitrogen atom and the other carbon atom,

And means cyano, amino, linear or branched aminoalkyl group containing 1-4 carbon atoms, amidino-, guanidino or guanidinoacetic group, and amino-, aminoalkyl-, amidino-, guanidino and guanidinoacetic groups at one of the nitrogen atoms, one or two hydrogen atoms may be substituted by one or two alkyl groups containing 1-4 carbon atoms, or one atom modernising group with the total number of carbon atoms 4-6, alkylcarboxylic group with the total number of carbon atoms 2-5, arylcarbamoyl, aryloxyalkyl, arelaxation, alkanolammonium, cycloalkylcarbonyl, uralenergosetstroy, ariloxipicolinamidei-, phosphono-, dialkylphosphorous - or O-alkyl-phosphonopropyl in which alcoholnye part contains 2-7 carbon atoms, and cycloalkenyl parts contain 4-8 carbon atoms, and metaxylene part can be substituted cycloalkyl group containing 3-6 carbon atoms, Uralkaliy, aryl or alkyl group or two alkyl groups, which together with the methylene carbon atom may also form a five - or six-membered ring, or, if means a cyclic amine containing 4-7 members, means hydrogen or an alkyl group connected to the nitrogen atom of aminogroup,

In the mean fenelonov group, which may be one or two times substituted by fluorine atoms, chlorine or bromine, alkyl group, hydroxy-group, alkoxygroup, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl groups, the nitro-group, amino group, alkylamino, dialkylamino, alkylcarboxylic, alkylsulfonamides or two methine groups in the above filinovich groups can be substituted respectively with one or two nitrogen atoms, or cycloalkenyl group containing 3-7 carbon atoms, and in four - or five-membered cycloalkanones ring one ring member means a nitrogen atom in the six - or semikina cycloalkylation ring one or two members of the ring means a nitrogen atom, can be binding to carbon atoms of adjacent residues via the nitrogen atom,

indianremoval group or 1,2,3,4-tetrahydronaphthalene group, which is saturated ring associated with the residue and the aromatic ring is connected with balance or with condensed five-membered heterocycle,

With means of communication, alkylenes group, Allenova group, -O-alkylenes group, -S-alkylenes group, -NH-alkylenes group, -N(alkyl)-alkylenes group-alkylene-NH-group, -alkylene-N-(alkyl)-group,- SO - or-SO2-alkylenes group;

D represents a relationship or alkilinity group;

E. means alkylenes group containing 1-7 carbon atoms, alkenylphenol or alkenylphenol group containing 2 to 7 carbon atoms, and a double or triple bond may not be directly linked to the nitrogen atom Z1-Z2-Z3-Z4group, or, if E is not connected directly to the nitrogen atom Z1-Z2-Z33, alkylsulfonyl or arylsulfonyl, and R3and R4have the above values or cycloalkenyl group containing 4-7 carbon atoms, and in four - or five-membered cycloalkanones the one ring member of the ring can mean a nitrogen atom in the six - or semikina cycloalkylation ring one or two members of the ring can mean a nitrogen atom and optionally adjacent to the nitrogen atom, methylene group may be replaced by a carbonyl group, and at the same time may occur, binding to carbon atoms of adjacent residues via the nitrogen atom,

F denotes a bond, a linear or branched alkylenes group containing 1-6 carbon atoms, linear or branched alkenylamine or alkynylamino group containing 2-6 carbon atoms, and a double or triple bond may not adhere directly to the heteroatom or triple bond balance E and the above-mentioned Allenova, Alcanena and akinlana group can be a substituted aryl group, -R6-, -CON(R3)2- or-CO-N(R3)-alkyl groups, and remnants of R3and R6have the above values and the alkyl portion of-CO-N(R3)- alkyl gr/SUB> and R7and R8may be the same or different and mean a hydrogen atom, aryl, or-COO-R6group, where R6defined above.

cycloalkenyl, alkylene-cycloalkyl and cycloalkyl-alkylenes group containing 4-6 carbon atoms in cycloalkanones parts, which are in the ring CH group is replaced by a nitrogen atom, and linking with neighboring residue E can also occur through the nitrogen atom, if binding occurs through the carbon atom of the residue is E, and if D is a bond, E is an oxygen atom and F is an alkyl group, And may not be directly linked to a phenyl ring amino - or allmineral, and if at the same time X is a sulfur atom and Y is a nitrogen atom, group a-b-C may not be 4-atsetamino-piperazinone, and

G means not associated with the heteroatom balance E carbonyl group which may be substituted by a hydroxyl group, arylalkylamines containing 3-4 carbon atoms in alkenylphenol part, alkoxygroup containing 1-8 carbon atoms in which the alkoxy residue with 1 to 5 carbon atoms may be substituted by an aryl group or alkoxylated with 1-3 carbon atoms in the 1-, 2 - or 3-positions may be samewe the-2-on-1-yl-, morpholino, thiomorpholine - or 1-oxido-thiomorpholine, cycloalexie containing 4-8 carbon atoms which may be substituted by 1-3 alkyl groups, possibly substituted by 1-3 methyl groups, benzocyclobutene, benzocyclobutene, bicycloalkanes and bicyclogermacrene containing 4-8 carbon atoms in cycloalkyl parts and 6-8 carbon atoms in bicycloalkyl part, alkanolammonium with the total number of carbon atoms 2-7 in alkanoyloxy part, cycloalkanoprogesterones with the total number of carbon atoms 4-8 in cycloalkanones part, alkoxycarbonylmethyl with 1-6 carbon atoms in the alkyl part, cycloalkylcarbonyl with 3-7 carbon atoms in cycloalkyl part, rolexcellini, arachnologists, aryloxypropanolamine or urlconnection.setrequestproperty, in which detoxicate may be substituted by an alkyl group with 1-6 carbon atoms, cycloalkyl group having 3-7 carbon atoms, aranceles or aryl groups,

alphagroup, phosphonopropyl, alkylphosphonate or tetrazol-5-yl group,

and their tautomers, mixtures of isomers, or individual isomers and their salts, psli do not specify anything else, the above-mentioned alkyl-, alkylene and alkoxygroup contain 1-3 carbon atoms. In addition, under the expression "aryl group" is understood phenyl group which may be from one to three times substituted by fluorine, chlorine, bromine or iodine, alkyl, triptorelin, nitro-, amino-, alkylamino, dialkylamino, alkanolamine, alkylsulfonyl-, aminosulfonyl-, alkylaminocarbonyl-, dialkylaminoalkyl-, hydroxy-, alkoxy-, arakaki-, carboxy-, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylsulfanyl, alkylsulfonyl or alkylsulfonyl, moreover, the substituents may be the same or different, or naftalina group;

the term "heteroaryl group" is understood five-membered heteroaromatic ring, which contains aminogroup, oxygen atom or sulfur, from one to two nitrogen atoms and an oxygen atom, or sulfur, or aminogroup and from one to three nitrogen atoms, or six-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atom, and the above rings may be precondensation phenyl ring, and in addition they can be mono - or di - substituted by fluorine, chlorine, bromine, alkyl group, alkoxy-, hydroxy what oppai, containing 1-4 carbon atoms.

Preferred are those compounds of General formula (I), in which

R1means hydrogen, fluorine, chlorine or bromine, alkoxycarbonyl - or N-alkoxycarbonyl-alkylamino containing 1-4 carbon atoms in the CNS, alkyl-, hydroxy-, alkoxy-, phenylacetic-, amino-, alkylamino, dialkylamino-, pyrrolidino-, piperidino, alkylcarboxylic or alkylsulfonamides, and, unless otherwise nothing else, alkyl and CNS part can contain 1-3 carbon atoms, and optionally alkyl part of alkylamino and dialkylamino can be substituted by carboxy or alkoxycarbonyl containing 1-3 carbon atoms in the alkyl part;< / BR>
X means an oxygen atom, sulfur or nitrogen or the group NR2where R2means a hydrogen atom, a linear or branched alkyl group containing 1 to 14 carbon atoms, alkenylphenol or alkenylphenol group containing 3 or 4 carbon atoms, and a double or triple bond cannot attach directly to the nitrogen atom, alkyl group containing 1-5 carbon atoms, which is substituted by carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl - Neal, 2 - or 4-imidazolyl or perivleptos, piperidinecarbonitrile, in which the methylene group in the 4 position may be replaced by oxygen atom, sulfenyl, sulfinil, sulfonyl-, imino-, alkylamino or phenylalkylamine groups, or phenyl group which may be mono - or tizamidine chlorine or bromine, amino-, hydroxy-, alkoxy - or alkyl group, or two phenyl groups,

cycloalkyl group having 3-7 carbon atoms, pyridyloxy group, phenyl group which may be mono - or tizamidine fluorine, chlorine or bromine, alkyl, CNS, alkylsulfanyl, alkylsulfonyl or alkylsulfonyl groups, the alkyl group containing 2-4 carbon atoms, which is substituted in the 2, 3 - or 4-Ohm position, hydroxy-, alkoxy-, alkylsulfanyl, alkylsulfonyl-, alkylsulfonyl-, 1-imidazolyl or pyrrolidinone or piperidino, in which the methylene group in the 4 position may be replaced by oxygen atom, sulfenyl-, sulfinil, sulfonyl-, imino-, alkylamino or phenylalkylamines, or alkyl group containing 2-6 carbon atoms which is substituted in the 2, 3, 4, 5 or 6th position amino, alkylamino or dialkylamino group, and, if not governace NO-group, the nitrogen atom, or possibly substituted alkyl group with 1-3 carbon atoms methine group,

Z1, Z2, Z3and Z4may be the same or different and mean methine group, carbon atoms, aminogroup or nitrogen atoms, and at least one of the residues Z1-Z4must contain a carbon atom and one or two neighboring nitrogen atom of the methine group may be substituted by carbonyl groups.

Z5and Z6mean carbon atoms or one of the residues Z5or Z6means a nitrogen atom and the other carbon atom

And means cyano, amino, linear or branched aminoalkyl group containing 1-4 carbon atoms, amidinopropane, guanidinium or guanidinoacetic group, and in the above-mentioned amino, aminoalkyl-, amidino-, guanidino or guanidinoacetic groups at one of the nitrogen atoms, the hydrogen atom may be substituted by an alkyl group containing 1-4 carbon atoms, alkoxycarbonyl group with the total number of carbon atoms from two to five, generalconditions, vinyloxycarbonyl - XI - or benzoline group or alcoholcontaining group, which alkanoyloxy part of the if is cyclic Eminem, also means a hydrogen atom or alkyl group with 1-3 carbon atoms that are attached to the imine nitrogen atom,

In the mean fenelonov group which may be substituted once or twice by fluorine atoms, chlorine or bromine, alkyl, hydroxyl, CNS, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, nitro-, amino-, alkylamino, dialkylamino, alkylcarboxylic, alkylsulfonate or triptorelin groups, while the substituents may be the same or different, alkyl and CNS part can contain 1-3 carbon atoms,

piperidino or piperazinylcarbonyl group, which can also through the nitrogen atoms to join the carbon atom adjacent residues,

indianremoval or 1,2,3,4-tetrahydronaphthalene group, which is saturated ring associated with the residue and the aromatic ring residue or a condensed five-membered heterocycle,

With means of communication, methylene-, ethylene-, phenylene-, O-methylene, S-methylene-, SO-methylene-, SO2-methylene -, or-N(alkyl)-MEDIENGRUPPE that are linked by a heteroatom with balance, or methylene-N(alkyl)-group, and the alkyl part can contain 1-3 carbon atom,

D represents a relationship, met alkynylamino group, containing 3-5 carbon atoms, and a double or triple bond may not be directly linked to the nitrogen atom Z1-Z2-Z3-Z4group, or, if E is not connected directly to the nitrogen atom Z1-Z2-Z3-Z4group means-O-, -S-, -SO-, -SO2-, -NH-, -N(alkyl)-, -N(CO alkyl)-, -CO-, -NH-CO-, -N(alkyl)-CO-, -CO-NH-, -CO-N(alkyl)-, -SO2NH-, -SO2-N(alkyl)- or alkylsulfonamides, and the alkyl part can contain 1-3 carbon atoms, cyclohexylprop, piperidinyl or piperidinovomu, in addition the neighboring nitrogen atom of the methylene group may be replaced by a carbonyl group, and at the same time may occur, binding to carbon atoms of adjacent residues through the nitrogen atom,

F represents a relationship, alkylenes group containing 1-4 carbon atoms which may be substituted by phenyl, carboxyl, alkoxycarbonyl, generalquartiermeister or alkylaminocarbonyl group, and alkylaminocarbonyl group in the alkyl part, which may contain 1-3 carbon atoms may be substituted by phenyl, hydroxyproline, metoksifenilny, benzyloxyaniline, carboxyl, alkoxycarbonyl or generalk onlineu group

cyclohexylamino, cyclohexene-alkylenes or alkyltrimethylenedi group containing 1-3 carbon atoms in the alkyl, alkilinity and CNS side, piperidinylidene or pyrrolidinium group, which can also be linked through the nitrogen atom with neighboring residue is E, if the communication takes place via a carbon atom of the residue is E, and if D is a bond, E denotes an oxygen atom and F-alkyl group, And may not be directly attached to the phenyl ring amino or allmineral, and

G means not associated with the heteroatom balance E carbonyl group which may be substituted by a hydroxy-group, cinnamoyloxy, alkoxygroup containing 1-6 carbon atoms, in which alkoxylates with 1-5 carbon atoms may be substituted by phenyl group, or alkoxylated with 1-3 carbon atoms in the 1-, 2 - or 3-position may be substituted naftilos group, cycloalkyl group, cycloalkyl group containing 5 or 6 carbon atoms, peredelnoj group or a 2 - or 3-position of pyrrolidin-2-on-1-yl group, cycloalexie, containing from 5 to 8 carbon atoms, inanimate-, 1,2,3,4-tetrahydronaphthalene, bicycloheptane or bicycloheptene what Ruppel, containing 2-5 carbon atoms in alkanoyloxy part, alkoxycarbonylmethyl containing 1-2 carbon atoms in the alkyl part, or cycloalkylcarbonyl containing 5 or 6 carbon atoms in cycloalkyl part, in which detoxicate can be substituted by an alkyl group,

On-alkylphosphonium containing 1-3 carbon atoms, sulfo-, phosphono or tetrazol-5-yl group, as well as their tautomers, mixtures of isomers, individual isomers and their salts with inorganic or organic acids or bases.

