Cyclic nitrogen-containing derivative, mixture of isomers, an individual isomers or their salts

 

(57) Abstract:

New heterocycles of the formula I, where X is carbinieri, substituted at the nitrogen atom by a cyano, carbonyl, sulfonyl, Y is unsubstituted or substituted by a residue Rc, Rdor Rcand Rda group of the formula - CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-, CH2CO - or-PINES2-, unsubstituted radical Rcor Rda group of the formula-CO-NH-, -NH-CO-, -CH=N-, or-N=CH-, one of the residues Ra-Rdmeans a group In which a group of the formula a-b (the values of other radicals, see p. 1 claims). The compounds I, in addition to anti-inflammatory actions and inhibiting bone decay steps have antithrombotic, antiaggregatory, antitumor and protivoglistnym actions. 3 c. and 3 C. p. F.-ly, 2 PL.

The invention relates to new chemical substances possessing valuable properties, in particular nitrogen-containing cyclic derivative of General formula

< / BR>
where X is carbinieri, unsubstituted or substituted at the nitrogen atom by alkyl, aryl, heteroaryl or cyano, carbonyl, thiocarbonyl, sulfonyl, 1-nitroethene-2,2-diyl or 1,1-dicyano-Eten-2,2-diyl,

Y - nezameshchenny the Mami carbon which may optionally be substituted by one or two alkyl groups and in which one or two methylene groups can be replaced by a carbonyl, 1,2-cycloalkyl with 5 to 7 carbon atoms, unsubstituted or substituted Rcor Rdor Rcand Rd, 1,2 - cycloalkenyl with 5 to 7 carbon atoms, unsubstituted or substituted Rcor Rdor Rcand Rd, 1,2-Allen, 1,2-phenylene, in which one or two methine groups are replaced by nitrogen atom or one or two groups-CH=CH - replaced by a group-CO-NH - or a methine group substituted by nitrogen atom and one group-CH= CH - replaced by a group-CO-NH-, with the above-mentioned heterocyclic groups may be substituted by one or two alkyl groups, a group-CO-NH-, -NH-CO-, -CH=N - or-N=CH-, unsubstituted or substituted Rcor Rd,

the first of the residues Ra- Rdmeans A group-B-, in which A group of the formula

< / BR>
< / BR>
or

< / BR>
where pentostatin can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents R25and R26that may be the same or different, are below the group-CH= CH - may be replaced by a group-CO-NR1or one methine group may be replaced by nitrogen atom and one group-CH=CH - may be replaced by a group-CO-NR1-, where R1means a hydrogen atom or alkyl,

G1and G4- bond or methylene which may be mono - or Disaese the alkyl, aryl or heteroaryl, and the substituents may be the same or different,

G2- bond or methylene, substituted residues R7and R8,

G3- bond, methylene, substituted residues R9and R10or carbonyl, if G2doesn't mean the relationship,

G5is a nitrogen atom or Metin, unsubstituted or substituted by alkyl, aryl or heteroaryl,

R2is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl if at least one of the groups G2and G3doesn't mean the relationship,

R3is a hydrogen atom, alkyl, aryl or heteroaryl or R3together with R2form an oxygen atom, if at least one of the groups G2and G3doesn't mean the relationship,

R4and R14is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl parts, alkyl with 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, n is alkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, arylalkyl, heteroallyl, alkoxycarbonyl, allmediascotland, formyl, acetyl, TRIFLUOROACETYL, allyloxycarbonyl, amidino or R11CO-0-(R12CR13)-O-CO-, where R11is alkyl with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, aryl or arylalkyl, R12is a hydrogen atom, alkyl, cycloalkyl with 5 to 7 carbon atoms or aryl and R13is a hydrogen atom or alkyl, or R4together with R3mean the unbranched alkylene with 2 to 4 carbon atoms or methylene, if G2doesn't mean the relationship,

R5is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G1no means of communication, or R4together with R5mean an additional bond, if G1means of communication,

R6is a hydrogen atom, alkyl, aryl or heteroaryl or a chlorine atom, a hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G1means linking and R4together with R5mean an additional bond, or R6together with R5mean oxygen atom, if G1doesn't mean the relationship,

R78together with R4mean the unbranched alkylene with 2 to 5 carbon atoms,

R9is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G2doesn't mean the relationship,