Especially preferred compounds of General formula (I), in which

R1means a hydrogen atom, fluorine, chlorine or bromine, alkoxy or fenilalanina containing 1-3 carbon atoms in the CNS part, alkoxycarbonyl - or N-alkoxycarbonylmethyl containing 1-4 carbon atoms in the CNS part, a methyl, hydroxyl, amino, methylamino, dimethylamino, N-carboxymethylamino-, N-carboxy - methyl-methylamino-, N-methoxycarbonyl - methyl-methylamino-, acetylamino-, piperidino or methylsulfonylamino,

X means an oxygen atom, sulfur or nitrogen or the group-NR2and

R2means a hydrogen atom, a linear alkiline group, containing 1-3 carbon atoms, which is substituted by carboxy, methoxycarbonyl-, etoxycarbonyl, aminocarbonyl, methylaminomethyl, dimethylaminoethyl, benzylamino-, carbonyl, fenilatilmalonamid, carboxymethylaminomethyl, methoxycarbonylaminophenyl or perivleptos or piperidinecarbonitrile group in which the methylene group in the fourth position may be substituted by oxygen atom, sulfanilic, sulfanilic, sulfonyloxy, imino - or benzylaminopurine,

altergroup containing 1-4 carbon atoms, which is substituted by phenyl group, which in turn may be one or two times substituted by a bromine atom or chlorine, amino, hydroxy, methoxy or methyl groups or two phenyl groups,

cycloalkyl group containing 3-6 carbon atoms, pyridyloxy group, phenyl group, which may be one or two times substituted by chlorine atoms, methyl, metaxylene, methylsulfinyl, methylsulfonyl or methylsulfonylamino groups, while the substituents may be the same or different,

alkyl group containing 2 or 3 carbon atoms, which is substituted in the 2 or 3 position hydroxyl, metaxylene, methylsulfone is in which the methylene group in the 4 position may be replaced by oxygen atom, Solferino, sulfanilic, sulfonyloxy, imino - or benzylaminopurine, or

alkyl group containing 2-6 carbon atoms, in which 2, 3, 4, 5 or 6th position of the substituted amino group,

Y means NO-group, nitrogen atom or a methine group which may be substituted methyl group,

Z1, Z2, Z3, Z4 are the same or different and mean methine group, carbon atoms, aminogroup or nitrogen atoms, and at least one of the residues Z1-Z4 must contain a carbon atom and one or two adjacent to the nitrogen atom of the methine group may be substituted by carbonyl groups,

Z5 and Z6 mean carbon atoms or one of the remnants of Z5 or Z6 means nitrogen, and the other carbon

And means amino group, linear or branched aminoalkyl group containing 1-3 carbon atoms, amidino-, guanidino or guanidinium group, and in the above-mentioned amino, aminoalkyl-, amidino-, guanidino or guanidinosuccinic groups hydrogen at the nitrogen atom may be substituted by an alkyl group containing 1-4 carbon atoms, alkoxycarbonyl group with the total number of carbon atoms 2-5, benzyloxycarbonyloxy group, acetylcysteamine group, dimethylphosphoric - Illora or bromine, methyl, hydroxyl or metaxylene group

pyridinylamino group or cycloalkenyl group containing 3-6 carbon atoms, indianremoval or 1,2,3,4-tetrahydronaphthalene group, which is saturated ring attached to the residue and the aromatic ring attached to the residue With or condensed the five-membered heterocycle,

piperidinylidene or piperazinylcarbonyl group, which can also be through the nitrogen atoms attached to carbon atoms adjacent residues,

With means of communication, fenelonov or-O-methylene group,

D means the bond or methylene group,

E. means alkylenes group containing 3-5 carbon atoms, alkenylamine group containing 3-5 carbon atoms and a double bond may be attached directly to the nitrogen atom-Z1-Z2-Z3-Z4-group, or if E is not attached directly to the nitrogen atom of Z1-Z2-Z3-Z4-group, mean-O-, -S-, -SO-, -SO2-, -NH-, -N(methyl)-, -N(acetyl)-, -N(S2CH3)-, -CO-, -NH-CO-, -N(CH3)-CO-, -CO-NH-, -CO-N(CH3)-, -SO2-NH - OR-SO2-N(CH3)-group, piperidinylidene, piperazineethanol or hydroxy-piperazinylmethyl group, and the nitrogen atoms can also be linked to the carbon atoms of adjacent residues,

F represents a relationship, alkylenes GRU, unselectable, phenylethylenediamine, (methoxyphenyl)ethylaminoethanol or alkylaminocarbonyl group, and alkylaminocarbonyl group in the alkyl part contains 1 to 4 carbon atom may be substituted by phenyl, hydroxyproline, metoksifenilny, carboxyl or benzyloxycarbonyloxy group or optionally other carboxy - or benzyloxycarbonyl groups

piperidinylidene or pyrrolidinium group, which can also be through the nitrogen atom linked to the neighbouring residue is E, if the communication occurs through the nitrogen atom of residue E,

cyclohexylamino or cyclohexylmethanol group, and, if D is a bond, E is an oxygen atom and F alkyl group, And may not be directly linked to the phenyl ring amino - or allmineral,

G means not associated with the heteroatom balance E carbonyl group which is substituted by a hydroxyl group, alkoxygroup containing 1-6 carbon atoms which may be substituted in positions 1-5 phenyl group or 1-or 2-Ohm position cyclohexyl-, naphthyl - or perivleptos or 2nd position pyrrolidin-2-on-1-yl group, cinnamoyloxy, cycloalexie, stereopol with the total number of carbon atoms 2-5 in alkanoyloxy part, alkoxycarbonylmethyl containing CNS parts 1-3 carbon atoms, or cyclohexyloxycarbonyloxy in which methoxy-part can be substituted methyl group,

sulfo-, phosphono-, O-methyl-phosphono or tetrazol-5-yl group.

The object of the invention are, in particular, those compounds in which

R1 means hydrogen, methyl group, methoxy group, methylaminopropyl, dimethylaminopropyl, N-butyloxycarbonyl, N-isobutylacetophenone, N-carboxymethyl-amino group, N-carboxymethyl-methylaminopropyl, N-methoxycarbonyl-methyl-amino or N-methoxycarbonylmethyl-methylaminopropyl,

X means an oxygen atom or nitrogen or a-NO2 group, and

R2 means a hydrogen atom, a linear or branched alkyl group containing 1 to 14 carbon atoms, the alkyl group containing 1-3 carbon atoms, which is substituted by carboxy or methoxycarbonyl group

alkyl group containing 1-4 carbon atoms, which is substituted by phenyl group, which may in turn be substituted once or twice by bromine, amino or methoxypropane, two phenyl groups or peredelnoj group

Alki who sing, in which the methylene group in the 4 position is replaced by aminogroups, benzylaminopurine, sulfanilic, sulfanilic or sulfonyloxy group

Z1, Z2, Z3, Z4are the same or different and mean methine group, carbon atoms, aminogroup or nitrogen atoms, and at least one of the residues Z1-Z4must contain a carbon atom and one or two adjacent to the nitrogen atom of the methine group may be substituted by carbonyl groups,

Z5and Z6mean carbon atoms or one of the residues Z5or Z6mean nitrogen and the other is carbon,

And means amino group, linear or branched aminoalkyl group containing 1-3 carbon atoms, amidino-, guanidino or guanidinium group, and in the above-mentioned amino, aminoalkyl-, amidino-, guanidino or guanidinosuccinic groups hydrogen at the nitrogen atom may be substituted by an alkyl group containing 1-4 carbon atoms, alkoxycarbonyl group with the total number of carbon atoms 2-5, benzyloxycarbonyloxy group, acetylcysteamine group, dimethylphosphoric or diethylphosphine group

B means fenelonov group, which is Elenovo group or cycloalkenyl group, containing 3-6 carbon atoms, indianremoval or 1,2,3,4-tetrahydronaphthalene group, which is saturated ring attached to the residue and the aromatic ring attached to the residue With or condensed the five-membered heterocycle,

piperidinylidene or piperazinylcarbonyl group, which can also be through the nitrogen atoms attached to carbon atoms adjacent residues,

With means of communication, fenelonov or-O-methylene group,

D means the bond or methylene group,

E. means alkylenes group containing 3-5 carbon atoms, alkenylamine group containing 3-5 carbon atoms and a double bond may be attached directly to the nitrogen atom-Z1-Z2-Z3-Z4group or if E is not attached directly to the nitrogen atom of Z1-Z2-Z3-Z4group means-O-, -S-, -SO-, -SO2-, -NH-, -N(methyl)-, -N(acetyl)-, -N(S2CH3)-, -CO-, -NH-CO-, -N(CH3)-CO-, -CO-NH-, -CO-N(CH3)-, -SO2-NH - or-SO2-N(CH3)-group, piperidinylidene, piperazineethanol or hydroxy-piperazinylmethyl group, and the nitrogen atoms can also be linked to the carbon atoms of adjacent residues,

F represents a relationship, alkylenes Goy, benzyloxycarbonyloxy, phenylethylamine - Niley, (methoxyphenyl)ethylaminoethanol or alkylaminocarbonyl group, and alkylaminocarbonyl group in the alkyl part contains 1 to 4 carbon atom may be substituted by phenyl, hydroxyproline, metoksifenilny, carboxyl or benzyloxy - bonalnoy group or optionally other carboxy - or benzyloxycarbonyl groups,piperidinylidene or pyrrolidinium group, which can also be through the nitrogen atom linked to the neighbouring residue is E, if the communication occurs through the nitrogen atom of residue E,

cyclohexylamino or cyclohexylmethanol group, and, if D is a bond, E is an oxygen atom and F alkyl group, And may not be directly linked to the phenyl ring amino - or allmineral,

G means not associated with the heteroatom balance E carbonyl group which is substituted by a hydroxyl group, alkoxygroup containing 1-6 carbon atoms which may be substituted in positions 1-5 phenyl group or 1-or 2-Ohm position cyclohexyl-, naphthyl - or perivleptos or 2nd position pyrrolidin-2-on-1-yl group, cinnamoyloxy, cycloalexie containing the total number of carbon atoms 2-5 in alkanoyloxy part, alkoxycarbonylmethyl containing CNS parts 1-3 carbon atoms, or cyclohexyloxycarbonyloxy - group, in which methoxy-part can be substituted methyl group,

sulfo-, phosphono-, O-methyl-phosphono or tetrazol-5-yl group.

The object of the invention are, in particular, those compounds in which

R1means hydrogen, methyl group, methoxy group, methylaminopropyl, dimethylaminopropyl, N-butyloxycarbonyl, N-isobutylketone - methylaminopropyl, N-carboxymethyl-amino group, N-carboxymethyl-methylaminopropyl, N-methoxycarbonyl-methyl-amino group or N-methoxycarbonylmethyl-methyl - amino group,

X means an oxygen atom or nitrogen, or-NR2group, and

R2means a hydrogen atom, a linear or branched alkyl group containing 1 to 14 carbon atoms, the alkyl group containing 1-3 carbon atoms, which is substituted by carboxy or methoxycarbonyl group

alkyl group containing 1-4 carbon atoms, which is substituted by phenyl group, which may in turn be substituted once or twice by bromine, amino or methoxypropane, two phenyl groups or pyridi the amino - AI piperidinol, in which the methylene group in the 4 position is replaced by aminogroups, benzylaminopurine, sulfanilic, sulfanilic or sulfonyloxy group

Y means NO-group, nitrogen atom or methine group;

Z1, Z2, Z3and Z4may be the same or different and mean methine group, carbon atoms, aminogroup or nitrogen atoms, and at least two of the residues of Z1-Z4must contain carbon atoms and one or two adjacent to the nitrogen atom of the methine group may be substituted by carbonyl groups;

Z5and Z6mean carbon atoms or one of the residues Z5or Z6the nitrogen atom and the other of these residues carbon atom,

And means aminomethyl or amidinopropane, in which one of the nitrogen atoms of the hydrogen atom may be substituted methoxycarbonyl group

B means fenelonov group;

With bond or-O-methylene group;

D link;

E. means alkylenes group containing 3 or 4 carbon atoms or, if E is not directly linked to the nitrogen atom Z1-Z2-Z3-Z4group means-O-, -NH-CO - or-CO-NH-group;

F link or alkilinity group containing 1 to 3 utili cyclohexyloxy,

their tautomers, mixtures of isomers, individual isomers and their salts, in particular their physiologically tolerated salts with inorganic or organic acids.

The new compounds of General formula (1) are obtained, for example, the following known methods:

a) to obtain compounds of General formula (1), in which G denotes a carboxyl group, carry out the hydrolysis, treatment with acids, thermolysis or hydrogenolysis of the compounds of General formula

(2)

in which

A to F, R1, Z1to Z6X and Y have the above values and

G1that is linked to a carbon atom, means the group transferred to the carboxyl group.

For example, you can translate functional derivatives of carboxylic groups, such as unsubstituted or substituted amides, esters, complex thioethers, trimethylsilyloxy esters, complex orthoepy, complex aminoether, amidine or anhydrides, or a nitrile group into a carboxyl group by hydrolysis of esters with tertiary alcohols, such as tert.butyl ether, transferred to a carboxyl group by treatment with acid or thermolysis, esters with arachnology, such as benzyl ether, transferred to a carboxyl GRU acid is transferred to bis(hydroxycarbonyl)methyl group, which then decarboxylase.

The hydrolysis should be carried out in the presence of acid, for example hydrochloric, sulphuric, phosphoric, trichloroacetic or triperoxonane, in the presence of a base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, in a suitable solvent, such as, for example water, methanol, a mixture of water/methanol, ethanol, a mixture of water/ethanol, water/isopropanol, water/tetrahydrofuran or water/dioxane at temperatures between -10)aboutWith and (120)aboutWith, for example at temperatures between room temperature and the boiling temperature of the reaction mixture. When processing an organic acid, for example, trichloroacetic or triperoxonane, in the presence of alcoholic hydroxyl groups occurs simultaneously translating them into the appropriate alloctype.

If G1in the compound of the formula (2) denotes cyano or aminocarbonyl, these groups can be converted to carboxyl group by using a nitrite, e.g. sodium nitrite, in the presence of acid, for example sulphuric, which should be applied simultaneously as solvent at a temperature between 0aboutand 50about.

If G1in the compound of the formula (2) means, for example tert.butyloxycarbonyl the traveler, ant, n-toluensulfonate, sulfuric, phosphoric or polyphosphoric, if necessary in an inert solvent, such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, preferably at room temperature between (-10)aboutWith the 120aboutWith, for example at temperatures between 0aboutand 60aboutor by heating, if necessary, in an inert solvent, such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of catalytic amount of acid, such as n-toluensulfonate, sulfuric, phosphoric or polyphosphoric, preferably at the boiling point of the used solvent, for example at 40aboutWith the 100aboutC.

If G1in the compound of the formula (2) means, for example, benzyloxycarbonyl group, the benzyl group may also be chipped off hydrogenations in the presence of a hydrogenation catalyst such as palladium on charcoal, in a suitable solvent, such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0aboutand 50aboutWith, for example at room temperature the nitro-group to the amino group or benzyloxy to the hydroxy-group.

b) To obtain a benzimidazole of General formula (1) conduct the cyclization of compounds of General formula

(3) in which

A to G, R1, R2and Z1-Z4have the above meanings and Y1means an amino group.

The cyclization should be carried out in a solvent or mixture of solvents such as methanol, ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, onomatology ether glycol, dimethyl ether of diethylene glycol, sulfolane, dimethylformamide, tetramin, or in excess of alkylating agents used to obtain the compounds of General formula (3), for example, the appropriate acid or the corresponding nitrile, anhydride, halogenide acid complex ester or amide, for example at temperatures between 0aboutand 250aboutWith, preferably at the boiling temperature of the reaction medium, optionally in the presence of a condensing means such as phosphorus oxychloride, thionyl chloride, sulfurylchloride, sulfuric acid, n-toluensulfonate, methanesulfonate, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally also in the presence of a base such as potassium ethylate Il">

Especially preferably the interaction so that the compound of General formula (3) are obtained in the reaction mixture by acylation of the corresponding diaminododecane or recovery of the corresponding o-nitro-acylaminoacyl.

When the interrupt nitrogroup reduction at the stage of hydroxylamine get with subsequent cyclization of the N-oxide compounds of General formula (1). Thus obtained N-oxide can finally translate the restoration of a corresponding compound of General formula (1).

Subsequent recovery of the N-oxide of formula (1) is conducted preferably in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as Raney Nickel, platinum or palladium on coal, metals, such as iron, tin or zinc in the presence of acid, such as acetic, hydrochloric or sulfuric, such salts as the sulphate of iron (II) chloride tin (II) or dithionite sodium, derivative of trivalent phosphorus, as triphenylphosphine, triethylphosphite trichloride or phosphorus, or with hydrazine in the presence of Raney Nickel at temperatures between 0aboutthe second formula (1), in which And means amidinopropane, which may be substituted by an alkyl group, spend interaction formed in the reaction mixture of the compounds of formula

(4)

in which

To G, R1, Z1Z6X and Y have the above values and

X1means alkoxy - or urlcategory, as, for example, methoxyethoxy-, n-propoxy, isopropoxy - or benzyloxy group, or alkylthio or arkitip as methylthio, ethylthio, h-propylthio or benzylthio, or amino group

with an amine of General formula

Ra-NH2, (5)

in which

Rameans a hydrogen atom or an alkyl group containing 1-4 carbon atoms, or an acid additive salts.

It is advisable to carry out the interaction in a solvent, such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxane at temperatures between 0aboutand 150aboutC, preferably at temperatures between 20 and 120aboutWith, with the corresponding free amine with the appropriate acid additive salt, such as ammonium carbonate or ammonium acetate.

Compounds of General formula (4) are obtained, for example, the interaction of nitram, in the presence of acid, for example hydrochloric, or in the presence of the corresponding alcoholate, such as sodium methylate or sodium ethylate, or the interaction of the amide salt trialkylamine, such as tetrafluoroborate trityloxy, in a solvent, such as methylene chloride, tetrahydrofuran or dioxane, at temperatures between (-10)aboutand 50aboutC, preferably at temperatures between 0aboutand 20aboutOr a corresponding nitrile with hydrogen sulphide, it is advisable in solvent such as pyridine or dimethylformamide and in the presence of a base, such as triethylamine and subsequent alkylation of the obtained thioamide with the corresponding alkyl - or aralkylamines.

g) To obtain compounds of General formula (1), And in which means aminoalkyl group, carry out the restoration of compounds of General formula

(6)

in which

To G, R1, Z1to Z6X and Y have the above values

AND1means cyano - or cyanoaniline group.

The restoration carried out preferably in a suitable solvent, such as methanol, methanol/water, methanol/ammonia, methanol/water/ammonia, methanol/hydrochloric acid, ethanol, Peeps excited hydrogen, for example hydrogen in the presence of Raney Nickel, platinum or palladium on charcoal, or in the presence of a metal hydride, for example sodium borohydride, lithium borohydride or sociallyengaged at a temperature between 0aboutand 100aboutC, preferably at temperatures between 20aboutand 80aboutC.

d) To obtain compounds of General formula (1), which contain sulfonyloxy or sulfonyloxy group connected to the nitrogen atom, carry out the oxidation of compounds of General formula

(7) in which

A to G, R1, Z1to Z6X and Y have the above values taking into account the fact that at least one of the residues R1A , B, C, E, G, or X contains sulfonyloxy or sulfonyloxy group, unrelated to the nitrogen atom.

The oxidation is preferably carried out in a solvent or mixture of solvents such as water, water/pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic/acetanhydride, diluted sulfuric acid or triperoxonane acid depending on the applied oxidant expediently at temperatures between -80 and 100aboutC. To obtain the corresponding S-oxycoedone General formula (1) is appropriate to carry out the oxidation with one equivalent of price when 0-20aboutWith or in acetone at 0 to 60aboutWith percolate, for example with permorming acid in glacial acetic acid or triperoxonane acid at 0-50aboutWith or with m-chloroperbenzoic acid in methylene chloride or chloroform at (-20) to 60aboutWith metaperiodate sodium in aqueous methanol or ethanol at (-15)about25aboutWith bromine in glacial acetic acid or aqueous acetic acid, optionally in the presence of a weak base, such as sodium acetate with N-bromo-succinimide in ethanol, with tert.butylhypochlorite in methanol at (-80) to (-30)aboutWith identilied in aqueous pyridine at 0-50aboutWith nitric acid in glacial acetic acid at 0 to 20aboutWith chromic acid in glacial acetic acid or in acetone at 0 to 20aboutAnd with chloride sulfuricum in methylene chloride at (-70)aboutWith the obtained complex chlorine-tiefer it is advisable to hydrolyze water-ethanol.

To obtain S,S-dictioanry General formula (1) is appropriate to carry out the oxidation on the basis of the corresponding alkylsulfonyl connection with one or more equivalents of the applied oxidant or from the corresponding alkylsulfonyl connection with two or more of aquiered, in triperoxonane acid or formic acid at 20 to 100aboutWith or in acetone at 0 to 60aboutWith percolate, as, for example, paranavitana acid or m-chloroperbenzoic acid in glacial acetic acid, triperoxonane acid, methylene chloride or chloroform at temperatures between 0 and 60aboutWith nitric acid in glacial acetic acid at 0 to 20aboutWith chromic acid or potassium permanganate in glacial acetic acid, a mixture of water/sulphuric acid or in acetone at 0 to 20aboutC.

e) To obtain compounds of General formula (1) in which a represents amino, aminoalkyl-, amidino-, guanidino or guanidinoacetic group, which is substituted alkoxycarbonyl group with the total number of carbon atoms 2-5, arylethoxysilanes, arylethoxysilanes, aryloxyalkyl, arylcarboxylic, aralkylamines or arylcarbamoyl group, conduct the interaction of compounds of General formula

(8)

in which

To G, R1, Z1to Z6X and Y have the first value and

AND2means amino, aminoalkyl-, amidino-, guanidino or guanidinoacetic group

with a compound of General formula

X2-CO Rb, (9)

in which

Rthe alkyl or aryl group, and

X2means nucleophilic useplease group as a halogen atom such as chlorine atom or bromine.

The interaction should be carried out in a solvent such as tetrahydrofuran, methylene chloride, chloroform or dimethylformamide and in the presence of a base, e.g. sodium carbonate, potassium carbonate or sodium alkali or in the presence of tertiary organic bases, such as triethylamine, N-ethyl-Diisopropylamine, N-methyl-research or pyridine, which may simultaneously serve as solvent, at temperatures between -30 and 100aboutC, preferably at temperatures between -10 and 80aboutC.

g) To obtain compounds of General formula (1), where G means not associated with the heteroatom balance E carbonyl group, which is substituted by cinnamoyloxy or alkoxygroup with 1-6 carbon atoms, in which alkoxylates with 1-5 carbon atoms may be substituted by phenyl group or alkoxylated with 1-3 carbon atoms 1, 2 or 3 position may be substituted naftilos group, cycloalkyl group with 5 or 6 carbon atoms, peredelnoj group or in the 2 or 3 position pyrrolidin-2-on-1-yl group, cycloalexie with 5-8 atoms by pinoygossipboy with the total number of carbon atoms in alkanoyloxy part 2-5, alkoxycarbonylmethyl with 1-2 carbon atoms in the alkyl part or cycloalkylcarbonyl - sing, containing 5 to 6 carbon atoms in cycloalkyl part, in which detoxicate can be substituted by an alkyl group, conduct the interaction of compounds of General formula

(10)

in which

A to F, R1, Z1to Z6X and Y have the first value and

G" means carboxy - or alkoxycarbonyl group, with an alcohol of General formula

X3-Rc, (11)

in which

X3means a hydroxy-group or nucleophilic useplease group such as halogen atom such as chlorine atom, bromine or iodine, and

Rcmeans cannabiscup or alkyl group with 1-6 carbon atoms in which the alkyl residue containing 1 to 5 carbon atoms may be substituted by phenyl group or the alkyl residue containing 1-3 carbon atoms, 1, 2 or 3 position may be substituted naftilos group, cycloalkyl group containing 5 or 6 carbon atoms, peredelnoj group or a 2 - or 3-position of pyrrolidin-2-on-1-yl group,

cycloalkyl group containing 5-8 carbon atoms, indenyl-, 1,2,3,4-tetrahydronaphthyl-, bicycloheptene Il is alkoxycarbonylmethyl group, containing 1-2 carbon atoms in the alkyl part, or cycloalkylcarbonyl group containing 5 or 6 carbon atoms in cycloalkyl part where methyl may be substituted by an alkyl group.

The interaction should be carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, tetrahydrofuran, toluene/tetrahydrofuran or dioxane, optionally in the presence of acid, for example hydrochloric, or in the presence of dehydrating agents, such isobutyl ether of Harborview acid, thionyl chloride, trimethylchlorosilane, titanium tetrachloride, hydrochloric acid, sulfuric acid, methanesulfonate, n-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N,N1-dicyclohexylcarbodiimide, a mixture of N,N1-dicyclohexylcarbodiimide N-hydroxysuccinimide or 1-hydroxy-benzotriazole, a mixture of N,N1-carbonyldiimidazole or N,N1-conidiomata, or triphenylphosphine with chetyrekhkhloristym carbon in the presence of a base, such as sodium carbonate, potassium carbonate, caustic soda, triethylamine, N-ethyldiethanolamine, N-methyl-morpholine, PIaboutC.

If X3means nucleophilic useplease group, it is advisable to carry out the interaction in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide or dimethylformamide optionally in the presence of a reaction accelerator, such as sodium iodide or potassium, and preferably in the presence of a base such as sodium carbonate or potassium or sodium alkali or in the presence of tertiary organic bases, for example N-ethyl-Diisopropylamine or N-methyl-research, which can simultaneously serve as solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100aboutWith preferably at a temperature between (-10)aboutand 80aboutC.

If X3means a hydroxy-group, it is advisable to carry out the esterification in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, tetrahydrofuran, toluene/tetrahydrofuran or dioxane optionally in the presence of acid, for example hydrochloric, or in the presence of dehydrating agents, such isobutyl ether of Harborview acid, thionyl chloride is sulfoxylate, trichloride of phosphorus, phosphorus pentoxide, N, N1-dicyclohexylcarbodiimide, a mixture of N,N1-DICYCLOHEXYL - carbodiimide and N-hydroxysuccinimide, or 1-hydroxybenzotriazole, a mixture of N, N1-carbonyldiimidazole or N, N1-conidiomata or triphenylphosphine with carbon tetrachloride at a temperature between -(30)aboutWith the 100aboutC, preferably at temperatures between -10 and 60aboutC.

C) To obtain compounds of General formula (1), And in which means guanidinoacetic group or amidinopropane, which is linked to the nitrogen atom of the cyclic aminogroup, spend the interaction of compounds of General formula

(12)

in which

To G, R1, Z1to Z6X and Y have the above values and

AND3means aminoalkyl group, or compounds of General formula

(12)

in which

To G, R1, Z1to Z6X and Y have the above values taking into account the fact that the residue contains a circular aminogroup,

with S-alkyl-estimaciones.