R10is a hydrogen atom, alkyl, aryl or heteroaryl or R10together with R4mean the unbranched alkylene with 2 to 4 carbon atoms,

R15is a hydrogen atom or chlorine, alkyl, aryl, heteroaryl, hydroxyl, methoxyl, amino, alkylamino or dialkylamino,

R16is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl parts, alkyl with 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl or arylalkyl,

R17is a hydrogen atom or alkyl, or R16together with R17mean an additional bond, if G4means of communication,

R18is a hydrogen atom, alkyl or fluorine atom, chlorine or bromine, hydroxyl, methoxyl, amino, alkylamino or dialky is about 1 or 2

In - line, alkylen, albaniles, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms may be associated with the remainder of A connection instead of a hydrogen atom, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one group is replaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, the second of the residues Ra- Rdmeans a group of the formula

F - E - D-,

where D is alkylene with 1 to 6 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, sulfinil, sulfonium or the group-NR19-, where R19means a hydrogen atom, alkyl, alkylaryl, alkylsulfonyl, arylcarbamoyl or arylsulfonyl, or in which one ethylene group may be replaced by a group-CO-NR20- or-NR20-CO-, g is strong, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms, together with the hydrogen atom may also be linked with the rest of E, if the latter does not mean the connection or not connected via a heteroatom or a carbonyl with the rest of D, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, indaniel, naftilan, 1,2,3,4-tetrahydronaphthalen or benzoguanamine, in which one of the rings is connected with the rest of E, and the other with a cyclic residue of General formula (I), and the saturated ring may be substituted by one or two alkyl groups and the aromatic rings may be substituted by fluorine atom, chlorine, bromine or iodine, alkyl, trifluoromethyl, hydroxyl, alkoxyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl or cyano, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one group is replaced by a nitrogen atom, and in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group can be replaced is at adjacent to a nitrogen atom of a methylene group may be replaced by carbonyl, or alkilenkarbonatov with the total number of carbon atoms 2-6, if E is a cyclic aminogroup, and a carbonyl linked to a nitrogen atom of a cyclic aminogroup group E, or a link, if E does not mean the relationship,

E - communication, alkylene with 1 to 6 carbon atoms which may be substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, a group HNR21- or N-alkyl-NR21-, where R21means alkylsulphonyl or alkylsulfonyl with 1 to 8 carbon atoms in the alkyl part, allyloxycarbonyl with the total number of carbon atoms 2 and 5 cycloalkylcarbonyl or cycloalkylcarbonyl with 5 to 7 carbon atoms in cycloalkyl part, arylalkylamines, arylalkylamines, arylethoxysilanes, arylcarbamoyl or arylsulfonyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which ar is clealkillinge part, unsubstituted or substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, a group HNR21- or N-alkyl-NR21-, where R21has the above meaning, or is associated with the remainder of D through the remainder of W alkylen, in which W denotes an oxygen atom or sulfur, sulfinil, sulfonyl, the group-NR19-, -NR20-CO - or-CO-NR20-, where R19and R20have the above meanings, with alkylene may be optionally substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, group-HNR21- or N-alkyl-NR21where R21have the above significance, with an additional heteroatom substituent heteroatom is separated from the remainder of W by at least two carbon atoms, if D does not mean the relationship,

F - carbonyl, substituted by hydroxyl and the 4 - 8 carbon atoms and cycloalkyl with 3 to 8 carbon atoms in cycloalkyl part, in which cycloalkyl part may be substituted by alkyl, alkoxyl or dialkylamino, or alkyl and 1 to 3 methyl groups, with one methylene group in the 4 - to 8-membered cycloalkyl part may be replaced by oxygen atom or alkylaminocarbonyl, benzocyclobutene from 9 to 12 carbon atoms, aryl, sulfo-, phosphono-, O-alkylphosphine-, O,O'-dialkylphosphorous, tetrazol-5-yl or a group R23CO-O-CHR24-O-CO-, where R23means alkyl or alkoxy with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, cycloalkyl with 5 to 7 carbon atoms in cycloalkyl parts, aryl, aryloxy, arylalkyl or Allakaket and R24is a hydrogen atom or alkyl,

the shortest distance between the residue of F and located at a maximum distance from the rest F the nitrogen atom of the group A-B - is at least 11 links,

the third of the residues Ra- Rdmeans a hydrogen atom, alkyl, perfluoroalkyl, alkoxy, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, aryl, heteroaryl or arylalkyl,