The interaction should be carried out in a solvent, for example dimethylformamide, and preferably in the presence of a base, for example sodium carbonate, at elevated temp(1), in which And means associated with the aromatic ring guanidinium, spend the interaction of compounds of General formula

(14)

in which

To G, R1, Z1to Z6X and Y have the above values, that means an aromatic or heteroaromatic ring, and

AND4means an amino group with cyanamide or its acid salt additive. The interaction should be carried out in a solvent, for example dioxane, mixtures of dioxane with water or tetrahydrofuran, preferably at temperatures between 60 and 120aboutWith, for example at the boiling temperature of the reaction mixture.

K) To obtain the compounds of General formula (1) in which D is a bond and E means-NR3-CO-group, conduct the interaction of compounds of General formula

(15)

in which

A to C, R1, R3, Z1to Z6X and Y are the specified values

with a compound of General formula

X4-CO-F-G, (16) where

F and G have the above values and

X4means nucleophilic useplease group, such as hydroxy - or alkoxygroup, or halogen atom such as chlorine atom, bromine or iodine, or methoxy - or ethoxypropan, or his reaction sposored, chloroform, carbon tetrachloride, simple ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of activating acid funds or dehydrating means, for example in the presence of ethyl ether of Harborview acid, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N1-dicyclohexylcarbodiimide, a mixture of N,N1-dicyclohexylcarbodiimide with N-hydroxysuccinimide, N,N1-carbonyldiimidazole or N,N1-conidiomata or a mixture of triphenylphosphine with carbon tetrachloride, optionally in the presence of inorganic bases such as sodium carbonate or a tertiary organic base, such as triethylamine, pyridine or 4-dimethylaminopyridine, which can be a solvent, at a temperature between (-25) and 150aboutC, preferably at temperatures between (-10)aboutC and the boiling point of the applied solvent.

The acylation is carried out as indicated above, preferably with the corresponding halogenerator acid or anhydride of the acid, and it may also be carried out without solvent.

l) To obtain compounds of the General formula

(17)

in which

R1, B to G, X, Y, and Z1to Z6have the above values and

AND5means H2N-CO-T-group, in which T connection or Allenova group with 1-4 carbon atoms with a compound period (III) General formula

(18)

in which

R9means acyl residues of organic carboxylic acids, for example acetoxy or triptracker.

The interaction is carried out preferably in an aqueous solvent, e.g. in water or a mixture of water/acetonitrile, at temperatures between 0 and 50aboutC, preferably at room temperature.

m) To obtain compounds of General formula (1), And in which means aminoalkyl group in which the amino group is not associated with the Quaternary carbon atom, or amino group, which is associated with the CH - or CH2group of the residue In or With, carry out the restoration of compounds of General formula

(19)

in which

R1, B to G, X, Y, and Z1to Z6have the above values and

AND6means hydroxyimino or hydroxyalkyloxy group with 1-4 carbon atoms.

The restoration should be carried out in a suitable solvent, for example methanol, a mixture of methane the STI with the addition of acid, for example salt, in the presence of catalytically activated hydrogen, e.g. hydrogen with Raney Nickel, platinum or palladium on charcoal, at a temperature between 20 and 80aboutC.

n) To obtain the compounds of General formula (1) in which a represents amino, aminoalkyl-, amidino-, guanidino or guanidinoacetate group, substituted dialkylphosphinate groups with 1-3 carbon atoms in the alkyl part, spend the interaction of compounds of General formula

(20)

in which

R1, B to G, X, Y, and Z1to Z6have the above values and

AND7means an amino group, a linear or branched aminoalkyl group with 1-4 carbon atoms, amidino-, guanidino or guanidinoacetic group with 1-3 carbon atoms in the alkyl part

with a compound of General formula

X5-PO(OR10)2, (21)

in which

R10means an alkyl group with 1-3 carbon atoms, and

X5nucleophilic useplease group, such as cyano, chlorine atom or bromine. The interaction should be carried out in a solvent, for example dimethylformamide, at temperatures between 0 and 100aboutC, preferably at temperatures between 15 and 50aboutC.

of compounds of General formula

(22)

in which

A to D, X, Y, and Z1to Z6have the above values with the compound of General formula

HNR3-F-G, (23) in which

F, G, and R3have the above values.

The interaction should be carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, simple ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of activating acid funds or dehydrating means, for example in the presence of ethyl ether of Harborview acid, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N1-dicyclohexylcarbodiimide, a mixture of N,N1-dicyclohexylcarbodiimide with N-hydroxysuccinimide or 1-hydroxybenzotriazole, tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea, N,N1-carbonylcyanide - ash or N, N1-conidiomata or a mixture of triphenylphosphine with carbon tetrachloride, optionally in the presence of inorganic bases such as sodium carbonate or a tertiary organic base, such as triethylamine, N-methyl-research, pyridine or 4-dimethylaminopyridine, which at once is(-10aboutC) and the boiling point of the used solvent.

If the above methods have the compound of General formula (1) in which R1means the above-mentioned amino - or aminoalkyl group, it may be converted by alkylation into a corresponding, alkylamino or dialkylaminomethyl General formula (1).

Subsequent alkylation should be carried out in a solvent or mixture of solvents, such as methylene chloride, dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, tetrahydrofuran, toluene/tetrahydrofuran or dioxane, optionally in the presence of a base, for example sodium carbonate, potassium, caustic soda, tert. of potassium butyl or N-ethyl-Diisopropylamine, at temperatures between 0 and 150aboutC, preferably at temperatures between 0 and 50aboutC.

When the above-described reactions of the available reactive groups, for example hydroxy-, carboxy-, phosphono-, amino-, alkylamino or aminogroup can protect conventional protective groups after the reaction hatshepsuts.

For example, a protective group for the hydroxy-group is trimethylsilyl-, acetyl-, benzoyl-, tert. butyl, trityl-, benzyl - then it is carbonated or the em.butyl-, benzyl or tetrahydropyranyl;

for phosphonopropyl protective can be (trimethylsilyl) -, methyl-, ethyl-, or benzerga and for the amino group, alkylamino or aminogroup protective can be acetyl, trifluoracetyl, benzoline, ethoxycarbonyl, tert. butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and an amino group optionally Tallina group.

Conducted, if necessary, subsequent removal of the protective groups are, for example, by hydrolysis in aqueous solvent, for example water, mixtures of isopropanol and water, a mixture of tetrahydrofuran and water or in a mixture of dioxane and water, in the presence of acid, for example triperoxonane, hydrochloric or sulfuric, or in the presence of alkali metal base such as sodium hydroxide or potassium, or by cleavage of the ether compounds, for example in the presence of attributively, at a temperature of 0-100aboutC, preferably at 10-50aboutC. However, cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl carried out, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst, for example palladium on charcoal, in an environment Rast is, if necessary with the addition of acid, for example hydrochloric, when 0-50aboutC, preferably at room temperature and under a hydrogen pressure of 1 to 7 bar, preferably 3-5 bar.

Removal methoxybenzyl can also be carried out in the presence of an oxidant, such as ammoniumnitrate cerium (1U), in the environment of a solvent such as methylene chloride, acetonitrile or a mixture of acetonitrile and water, at 0-50aboutC, preferably at room temperature.

However, the removal of 2,4-dimethoxybenzyl preferably carried out in trifluoroacetic acid in the presence of anisole.

The removal of only one alkyl residue from the O1-dialkylphosphorous group is, for example, with sodium iodide in a solvent, for example acetone, ethylmethylketone, acetonitrile or dimethylformamide, at a temperature between 40 and 150aboutC, preferably at temperatures between 60 and 100aboutC.

Cleavage of both alkyl residues O1-dialkylphosphorous group is, for example, attributively, bromotrimethylsilane or a mixture of chlorotrimethylsilane with sodium iodide in a solvent such as methylene chloride, chloroform or acetonitrile, at temperatures/SUP>C.

Cleavage of the tert.butyl or tert.butyloxycarbonyl preferably carried out by treatment with acid, for example triperoxonane or salt, if necessary, in the environment of a solvent such as methylene chloride, dioxane or a simple ester.

Cleavage talila preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine, in the environment of the solvent, for example methanol, ethanol, isopropanol, a mixture of toluene and water, or dioxane, at a temperature of 20-50aboutC.

In addition, the compounds of General formula (1) can be divided into their enantiomers and/or diastereomers. Thus, for example, a mixture of CIS - and TRANS-isomers can be divided into separate CIS - and TRANS-isomers, and compounds with at least one optically active carbon atom can be divided into their enantiomers.

Thus, for example, the mixture of CIS - and TRANS-isomers can be divided into separate CIS - and TRANS-isomers by chromatography obtained in modifications in the General formula (1), existing in the form of the racemates, can be divided into their optical antipodes by known method (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", and the carbon atoms can be divided into their diastereomers in a known manner, on the basis of their physical and chemical differences, for example, by chromatography and/or fractional crystallization. In that case, if the diastereomers are in the form of the racemates, can in this way be separated into the enantiomers.

The separation of enantiomers is preferably carried out by column chromatography on chiral phases or by recrystallization from an optically active solvent or by reacting with an optically active substance, forming with matematicheski compound or salt derivatives, such as esters or amides, in particular acid and its activated derivatives or alcohols, and separating the thus obtained mixture of diastereoisomeric salts or a derivative thereof, for example, due to different solubility, and from the pure diastereomeric salts or derivatives by treatment with a suitable substance you can get free antipodes. Commonly used optically active acids are, for example, D - and L-forms of tartaric or Dibenzoyl-tartaric acid, di-o-tolyl-tartaric acid, malic acid, almond acid, camphor sulphonic acids, glutamic acid, aspartic acid or Hinn acid. As optical aktivnye -(-)-methyloxycarbonyl.

In addition, the compounds of General formula (1) inorganic or organic acid can be converted to their salts, particularly for pharmaceutical use the physiologically tolerated salts. The acid can be used, for example, hydrochloric, Hydrobromic, sulfuric, phosphoric, fumaric, succinic, lactic, citric, tartaric or maleic.

In addition, if obtained new compounds of General formula (1) contain a carboxyl group, they can then turn in their additive salts with inorganic or organic bases, in particular for use in the pharmaceutical industry, their physiologically tolerated salt additive. As a basis you can use, for example, sodium hydroxide or potassium cyclohexylamine, ethanolamine, diethanolamine or triethanolamine.

Used as starting compounds substances partially known from the literature, or get them known from the literature methods.

As already stated above, the new condensed 5-membered heterocycles of General formula (1) and their additive salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases, GU or substituted at the nitrogen amino, aminoalkyl-, amidino-, guanidino or guanidinoacetic group, or the group, if necessary, capable of translation in vivo unsubstituted or substituted at the nitrogen atom of amino, amidino or guanidinium, for example amino, aminoalkyl-, amidino-, guanidino or guanidinoacetic group, substituted at the nitrogen atom by alkoxycarbonyl, alkanolammonium, alcoxycarbenium, alkylcarboxylic, arylcarbamoyl, aryloxyalkyl, alkanolammonium, cycloalkylcarbonyl, uralenergosetstroy, aryloxyalkanoic, phosphono-, dialkylphosphorous - or-alkylphosphonates, or means dealkilirovanny or alkilirovanny the nitrogen cycle aminogroup and D-E-F - mean carboxyl, sulfo-, phosphono-, O-alkyl-phosphono - or 5-tetrazolyl or group, translated in vivo into a carboxyl, sulfo-, phosphono-About-alkylphosphine or tetrazole groups, such as carbonyl group, substituted alkoxy, Alcoxy, aralkylated, cycloalkylation, heteroaromatics, pyrrolidin-2-on-1-yl-alkoxy, morpholinoethoxy, thiomorpholine-alkoxy, 1 oxido-thiomorpholine, cycloalkane, benzocyclobutene, bicycloalkanes, bicycloalkyl, alcoholicxanaxhealth-, rolexcellini, arachnologists, aryloxypropanolamine or urlconnection.setrequestproperty, exhibit valuable pharmacological properties, in particular along with inhibiting inflammation and osteoporosis effects, antithrombotic, antiagregatnoe and hindering the development of tumors and metastases action.

Compounds of General formula (1) in which a is a cyano, are valuable intermediate products for obtaining relevant aminomethyl and amidinopropane General formula (1). Biological activity of compounds of General formula (1) examined, for example, as follows.

1. The binding of fibrinogen to platelets person.

Extracted by puncture antecubital veins the blood to slow the clotting process triatriatum (final concentration: 13 mm) and centrifuged at 170 g for 10 minutes platelet-Rich plasma is fed to the column Sefiros 2B (firm Pharmacia, Sweden) and elute with a solution of 90 mm sodium chloride, 14 mm triacrylate, 5 mm glucose and 50 mm Tris(oxymethyl))-aminomethane, brought to a pH of 7.4. For binding experiments using the last gel-filtered platelets, poluchennym of calcium chloride, 50 μl of a solution of 0.6 mm adenosine diphosphate, 100 μl of a solution of the substance or solvent and 50 μl of a solution of fibrinogen (containing 3 µg 125-J-fibrinogen). Incubated at room temperature for 20 min, and Nonspecific binding determined in the presence of 3 mg per 1 ml of cold fibrinogen.

900 μl of the product of incubation using a pipette, carefully served on 250 μl of silicone oil (a mixture of commercial products AP 38 and AR 20 in a volume ratio of 1:2, Wacker Chemie), placed in Eppendorf vessels, and centrifuged at 10,000 g for 2 minutes the Aqueous phase and the oil taken by syringe, the tip of the syringe containing the platelets, cut and using a gamma counter to determine the amount of bound fibrinogen. On several samples with different concentrations of the substance to determine the concentration at which the substance inhibits the binding of fibrinogen to 50% (concentration braking CT50).

2. Antithrombotics action

Technique

Aggregation is determined by the method of born and Cross (J. Physiol. N 170 page 397, 1964) on platelet-rich plasma of healthy people. For inhibiting the coagulation of the blood type 3,14% sodium citrate in a volume ratio of 1:10.

Induced by collagen aggregatability causing the aggregation of matter. The rate of aggregation is determined on the basis of the angle of inclination of the density curve. The point of the curve, showing the highest light transmission, serves to rasschityvaet optical density.

The amount of collagen choose more small, but sufficient for irreversible reaction curve. Use commercially available collagen firm Harmonee, , Munich.

Before adding collagen plasma together with a test compound are incubated at 37aboutWith 10 minutes On the basis of the received data graphically determine the effective dose ED50, i.e. the dose at which achieved 50% change in optical density in terms of inhibition of aggregation.

The results of the experiment are shown in table.

125 I-fibrinogen was replaced with 3H-(3S,5S)-5-[(4'-amidino-4-biphenyl)-oxime-Tyl] -3-carboxymethyl - 2-pyrrolidone. Compounds according to the invention are of low toxicity, as at intravenous introduction of 30 mg/kg three mice were not lost a single animal.

Thanks inhibitory effect on the interaction between cells or between cells and matrix new condensed 5-membered nitrogen-containing heterocycles of General formula (1) and their physiological paranoimia cells of different sizes, or when a certain role is played by the interaction between cells and matrix, for example, for the control and prevention of venous and arterial thrombosis, cerebrosides pulmonary embolism, myocardial infarction, arteriosclerosis, osteoporosis and metastasis of tumors. In addition, these compounds are suitable for treatment of when thrombolyse when using fibrinolytic drugs or interventions in the vessels, for example, when cruzlaminates angioplasty, as well as for treatment in the event of a state of shock, psoriasis, diabetes and inflammation.

For the treatment and prevention of the above diseases new connections used in doses between 0.1 mg and 30 mg/kg body weight, preferably 1 μg to 15 mg/kg body weight, at 1-4 doses in 1 day.

The new compounds of General formula (1) can be converted to known drugs, such as tablets, pills, capsules, powders, suspensions, solutions, sprays or suppositories, if necessary in combination with other active substances, such as receptor antagonists and thromboxane inhibitors of the synthesis of thromboxane or their combinations, serotonin antagonists, antagonists of the receptor, alkyl nitrate, such as glycerine tissue plasminogen PUK, urokinase, streptokinase, or anticoagulants, such as heparin, dermatosurgical, activated protein C, vitamin K antagonists, hirudin, inhibitors of thrombin or other activated coagulation factors, together with one or more known inert carriers and/or diluents, e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, mixture of water and ethanol, a mixture of water with glycerol, a mixture of water with sorbitol, a mixture of water with ethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose, or fatty substances, for example utverzhdennym fat, or their suitable mixtures.

The following examples illustrate how to obtain the new compounds of General formula (1).

P R I m e R 1. 2-(4-amidino-phenyl)-5-[(3-carboxy-propyl)-aminocarbonyl] -1 - methyl-benzimidazole.

A mixture of 2.0 g of 2-(4-amidino-phenyl)-5-[(3-methoxy-carbonylmethyl)-aminocarbonyl] -1 - methyl-benzimidazole, 20 ml of methanol and 15.8 ml of 1 N caustic soda stirred for 16 h at room temperature. Evaporated in vacuum, absorb water and neutralized after the 5aboutC.

the value of Rf: 0,75 (silikagelevye plate RP 18; methanol/ 5% aqueous solution of chloride nutria:4)

Similarly receive the following connections:

(1) 2-(4-amidino-phenyl)-5-(6)-[(2-carboxy-ethyl)-carbonyl-amino]-benzimidazole

So pl. over 200aboutWITH

the value of Rf: 0,63 (silikagelevye plate RP 18; methanol/ 5% aqueous solution of chloride nutria:4)

Designed HN2O: C 53,46 H 5,73 N 17,31

Found: 53,67 5,54 17,29

(2) the Hydrochloride of 2-(4-amidino-phenyl)-5(6)-[(2-carboxyethyl)-aminocarbonyl]-benzimidazole

Apply lithium hydroxide.

the value of Rf: of 0.26 (silica gel; methylene chloride/methanol=7:3)

(3) 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-1 - methyl-benzimidazole

So pl. 247-249oC

the value of Rf: 0,70 (silikagelevye plate RP 18; methanol/ 5% aqueous solution of chloride nutria:4)

(4) 2-(4-amidino-phenyl)-6-[(2-carboxy-ethyl)-aminocarbonyl]-3-methyl-imidazo [4,5-b] pyridine

the value of Rf: 0,74 (silikagelevye plate RP 18; methane/5% solution of chloride nutria:4)

(5) the hydrochloride of 2-(4-amidino-phenyl)-1-benzyl-5-[(2-carboxy-ethyl)-aminocarb - Neil] benzimidazole

the value of Rf: of 0.25 (silica gel; methylene chloride/methanol=8:2)

(6) 2-(4-amidino-the Oia in a mixture of tetrahydrofuran/water.

the value of Rf: 0,06 (silica gel; methylene chloride/methanol/conc. ammonia=2:1: 0,1 after two manifestations)

(7) 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-1- [3-(S-oxido-thiomorpholine)-propyl]-benzimidazole.

Apply lithium hydroxide in a mixture of tetrahydrofuran/water.

the value of Rf: to 0.28 (silica gel; n-butanol/glacial acetic acid/water= 4:1:2, after three manifestations)

(8) 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl] -1- [3-(S, S-dioxido-thiomorpholine)-propyl]-benzimidazole

Apply the aluminum hydroxide in a mixture of tetrahydrofuran/water.

the value of Rf: of 0.14 (silica gel, isopropanol/water/conc. ammonia=7:2:1, after two manifestations)

(9) diacetate 2-(4-amidino-phenyl)-1-(3-amino-propyl)-5-[(2-carboxy-ethyl) aminocarbonyl]-benzimidazole

Apply lithium hydroxide in a mixture of tetrahydrofuran/water

So pl. above 110aboutC (decomp.)

the value of Rf: of 0.13 (silica gel; isopropanol/water/conc. ammonia=7:2:1)

(10) 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-1-methyl-benzimidazole-3-oxide

So pl. 263-265aboutC (decomp.)

the value of Rf: 0,79 (silica gel plate RP 18; methanol/ 5% saline nutria:4)

(11) 2-[(4-amidino-deepna acid/water= 4:1:1, the twofold manifestation)

Calculated: C H 60,0 4,74 N 16,46

Found: 59,60 4,82 16,52

(12) 2-(4-amidino-phenyl)-1-[2-(4-benzyl-piperazine derivatives)-ethyl]-5- [(2-carboxy-ethyl)-aminocarbonyl]-benzimidazole

Apply lithium hydroxide in a mixture of tetrahydrofuran/water

So pl. 82aboutC (decomp.)

the value of Rf: of 0.51 (silica gel; isopropanol/water/conc. ammonia=7:2:1)

(13) 2-(4-aminomethyl-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl] -(3 - thioproline-propyl)-benzimidazole

Apply lithium hydroxide in a mixture of tetrahydrofuran/water, the value of Rf: 0,50 (silikagelevye plate RP 18; methanol/ 5% saline nutria: 10)

(14) 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-1- (3-carboxy-propyl)-benzimidazole

the value of Rf:of 0.10 (silica gel; methylene chloride/methanol=8:2)

(15) 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-1 - methyl-6-methylamino-benzimidazole

Apply lithium hydroxide.

So pl. 265-266aboutC (decomp.)

the value of Rf: of 0.35 (silica gel, n-butanol/glacial acetic acid/water= 4:1:2).

(16) 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-6- (N-carboxymethyl-methylamino)-1-methyl-benzimidazole

Apply lithium hydroxide.

the value of Rf: 0,62 (ciliegine-phenyl)-1-(4-carboxy-butyl)-3,9-dimethylxanthine.

So pl. 263-265aboutC (decomp.)

the value of Rf: to 0.48 (silica gel; n-butanol/glacial acetic acid/water= 4:1:1,5).

P R I m m e R 2. Hydrochloride of 2-(4-amidino-phenyl)-5-[(3-methoxycarbonyl-propyl)-AMI - noncarbonyl] -1-methyl-benzimidazole.

of 4.2 g of methyl ester of 4-[4-(4-amidino-benzoyl)-methylamino]-3-nitro-benzoyl - amino] -butyric acid are dissolved in 100 ml of methanol, mixed with 10 ml of ethereal hydrochloric acid and 0.5 g of 10% palladium on coal and treated at room temperature with hydrogen at a pressure of 5 bar 22 PM

Next, add 0.3 g of catalyst and leave for 1 hour, the Catalyst is filtered off, the filtrate evaporated and the residue is stirred with a mixture of 100 ml of acetic ether and 10 ml of methanol for 1 h at room temperature, with falls substance in crystalline form.

Output: 3.7V (100% of theory)

So pl. over 200aboutWITH

the value of Rf: 0,65 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

Similarly receive the following connections:

(1) 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-amino-carbonyl] -1 - methyl-benzimidazole

the value of Rf: 0,59 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

t similarly described above, but without the addition of hydrochloric acid.

the value of Rf: 0,63 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

P R I m e R 3. Hydrochloride of 2-[(4-amidino-phenyl)-oxymethyl]-5-(6)- ethoxycarbonylmethoxy-benzimidazole.

2.4 g of 2-[(4-cyan-phenyl)-oxymethyl]-5(6)-ethoxycarbonylmethoxy-benzimidazole are suspended in 300 ml of methanol. After the mixture is passed for 1 h at 0 to 10aboutWith gaseous hydrogen chloride and stirred for 4 h at 15-20aboutC. the Methanol is distilled off in vacuum, the residue is stirred with 75 ml of methanol, which is again distilled off in vacuum. The residue is suspended in 300 ml of methanol, after which portions are added 16.3 g of ammonium carbonate and stirred for further 16 hours with a Mixture of 3 h of methanol and 1 part of concentrated hydrochloric acid to bring the pH of the reaction mixture to 4. Evaporated to dryness and purify the residue on silica gel (eluent: methylene chloride/methanol=3:1 to 0:1).

Yield: 0.9 g (32% of theory)

So pl. 250aboutC (decomp.)

the value of Rf: of 0.64 (silica gel; methylene chloride/methanol/glacial acetic kislota:1:0,1)

Calculated: x H2O x HCl: C 52,87 H 5,18 N 13,70 Cl 8,67

Found: 53,07 5,02 13,81 8,80

Similarly receive the following connections:

(1) 2-(4-amidino-phenyl)-5(6)-[(2-methoxycarbonyl-ethyl)Oh acid/ethanol=7:3)

(2) 2-(4-amidino-phenyl)-6-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -3 - methyl-imidazo [4,5-b]pyridine

the value of Rf: 0,49 (silikagelevye plates RP 18; methanol/ 5% saline nutria:4)

(3) the hydrochloride of 2-(4-amidino-phenyl)-1-benzyl-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole

the value of Rf: 0,22 (silica gel; methylene chloride/methanol=7:3)

(4) the hydrochloride of 2-(4-amidino-phenyl)-1-[(2-(3,4-acid)-ethyl]-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-gasoline-midsole

the value of Rf: of 0.20 (silica gel; ether acetic acid/ethanol=7:3)

(5) 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-amidino-carbonyl] -1-(3-pyridylmethyl)-benzimidazole

the value of Rf: 0,60 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

(6) 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1- (3-thiomorpholine-propyl)-benzimidazole

the value of Rf: of 0.18 (silica gel; methylene chloride/methanol/conc. ammonia=8:2: 0,1)

(7) 2-(4-amidino-phenyl)-1-(3-amino-propyl)-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl]-benzimidazole

the value of Rf: to 0.29 (silica gel; n-butanol/glacial acetic acid/water= 4:1:1, after three manifestations)

(8) 2-(4-amidino-phenyl)-1-[2-(4-benzyl-piperazine derivatives)-aciid/methanol=8:2)

(9) 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1-n-tetradecyl-benzimidazole

the value of Rf: 0,04 (silica gel; ether acetic acid/ethanol=8:2)

(10) of the hydrochloride of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarb-Neil] -1-(3-methoxycarbonyl-propyl)-benzimidazole

the value of Rf: to 0.45 (silica gel; methylene chloride/methanol=8:2)

(11) 2-(4-amidino-phenyl)-1-(3-carboxy-propyl)-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole.

Is formed as a byproduct in (10)

The value of Rf: to 0.19 (silica gel; methylene chloride/methanol=8:2)

(12) 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1-(4-phenyl-butyl)-benzimidazole

So pl. 184-186aboutWITH

the value of Rf: 0,13 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

(13) hydrochloride-hydroheat 2-(4-amidino-phenyl)-5-[(2 - methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-6-methylamino - benzimidazole

So pl. 260-268aboutC (decomp)

the value of Rf: to 0.24 (silica gel; methylene chloride/methanol/conc. ammian:2: 0,1)

(14) of the Hydrochloride of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarb-Neil]-6- (-methoxycarbonylmethylene)-1-methyl-benzimidazole

the value of Rf: 0,42 (with the 5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzamide evil

So pl. 185about(Sintering at 165aboutC)

(16) 2-(4-amidino-phenyl)-1-(3,3-diphenyl-propyl)-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl]-benzimidazole

So pl. over 200aboutWITH

the value of Rf: 0,11 (silikagelevye plate RP 18; methanol/ 5% sodium chloride solution=6:4)

(17) 2-(4-amidino-phenyl)-6-(N-isobutylketone-N-methylamino)-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole.

So pl. 104-106oC (decomp.)

(18) Hydrochloride-hydroheat 8-(4-amidino-phenyl)-3,9-dimethyl-1-(4-meloxicam-bonyl-butyl)-xanthine.

So pl. 224-226aboutC (decomp.)

the value of Rf:of 0.58 (silica gel; n-butanol/glacial acetic acid/water=4: 1:1,5)

(19) 2-(4-amidino-phenyl)-5-[(3-methoxycarbonyl-piperidino)-carbonyl] -1-methyl-benzimidazole

the value of Rf: 0,61 (silikagelevye plate RP 18; methanol/ 5% sodium chloride solution=6:4)

(20) 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-pyrrolidine)-carbonyl]-1 - methyl-benzimidazole

the value of Rf: 0,26 (silikagelevye plate RP 18; methanol/ 5% sodium chloride solution=6:4)

P R I m e R 4. 2-(4-cyan-phenyl)-5-(6)-[(2-methoxycarbonyl-ethyl)-carbylamine] benzimidazole.

To a mixture of 1.5 g of 5(6)-amino-2-(4-cyan-phenyl)-benzimidazole, 0.84 g of N-ethyl-diisopropyl acid. For 16 h, incubated at room temperature and then added weakly acidified water, which contains small amounts of methanol. The resulting crystallized absorb a mixture of acetic ether, tetrahydrofuran and methanol, stirred with 0.1 N hydrochloric acid is distilled off in vacuum, the organic solvent and the precipitate is filtered off.

Yield: 1.4 g (63% of theory)

So pl. 154-156aboutC.

P R I m e R 5. Hydrochloride of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-amino - carbonyl]-1- [3-(S-oxido-thiomorpholine)-propyl]-benzimidazole.

2.2 g of the hydrochloride of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1-( 3-thiomorpholine-propyl)-benzimidazole are dissolved in 45 ml of glacial acetic acid and cooled with ice water mixed with a solution of 0.39 ml of 30% hydrogen peroxide in 5 ml of glacial acetic acid. Stirred for 4 h under ice cooling, and 16 h at room temperature, evaporated in vacuum, the solvent and the residue purified by chromatography (silica gel; methylene chloride/methanol/water=1:1:0 to 1:1:0,1).

Yield: 0.6 g (26% of theory)

the Rf-value: 0,46 (silica gel; methylene chloride/methanol/conc. ammonia=1:1: 0,1).

Similarly receive the following soedinenii]-benzimidazole. Get with a tenfold amount of hydrogen peroxide by heating to 50 ° C 7 o'clock

the Rf-value: of 0.26 (silica gel; butanol/glacial acetic acid/water=4: 1:2 after two manifestations).

P R I m e R 6. 2-(4-aminomethyl-phenyl)-1-(3-amino-propyl-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl]-benzimidazole.

3 g of 1-(3-amino-propyl)-2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole is treated in a mixture of 50 ml of methanol and 10 ml of methanolic solution of hydrochloric acid with hydrogen at a pressure of 5 bar in the presence of 1 g of 10% palladium on coal 20 h at room temperature. The catalyst is filtered off, evaporated in vacuum to dryness and purify the residue by chromatography on silica gel (eluent: methanol/2 ammonia=5:1.5 to 5:2).

Yield: 1.5 g (55% of theory)

the Rf-value: is 0.24 (silica gel; methanol/2 ammonia=5:1,5, after two manifestations)

Similarly receive the following connections:

(1) 2-(4-aminomethyl-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1- (3-thiomorpholine-propyl)-benzimidazole

the Rf value: 0.40 in (silica gel; methylene chloride/methanol/conc. ammonia=8:2: 0,1).

(2) the dihydrochloride of 2-(4-aminomethyl-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1-methyl-benzimidazole.

the Tria=6:4)

(3) the dihydrochloride of 2-(4-aminomethyl-phenyl)-1-[2(3,4-acid)-ethyl] -5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole

the Rf-value:0,03 (silica gel, ether acetic acid/ethanol/Koh.ammonia=8: 2:0,02)

(4) the dihydrochloride of 2-(4-aminomethyl-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1-n-tetradecyl-benzimidazole

the Rf-value: 0,03 (silica gel; ether acetic acid/ethanol/conc. ammonia 50:2:0,02)

P R I m e R 7. 2-(4-methoxycarbonylamino-phenyl)-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl]-1-methyl-benzimidazole

0.26 g of the hydrochloride of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1 - methyl-benzimidazole are suspended in 50 ml of methylene chloride and mixed while cooling with ice with 0.5 ml of N-ethyl-Diisopropylamine and 0,067 ml of methyl ether of chloroparaffins gislatif. Stirred at room temperature, add a half hour later, an additional 0.5 ml of N-ethyl-Diisopropylamine and 0.03 ml of methyl ether of Harborview acid and later, an additional 0.1 ml of N-atindianapolis, as well as of 0.03 ml of methyl ether of Harborview acid. Stirred for another half hour, evaporated in vacuum and purified through column chromatography (silica gel; eluent: ether acetic acid/ethanol 100:2.5 to 100:12,5)

Yield: 0.12 g (hadouma connection:

(1) 2-(4-cyan-phenyl)-6-(N-isobutylketone-N-methylamino)-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole

the Rf-value: 0,63 (silica gel; methylene chloride/methanol/glacial acetic kislota:1:0,1)

P R I m e R 8. The dihydrochloride of 2-(4-amidino-phenyl)-1-[(3,4-acid)-ethyl]-5- [(2-isopropoxycarbonyl-ethyl)-amino-carbonyl]-benzimidazole.

To 50 ml ice saturated isopropanolic hydrochloric acid solution was added 0.6 g of the hydrochloride of 2-(4-amidino-phenyl)-1-[2-(3,4-dimethoxy-phenyl)-ethyl] -5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole, cover with petroleum ether and gently mix until until a large part of the solid product does not go into solution. Left for 16 h at room temperature, filtered from the existing precipitate, the filtrate is evaporated in vacuum and the residue is stirred with tetrahydrofuran.

Yield: 0.5 g (76% of theory)

So pl. 210oC (sinters at 180oC)

Similarly receive the following connections:

(1) the Dihydrochloride of 2-(4-amidino-phenyl)-5-[(2-cyclohexyloxycarbonyl-ethyl)-aminocarbonyl] -1-(4-phenyl-butyl)-benzimidazole

the Rf-value: is 0.69 (silica gel; n-butanol/glacial acetic acid/water= 3:1:1)

(2) the Dihydrochloride of 2-(4-Amida Rf: to 0.67 (silica gel; n-butanol/glacial acetic acid/water= 3:1:1)

(3) the Dihydrochloride of 2-(4-amidino-phenyl)-5-[(2-cyclooctylmethyl-ethyl) -aminocarbonyl]-1-methyl-benzimidazole.

the Rf-value: to 0.67 (silica gel; n-butanol/glacial acetic acid/water= 3:1:1)

(4) the Dihydrochloride of 2-(4-amidino-phenyl)-1-(4-phenyl-butyl)-5- [(2-phenyl-ethyl)-oxycarbonyl]-aminocarbonyl]-benzimidazole

the Rf-value: 0,78 (silica gel; n-butanol/glacial acetic acid/water= 3:1:1)

(5) the Dihydrochloride of 2-(4-amidino-phenyl)-1-[2-(4-amino-3,5-dibromo-phenyl)-ethyl]-5- [(2-isopropoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole

the Rf-value: 0,18 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

(6) Dehydroacetate 2-(4-amidino-phenyl)-1-[(2-(2-bromo-4,5-dimethoxy-phenyl)-ethyl] -5- [[2-(2-norbornenedicarboxylic-ethyl)-aminocarbonyl]-benzimidazole.

Heat dihydrobromide 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-1- [2-(3,4-dimethoxy-phenyl)-ethyl]-benzimidazole with thionyl chloride for two hours and treated the resulting acid chloride norbornene oil. Cleaning produce chromatography on silica gel (Eluent: n-butanol/glacial acetic acid/water=3:1:1)

the Rf-value: 0,72 (silicagel; n-butanol/glacial acetic acid/water= 3:1:1)

Proceed as described in item (6)

the Rf-value: of 0.65 (silica gel; n-butanol/glacial acetic acid/water= 3:1:1).

P R I m e R 9. 2-[(4-cyan-phenyl)-oxymethyl]-5(6)-ethoxycarbonylmethoxy-benzimidazole

Melt 4.5 g of ethyl ester of 3-amino-4-[(4-cyan-phenyl)-oksietilirovannye]-phenoxy-acetic acid and incubated for 15 min at 200oC. The product was then purified by chromatography on a column, first on silica gel (eluent: methylene chloride/methanol/conc. ammonia= 30: 1:0,1) and then on neutral alumina (eluent: methylene chloride/methanol=100:1) and crystallized from a mixture of methylene chloride/ether=1:2.

Yield: 2.5 g (58% of theory)

So pl. 111-112oC

the Rf-value: 0,22 (silica gel; methylene chloride/methanol/conc.ammonia=30:1: 0,1)

Similarly receive the following connections:

(1) 1-[2-(4-benzyl-piperazine derivatives)-ethyl]-2-(4-cyan-phenyl)-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole

the Rf-value: EUR 0.58 (silica gel; methylene chloride/methanol/conc. ammonia=19:1: 0,1, after a threefold manifestation)

(2) the Hydrochloride of 1-(3-amino-propyl)-2-(4-cyan-phenyl)-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole. Hydroheat hydrochloride, N-(2-methoxycarbonyl-ethyl)-amide 3-amino-4-(3-amino-propylamino)-benzoic acid acelerou first is orbinson. The residue is heated for 10 min at us.

So pl. oC (decomp. spec. when OS)

the Rf-value: of 0.54 (silica gel; methylene chloride/methanol/conc. ammonia=9:1: 0,2, after two manifestations)

(3) 2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1 - methyl-6-methylamino-benzimidazole.

Heat 35 minutes

So pl. 203-OS

the Rf-value: of 0.68 (silica gel; methylene chloride/methanol/conc. ammonia=30:1: 0,1, after a threefold manifestation)

(4) 8-(4-cyan-phenyl)-3,9-dimethyl-xanthine

Acelerou 5-amino-3-methyl-4-methylamino-pyrimidine-2,6-dione 4-cyan - benzoyl-chloride in the presence of 4-dimethylamino-pyridine in tetrahydrofuran and the residue after evaporation is heated for 45 min at 200-OS

the Rf-value: 0,79 (silica gel; methylene chloride/methanol/glacial acetic acid=9:1:0.1, the after two manifestations)

P R I m e R 10. Hydroheat 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-1- (2-piperazine derivatives-ethyl)-benzimidazole

of 0.30 g of 2-(4-amidino-phenyl)-1-[2-(4-benzyl-piperazine derivatives)-ethyl]5- [(2-carboxyethyl)-aminocarbonyl]-benzimidazole are dissolved in 100 ml of glacial acetic acid and treated with hydrogen at a pressure of 5 bar in the presence of 1.8 g of palladium oxide for 36 h at room temperature. After filtering off natalieee)

So pl. 80 ° C (decomp)

the Rf-value: of 0.14 (silica gel; isopropanol/water/conc. ammonia=7:2:1, after two manifestations)

Similarly receive the following connection:

(1) of the Hydrochloride of 2-(4-amidino-phenyl)-5(6)-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -benzimidazole.

Working in methanol with 10% palladium on coal.

the Rf-value: of 0.65 (silica gel; methylene chloride/methanol=3:1).

2.2 g of the hydrochloride of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-amino - carbonyl]-1-( 3-thiomorpholine-propyl)-benzimidazole are dissolved in 45 ml of glacial acetic acid and cooled with ice water mixed with a solution of 0.39 ml of 30% hydrogen peroxide in 5 ml of glacial acetic acid. Stirred for 4 h under ice cooling, and 16 h at room temperature, evaporated in vacuum, the solvent and the residue purified by chromatography (silica gel; methylene chloride/methanol/water=1:1:0 to 1:1:0,1).

Yield: 0.6 g (26% of theory)

the value of Rf: 0,46 (silica gel; methylene chloride/methanol/conc. ammonia=1:1: 0,1).

Similarly receive the following connections:

(1) of the Hydrochloride of 2-(4-amidino-phenyl)-1-[(3-(S,S-dioxythiophene)-propyl]-5- (2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole. Get with a tenfold amount of the acetic acid/water=4: 1:2 after two manifestations).

P R I m e R 6. 2-(4-aminomethyl-phenyl)-1-(3-amino-propyl-5-[(2-methoxycarbonyl - ethyl) -aminocarbonyl]-benzimidazole.

3 g of 1-(3-amino-propyl)-2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole is treated in a mixture of 50 ml of methanol and 10 ml of methanolic solution of hydrochloric acid with hydrogen at a pressure of 5 bar in the presence of 1 g of 10% palladium on coal 20 h at room temperature. The catalyst is filtered off, evaporated in vacuum to dryness and purify the residue by chromatography on silica gel (eluent: methanol/2 ammonia=5:1.5 to 5:2).

Yield: 1.5 g (55% of theory)

the value of Rf: to 0.24 (silica gel; methanol/2 ammonia=5:1,5, after two manifestations)

Similarly receive the following connections:

(1) 2-(4-aminomethyl-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1- (3-thiomorpholine-propyl)-benzimidazole

the value of Rf: to 0.40 (silica gel; methylene chloride/methanol/conc. ammonia=8:2: 0,1).

(2) the dihydrochloride of 2-(4-aminomethyl-phenyl)-5-[(2-methoxycarbonyl-ethyl)-amino - carbonyl] -1-methyl-benzimidazole.

So pl. is sintered at 185aboutWITH

the value of Rf: 0,57 (silikagelevye plate RP 18; methanol/ 5% sodium chloride solution=6:4)

(3) the dihydrochloride of 2-(4-aminomethyl-phenyl)-1-[2(3,4-timeel, ether acetic acid/ethanol/Koh.ammonia=8: 2:0,02)

(4) the dihydrochloride of 2-(4-aminomethyl-phenyl)-5-[(2-methoxycarbonyl-ethyl)-amino - carbonyl] -1-n-tetradecyl-benzimidazole

the value of Rf: 0,03 (silica gel; ether acetic acid/ethanol/conc. ammonia 50:2:0,02)

P R I m e R 7. 2-(4-methoxycarbonylamino-phenyl)-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl]-1-methyl-benzimidazole

0.26 g of the hydrochloride of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-amino - carbonyl] -1 - methyl-benzimidazole are suspended in 50 ml of methylene chloride and mixed while cooling with ice with 0.5 ml of N-ethyl-Diisopropylamine and 0,067 ml of methyl ether of Harborview acid. Stirred at room temperature, add a half hour later, an additional 0.5 ml of N-ethyl-Diisopropylamine and 0.03 ml of methyl ether of Harborview acid and later, an additional 0.1 ml of N-atindianapolis, as well as of 0.03 ml of methyl ether of Harborview acid. Stirred for another half hour, evaporated in vacuum and purified through column chromatography (silica gel; eluent: ether acetic acid/ethanol 100:2.5 to 100:12,5)

Yield: 0.12 g (40% of theory)

the value of Rf: 0,41 (silica gel; ether acetic acid/ethanol=8:2).

Similarly receive the following connections:

(1) 2-(4-cyl

the value of Rf: to 0.63 (silica gel; methylene chloride/methanol/glacial acetic acid=25:1:0,1)

P R I m e R 8. The dihydrochloride of 2-(4-amidino-phenyl)-1-[2-(3,4-acid)-ethyl] -5- [(2-isopropoxycarbonyl-ethyl)-amino - carbonyl]-benzimidazole.

To 50 ml ice saturated isopropanolic hydrochloric acid solution was added 0.6 g of the hydrochloride of 2-(4-amidino-phenyl)-1-[2-(3,4-dimethoxy-Fe - nil)-ethyl]-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole, cover with petroleum ether and gently mix until until a large part of the solid product does not go into solution. Left for 16 h at room temperature, filtered from the existing precipitate, the filtrate is evaporated in vacuum and the residue is stirred with tetrahydrofuran.

Yield: 0.5 g (76% of theory)

So pl. 210oC (sintered at 180aboutC)

Similarly receive the following connections:

(1) the Dihydrochloride of 2-(4-amidino-phenyl)-5-[(2-cyclohexyloxycarbonyl-ethyl)-AMI-noncarbonyl] -1-(4-phenyl-butyl)-benzimidazole

the value of Rf: 0,69 (silica gel; n-butanol/glacial acetic acid/water= 3:1:1)

(2) the Dihydrochloride of 2-(4-amidino-phenyl)-5-[(2-cyclohexyl-methoxycarbonyl-ethyl) aminocarbonyl]-1-(4-phenyl-butyl)-gasoline-Mead is ID 2-(4-amidino-phenyl)-5-[(2-cyclooctylmethyl-ethyl) -aminocarbonyl]-1-methyl-benzimidazole.

the value of Rf: to 0.67 (silica gel; n-butanol/glacial acetic acid/water= 3:1:1)

(4) the Dihydrochloride of 2-(4-amidino-phenyl)-1-(4-phenyl-butyl)-5- [(2-phenyl-ethyl)-oxycarbonyl]-aminocarbonyl]-benzimidazole

the value of Rf: 0,78 (silica gel; n-butanol/glacial acetic acid/water= 3:1:1)

(5) the Dihydrochloride of 2-(4-amidino-phenyl)-1-[2-(4-amino-3,5-dibromo-phenyl)-ethyl]-5- [(2-isopropoxycarbonyl-ethyl)-aminostar-bonyl]-benzimidazole

the value of Rf: 0,18 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

(6) Dehydroacetate 2-(4-amidino-phenyl)-1-[(2-(2-bromo-4,5-dimethoxy-phenyl)-ethyl]-5- [[2-(2-norbornenedicarboxylic-ethyl)-amino - carbonyl]-benzimidazole.

Heat dihydrobromide 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminostar - bonyl] -1- [2-(3,4-dimethoxy-phenyl)-ethyl]-benzimidazole with thionyl chloride for two hours and treated the resulting acid chloride norbornene oil. Cleaning produce chromatography on silica gel (Eluent: n-butanol/glacial acetic acid/water=3:1:1)

the value of Rf: 0,72 (silicagel; n-butanol/glacial acetic acid/water= 3:1:1)

(7) Dihydro-acetate 2-(4-amidino-phenyl)-1-[(2-bromo-4,5-dimethoxy-phenyl)-ethyl] -5- [[2-(2-intenrational)-ethyl] -aminocarbonyl]-benzimidazole.

P R I m e R 9. 2-[(4-cyan-phenyl)-oxymethyl]-5(6)-ethoxycarbonylmethoxy-gasoline - imidazol

Melt 4.5 g of ethyl ester of 3-amino-4-[(4-cyan-phenyl)-oxymethylene-ylamino] -phenoxy-acetic acid and incubated for 15 min at 200aboutC. the Product was then purified by chromatography on a column, first on silica gel (eluent: methylene chloride/methanol/conc. ammonia= 30: 1:0,1) and then on neutral alumina (eluent: methylene chloride/methanol=100:1) and crystallized from a mixture of methylene chloride/ether=1:2.

Yield: 2.5 g (58% of theory)

So pl. 111-112oC

the value of Rf: 0,22 (silica gel; methylene chloride/methanol/conc.ammonia=30:1: 0,1)

Similarly receive the following connections:

(1) 1-[2-(4-benzyl-piperazine derivatives)-ethyl]-2-(4-cyan-phenyl)-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole

the value of Rf: of 0.58 (silica gel; methylene chloride/methanol/conc. ammonia=19:1: 0,1, after a threefold manifestation)

(2) the Hydrochloride of 1-(3-amino-propyl)-2-(4-cyan-phenyl)-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole. Hydroheat hydrochloride, N-(2-methoxycarbonyl-ethyl)-amide 3-amino-4-(3-amino-propylamino)-benzoic acid acelerou first processing 4-cyan-benzoyl chloride in chlorobenzene at a bath temperature of 140aboutAnd while TNK. at 115aboutC)

the value of Rf: of 0.54 (silica gel; methylene chloride/methanol/conc. ammonia=9:1: 0,2, after two manifestations)

(3) 2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1 - methyl-6-methylamino-benzimidazole.

Heat 35 minutes

So pl. 203-205aboutWITH

the value of Rf: to 0.68 (silica gel; methylene chloride/methanol/conc. ammonia=30:1: 0,1, after a threefold manifestation)

(4) 8-(4-cyan-phenyl)-3,9-dimethyl-xanthine

Acelerou 5-amino-3-methyl-4-methylamino-pyrimidine-2,6-dione 4-cyan - benzoyl-chloride in the presence of 4-dimethylamino - pyridine in tetrahydrofuran and the residue after evaporation is heated for 45 min at 200-205aboutWITH

the value of Rf: 0,79 (silica gel; methylene chloride/methanol/glacial acetic acid=9:1:0.1, the after two manifestations)

P R I m e R 10. Hydroheat 2-(4-amidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarb - Neil]-1- (2-piperazine derivatives-ethyl)-benzimidazole

of 0.30 g of 2-(4-amidino-phenyl)-1-[2-(4-benzyl-piperazine derivatives)-ethyl]5- [(2-carboxyethyl)-aminocarbonyl]-benzimidazole are dissolved in 100 ml of glacial acetic acid and treated with hydrogen at a pressure of 5 bar in the presence of 1.8 g of palladium oxide for 36 h at room temperature. After filtering off the catalyst, evaporated in VA is SUP>C (decomp.)

the value of Rf: of 0.14 (silica gel; isopropanol/water/conc. ammonia=7:2:1, after two manifestations)

Similarly receive the following connection:

(1) of the Hydrochloride of 2-(4-amidino-phenyl)-5(6)-[(2-methoxycarbonyl-ethyl)-aminocarb - Neil] -benzimidazole.

Working in methanol with 10% palladium on coal.

the value of Rf: of 0.65 (silica gel; methylene chloride/methanol=3:1).

P R I m e R 11. 2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1-(3-thiomorpholine-propyl)-benzimidazole

48.6 g of the hydrochloride of N-(2-methoxycarbonyl-ethyl)-amide 3-amino-4-(3-thiomorpholine-propylamino)-benzoic acid are dissolved while heating in 500 ml of glacial acetic acid, mixed with 19.5 g of 4-cyan-benzoyl-chloride, heated 1 h on the steam bath and then 2 hours at a bath temperature 120aboutC. Evaporated in vacuo and purify the residue by chromatography on silica gel (eluent: methylene chloride/methanol/conc. ammian:1:0 to 8:2:0,2)

Output: 33,7 g (58% of theory)

the value of Rf: 0.84 (silica gel; methylene chloride/methanol/conc. ammonia=19:1: 0,1, after a threefold manifestation)

Similarly receive the following connections:

(1) 2-(4-cyan-phenyl)-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzamidopiperidine. After removal of the solvent is placed in glacial acetic acid and heated for 1.5 h at 100aboutWITH

the value of Rf: of 0.36 (silica gel; ether acetic acid/ethanol/conc. ammonia=50:2:0,1)

(2) 2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1-(3-pyridylmethyl)-benzimidazole.

Proceed as described in item (1), heated 3 h in glacial acetic acid.

the value of Rf: to 0.40 (silica gel; ether acetic acid/ethanol=8:2)

(3) 2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl)-amino-carbonyl] -1-n-tetradecyl-benzimidazole.

Proceed as described in item (1)

the value of Rf: of 0.60 (silica gel; ether acetic acid/ethanol/conc. ammonia=50:2:0,02)

(4) 2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1- (3-methoxycarbonyl-propyl)-benzimidazole. Proceed as described in item (1) with triethylamine as an auxiliary base. The solvent is a mixture of tetrahydrofuran/methylenchlorid:1

The value of Rf: to 0.68 (silica gel; methylene chloride/methanol=37:3).

(5) 1-benzyl-2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -benzimidazole.

Proceed as described in item (4).

The value of Rf: 0,77 (silica gel; methylene chloride/meta/P> Comes, as in position (1).

The value of Rf: 0,61 (silica gel; ether acetic acid/ethanol=50:2).

(7) 1-[2-(4-amino-3,5-dibromo-phenyl)-ethyl]-2-(4-cyan-phenyl-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole.

Proceed as in item (1).

So pl. 168-170aboutWITH

the value of Rf: 0,66 (silica gel; ether acetic acid/ethanol=8:2).

(8) 2-(4-cyan-phenyl)-1-(3,3-diphenyl-propyl)-5- [(2-methoxy-carbonyl-ethyl)-aminocarbonyl]-benzimidazole

So pl. 157-159aboutWITH

the value of Rf: of 0.65 (silica gel; ether acetic acid/ethanol=9:1).

(9) 2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-pyrrolidine)-carbonyl] -1-methyl-benzimidazole.

Proceed as in item (1).

So pl. 174-176aboutWITH,

the value of Rf: of 0.36 (silica gel; ether acetic acid/ethanol=9:1).

(10) 2-(4-cyan-phenyl)-5-[(3-methoxycarbonyl-piperidino)-carbonyl] -1-methyl-benzimidazole.

Proceed as in item (1)

So pl. 185-186aboutWITH

the value of Rf: of 0.43 (silica gel; ether acetic acid/ethanol=9:1)

(11) 2-(4-cyan-phenyl)-6-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -3-methyl-imidazol [4,5-b]pyridine.

Proceed as in item (1).

So pl. 195-197aboutWITH,

C is)-1-(3-aminopropyl)-5-[(2-carboxy - ethyl) -aminocarbonyl]-benzimidazole

0.8 g of 2-(4-aminomethyl-phenyl)-1-(3-amino-propyl)-5- [(2-methoxycarbonyl-ethyl)-aminocarbonyl] -benzimidazole incubated 20 h at room temperature in 10 ml of 48% Hydrobromic acid. Concentrated in vacuo and the residue purified by chromatography on silica gel (eluent: n-butanol/glacial acetic acid/water=4:1:1 to 4:2:2).

Yield: 0.6 g (67% of theory)

the value of Rf: 0,66 (silikagelevye plate RP 18; methanol/5% sodium chloride solution/conc. Hydrobromic acid=6:10:0,01).

Similarly receive the following connections:

(1) Dihydrobromide 2-(4-aminomethyl-phenyl)-5- [(2-carboxyethyl)-aminocarbonyl]-1-methyl-benzimidazole.

So pl. is sintered at 220aboutC.

the value of Rf: 0.87 g (silikagelevye plate RP 18; methanol/5% sodium chloride solution=6:4)

(2) Dihydrobromide 2-(4-amidino-phenyl)-5- [(2-carboxyethyl)-aminocarbonyl]-1-[2-(3,4-dimethoxy-phenyl)-ethyl] -benzylimidazole

the value of Rf: 0,72 (silikagelevye plate RP 18; methanol/5% saline nutria:4)

(3) Dihydrobromide 2-(4-amidino-phenyl)-5-[(2-carboxyethyl)-aminocarbonyl] -1-(3-pyridylmethyl)-benzimidazole

the value of Rf: 0,73 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

Uchenie Rf: 0,05 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

(5) Dihydrobromide 2-(4-aminomethyl-phenyl)-5- [(2-carboxyethyl)-aminocarbonyl]-1-[2-(3,4-dimethoxy-phenyl)-ethyl] benzimidazole

the value of Rf: 0,67 (silikagelevye plate RP 18; methanol/ 5% sodium chloride solution=6:4)

(6) Dihydrobromide 2-(4-amidino-phenyl)-5- [(2-carboxyethyl)-aminocarbonyl]-1-n-tetradecyl-benzimidazole

the value of Rf: 0,01 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

(7) Dihydrobromide 2-(4-amidino-phenyl)-5- [(2-carboxyethyl)-aminocarbonyl]-1-(4-phenyl-butyl)-benzimidazole

the value of Rf: 0,08 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

(8) Dihydrobromide 2-(4-amidino-phenyl)-1- [2-(4-amino-3,5-dibromo-phenyl)-ethyl]-5-(2-carboxy-ethyl)-aminocarbonyl] -benzimidazole

So pl. over 225aboutC

the value of Rf: 0,57 (silikagelevye plate RP 18; methanol/ 5% sodium chloride solution=6:4)

(9) Dihydrobromide 2-(4-amidino-phenyl)-5-[(2-carboxyethyl)-aminocarbonyl] -1-(3,3-diphenyl-propyl)-benzimidazole

the value of Rf: of 0.71 (silica gel; n-butanol/glacial acetic acid/water= 3:1:1)

(10) Dihydrobromide 2-(4-amidino-phenyl)-5- [(3-carboxy-piperidino)-carload sodium=6:4)

(11) Dihydrobromide 2-(4-amidino-phenyl)-5-[(2-carboxy-pyrrolidine)-Carbo - Neil]-1-methyl - benzimidazole

the value of Rf: 0,46 (silikagelevye plate RP 18; methanol/ 5% sodium chloride solution=6:4)

(12) Dihydrobromide 2-(4-amidino-phenyl)-6- [(2-carboxyethyl)-aminocarbonyl]-3-methyl-imidazo[4,5-b]pyridine

the value of Rf: 0,74 (silikagelevye plate RP 18; methanol/ 5% saline nutria:4)

P R I m e p 13. 2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1-methylene-benzimidazole

4.7 g [N-(2-methoxycarbonyl-ethyl)-amide]-3-amino-4-methylamino-benzoic acid is stirred first at room temperature with 40 ml of phosphorus oxychloride, then treated with 3.1 g 4-cyan-benzoyl chloride and heated for 8 h at 90aboutC. Distilled off in vacuum, phosphorus oxychloride, the residue is mixed with 30aboutWith 500 ml of water and neutralized by addition of portions of sodium bicarbonate. The precipitate is filtered off and extracted with ether acetic acid. Acetic ether phase evaporated, the residue is combined with the precipitate and purified by chromatography on silica gel (eluent: ether acetic acid/ethanol=100:1 to 100:5). The resulting product is boiled for final purification with ether acetic acid.

Yield: 1.86 g (27% of theory)

the value of R
5.0 g of 2-(4-cyan-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl] -1-methyl-6-methylamino-benzimidazole are dissolved by heating in 20 ml of dimethylformamide and added to 2.3 ml of N-ethyl-Diisopropylamine. Was added dropwise 1.2 ml of methyl ester bromoxynil acid and heated 5 h on the steam bath. Mix additionally with 1.2 ml of N-ethyl-Diisopropylamine and 0.6 ml of methyl ester bromoxynil acid and heated again for 3 hours In vacuum, the solvent is distilled off, stirred for 2 h with 50 ml of water at room temperature, filtered off and grind the dried residue with ether acetic acid.

Yield: 3.2 g (54% of theory)

So pl. 174-176aboutWITH

the value of Rf: 0,34 (silica gel; methylene chloride-methanol= 19:1 after three manifestations)

Similarly receive the following connection:

(1) 8-(4-cyan-phenyl)-3,9-dimethyl-1-(4-etoxycarbonyl-butyl)-xanthine

The solvent is dimethyl sulfoxide, the base potassium carbonate, and heated 4 h at 80aboutC.

So pl. 148-150aboutC.

the value of Rf: 0,33 (silica gel, ether acetic acid).

Condensed 5-membered heterocycles of General formula

< / BR>
where R1hydrogen, fluorine, chlorine or bromine, alkyl-, aralkyl-, aryl-, SUB>S-,

R3S2O or R5group, where R3hydrogen, C1- C6is an alkyl group, aryl, heteroaryl, kalkilya, carboxialkilnuyu or alkoxycarbonylmethyl group, R4hydrogen, C1C6-alkyl or C1C6-CNS group, aryl, heteroaryl or kalkilya group containing from 1 to 6 carbon atoms in the alkyl part, R5azetidinone, pyrolidine, hexamethyleneimino or heptamethylnonane or piperidino group in which the methylene group in the 4 position may be replaced by oxygen, sulfenyl, sulfinil or sulfonylureas or aminogroups, which can be substituted for R3, R4CO-, alkylsulfonyl - or arylsulfonyl, and R3and R4have the specified values;

X is sulfur or nitrogen or the group NR2where R2hydrogen, linear or branched C1C15is an alkyl group, linear or branched C3C10-Alchemilla and C3- C10-Alchemilla group, with a double and a triple bond may not be directly connected to the nitrogen atom, cycloalkyl or cycloalkenyl group containing 3 to 7 atoms of plastics technology: turning & the ince-position to the nitrogen atom - NR2groups, substituted R3O-, (R3)2N-, R4CO NR3-, alkylsulfonyl-NR3-, arylsulfonyl-NR3alkylsulfanyl, alkylsulfonyl, alkylsulfonyl - or R5groups, or C1C6is an alkyl group which is substituted by one or two aryl groups, heteroaryl group, groups of R6OCO-, (R3)2NCO-, R5CO-, R3O CO-alkylene-NR3CO-, (R3)2N CO-alkylene-NR3CO or R5CO-alkylene-NR3CO; R3and R5have the specified values, R6hydrogen, C1C6is an alkyl group, cycloalkyl group containing 5 to 7 carbon atoms, or kalkilya group;

Y-O-group, nitrogen, or unsubstituted or substituted alkyl group methine group;

Z1, Z2, Z3and Z4the same or different, is a methine group carbon, aminogroup or nitrogen, with at least one of the residues Z1Z4must contain carbon and one or two neighboring nitrogen atom of the methine group may be substituted by carbonyl groups;

Z5and Z6carbon or one of the residues Z5or Z6nitrogen and the other is carbon;

A cyano-, amino group, linear or branched AMM in amino-, aminoalkyl-, amidino-, guanidino and guanidinoacetic groups at one of the nitrogen atoms, one or two hydrogen atoms may be substituted by one or two C1C4-alkyl groups, or one hydrogen atom may be substituted alkoxycarbonyl group with the total number of carbon atoms 2 and 5 alkenylcarbazoles group with the total number of carbon atoms of 4 to 6, alkylcarboxylic group with the total number of carbon atoms 2 and 5 arylcarbamoyl, aryloxyalkyl, arelaxation, alkanolammonium, cycloalkylcarbonyl, uralenergosetstroy, ariloxipicolinamidei-, phosphono-, dialkylphosphorous - or O-alkylphosphonate in which alcoholnye parts contain 2 to 7 carbon atoms and cycloalkenyl parts contain 4 to 8 carbon atoms, and metaxylene part can be substituted cycloalkyl group, containing 3 to 6 carbon atoms, Uralkaliy, aryl or alkyl group or two alkyl groups, which together with the methylene carbon atom may also form a five - or six-membered ring, or, if B is a cyclic amine containing 4 to 7 members, means hydrogen or an alkyl group connected to the nitrogen atom of aminogroup,

C stands for communication, alkylenes, Allenova, O-alkylenes, S-alkylenes, NH-alkylenes, N-(alkyl)-alkylenes group-alkylene-NH-group, -alkylene-N-(alkyl)-group, -SO-or-SO2-alkylenes Gunilla or C2C7-Alchemilla group, and double or triple bond may not be directly linked to the nitrogen atom Z1Z2Z3Z4group, or, if E is not connected directly to the nitrogen atom Z1Z2Z3- Z4group means-O-; -S-; -SO-; -SO2-; -NR3-; -N(COR4)-, -CO-, -NR3CO; -CONR3-; -SO2- NR3, alkylsulfonyl or arylsulfonamides, where R3and R4have the specified values, or cyclo-C4C7-Allenova group, and in four - or five-membered cycloalkanones the one ring member of the ring can mean a nitrogen atom in the six - or semikina cycloalkylation ring one or two members of the ring can mean a nitrogen atom, and optionally adjacent to the nitrogen atom, methylene group may be replaced by a carbonyl group, and at the same time may occur, binding to carbon atoms of adjacent residues through the available nitrogen atoms;

F denotes a bond, a linear or branched C1- C6-alkylenes group, linear or branched C2- C6-alkenylamine or C2C6-alkynylamino group, and double or triple bond may not be directly adjoin the ut being substituted aryl group, -COOR6-, CON(R3)2or-CO-N(R3)-alkyl groups, and remnants of R3and R6have the specified values and the alkyl portion of-CO-N(R3)-alkyl groups, which may contain 1 to 6 carbon atoms, may additionally be substituted residues R7and R8where R7and R8the same or different, hydrogen, aryl or-COO-R6group, where R6has the specified value, cycloalkenyl, alkylene, cycloalkyl and cycloalkylcarbonyl group containing 4 to 6 carbon atoms in cycloalkanones parts, which are in the ring CH group is replaced by a nitrogen atom, and linking with neighboring residue E can also occur through the nitrogen atom, if binding occurs through the carbon atom of the residue E, and if D communication E oxygen and F-alkyl group, A may not be directly linked to the phenyl ring amino - or allmineral, and if at the same time X is sulfur and Y is nitrogen, group A - B-C may not be 4-atsetamino-piperazinone;

G is not associated with the heteroatom of the residue E carbonyl group which may be substituted by a hydroxyl group, arylalkylamines containing 3 to 4 carbon atoms in alkenylphenol part, alkoxygroup, is POI or alkoxylated with 1 to 3 carbon atoms in the 1-, 2 - or 3-positions may be substituted heteroaryl or cycloalkyl group containing 4 to 8 carbon atoms, or 2 - or 3-position pyrrolidin-2-on-1-yl, morpholino, thiomorpholine - or 1-oxido-thiomorpholine, cycloalexie containing 4 to 8 carbon atoms which may be substituted by 1 to 3 alkyl groups, possibly substituted by 1 to 3 methyl groups, benzocyclobutene, benzocyclobutene, bicycloalkanes and bicyclogermacrene, containing 4 to 8 carbon atoms in cycloalkyl part and 6 to 8 carbon atoms in bicycloalkyl part, alkanolammonium with the total number of carbon atoms 2 7 alkanoyloxy part, cycloalkanoprogesterones with the total number of carbon atoms of 4 to 8 in cycloalkanones part, alkoxycarbonylmethyl with 1 to 6 carbon atoms in the alkyl part, cycloalkylcarbonyl with 3 to 7 carbon atoms in cycloalkyl part, rolexcellini, arachnologists, aryloxypropanolamine or urlconnection.setrequestproperty in which detoxicate may be substituted by an alkyl group with 1 to 6 carbon atoms, cycloalkyl group with 3 to 7 carbon atoms, aranceles or aryl groups, sulforhodamine aggregation.

 

Same patents:

The invention relates to the chemistry and technology of thioesters and amides of carboxylic acids, in particular to an improved process for the preparation of thioesters and amides of carboxylic acids of the General formulas I and II, respectively

(I)< / BR>
(II),whereR is the residue of carboxylic acids, which are used as intermediates in obtaining antibiotics cephalosporin and penicillin ranks as the number of individual substances and mixtures

The invention relates to new chemical compounds of benzimidazole series, namely salts of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole General formula

where I X = 2HCl;

II X = 0,5 (CH2COOH)2that have anti-ischemic, hypoxic and anti-arrhythmic activity and can find application in medicine for the treatment of ischemic heart disease, as well as to the intermediate product to obtain

The invention relates to medicine and can find application in practical medicine as a remedy to relieve alcohol withdrawal

The invention relates to derivatives of 4,5,6,7-tetrahydroimidazo General formula I or their salts, which are useful as drugs:

RR6(I) in which groups are represented as follows: R1, R2, R3independently represent a hydrogen atom, hydroxy group, lower alkyl group, which optionally can be substituted by halogen atom, lower alkoxy group, a lower alkylthio group, aralkylated group, aryloxy group, lower alkanoyloxy group, carboxy group, lower alkoxycarbonyl group or nitro group;

R4, R5, R6represent a hydrogen atom or a lower alkyl group;

X represents an oxygen atom or a sulfur atom
The invention relates to medicine, namely to ophthalmology

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to the chemistry and technology of thioesters and amides of carboxylic acids, in particular to an improved process for the preparation of thioesters and amides of carboxylic acids of the General formulas I and II, respectively

(I)< / BR>
(II),whereR is the residue of carboxylic acids, which are used as intermediates in obtaining antibiotics cephalosporin and penicillin ranks as the number of individual substances and mixtures

The invention relates to new chemical compounds of benzimidazole series, namely salts of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole General formula

where I X = 2HCl;

II X = 0,5 (CH2COOH)2that have anti-ischemic, hypoxic and anti-arrhythmic activity and can find application in medicine for the treatment of ischemic heart disease, as well as to the intermediate product to obtain

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: veterinary science.

SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.

EFFECT: higher efficiency of therapy.

4 cl,262 ex, 12 tbl

FIELD: medicine, gynecology, anesthesiology.

SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.

EFFECT: improved assistance method.

7 tbl, 4 ex

FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.

EFFECT: improved preparing method, valuable medicinal properties of composition.

2 cl, 1 tbl, 11 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with applying selector as a selenium-containing organic preparation to be introduced for cows and calves monthly intramuscularly at the dosage of 10 mcg/kg body weight. The method provides decreased fodder expenses for the synthesis of the production obtained.

EFFECT: higher productivity in cattle.

2 ex, 7 tbl

FIELD: organic chemistry, medicine, allergology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)

. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.

EFFECT: improved method for treatment.

9 cl, 2 tbl, 2 dwg, 40 ex

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