the fourth of the residue Ra- Rdmeans a hydrogen atom, alkyl or ar is which can be monogamist the remainder R25mono-, di - or triamese the remainder R26or monogamist the remainder R25and additionally mono - or Disaese the remainder R26and the substituents may be the same or different, R25means cyano, carboxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxycarbonyl, alkylsulphonyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonate, perfluoroalkyl, performace, nitro, amino, alkylamino, dialkylamino, alkylcarboxylic, phenylalkylamine, phenylcarbonylamino, alkylsulfonyl, phenylalkylamine, phenylcarbonylamino, N-alkyl-alkylcarboxylic, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, N-alkyl-alkylsulfonyl, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, R26- alkyl, hydroxyl or alkoxy, fluorine atom, chlorine, bromine or iodine, and two residue R26if they are linked to adjacent carbon atoms, may also be alkylene with 3 to 6 carbon atoms, 1,3-butadiene-1,4-deelen or methylendioxy group

under the above term "Allen" should be understood phenylene, which can provide the>and additionally monogamist the remainder R26and the substituents may be the same or different and have the above values,

under the above term "heteroaryl" should read 5-membered heteroaromatic ring containing one atom of oxygen, sulfur or nitrogen, one atom of nitrogen and one atom of oxygen, sulfur or nitrogen, or two atoms of nitrogen and one atom of oxygen, sulfur or nitrogen, or containing 1, 2 or 3 nitrogen atom of the 6-membered heteroaromatic ring in which one or two of the groups-CH= N - can be replaced by a group-CO-NR20where R20has the above value, the heteroaromatic ring can be substituted by one or two alkyl groups or by a fluorine atom, chlorine, bromine or iodine, hydroxyl or alkoxyl in the carbon skeleton,

and, if nothing else is mentioned, the above alkyl, alkylene or CNS groups can contain 1 to 4 carbon atoms and each of the carbon atoms in the above alkilinity and cycloalkenes groups associated at least one heteroatom,

mixtures of their isomers, or individual isomers or their salts.

Preferred compounds of the above General formula (I)and cyano, carbonyl, thiocarbonyl or sulfonyl,

Y is unsubstituted or substituted Rcor Rdor Rcand Rdnonbranched alkylene with 2 or 3 carbon atoms, which may optionally be substituted by one or two alkyl groups and in which one methylene group may be replaced by carbonyl, unsubstituted or substituted Rcor Rdor Rcand Rdnonbranched albaniles with 2 or 3 carbon atoms, in which one possible methylene group may be replaced by carbonyl, unsubstituted or substituted Rcor Rdor Rcand Rd1,2-cycloalkyl with 5 to 7 carbon atoms, 1,2-cycloalkenyl with 5 to 7 carbon atoms, 1,2-Allen, 1,2-phenylene, in which one or two methine groups substituted by a nitrogen atom, and the above-mentioned heterocyclic groups may be substituted by one or two alkyl groups, a group-CO-NH-, -NH-CO-, -CH=N - or-N=CH-, unsubstituted or substituted Rcor Rd,

the first of the residues Ra- Rdmeans A group-B-, in which

A group of the formula

< / BR>
< / BR>
or

< / BR>
where pentostatin can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist ostad which may be identical or different, have the meanings stated below, in one bancoestado 1 - 3 methine group may be replaced by a nitrogen atom or a group-CH= CH - may be replaced by a group-CO-NR1or one methine group may be replaced by nitrogen atom and one group-CH=CH - may be replaced by a group-CO-NR1-, where R1means a hydrogen atom or alkyl,

G1and G4- bond or methylene which may be mono - or Disaese by alkyl or aryl, the substituents may be the same or different,

G2- bond or methylene, substituted residues R7and R8,

G3- bond or methylene, substituted residues R9and R10,

G5is a nitrogen atom or Metin, unsubstituted or substituted by alkyl or aryl,

R2is a hydrogen atom, alkyl or aryl, or hydroxyl or alkoxyl if at least one of the groups G2and G3doesn't mean the relationship,

R3is a hydrogen atom, alkyl or aryl,

R4and R14is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl parts, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, which may not be linked to the nitrogen atom via vinyl Grouville, N,N-dialkylaminoalkyl, arylalkyl, alkoxycarbonyl, allmediascotland, formyl, acetyl, TRIFLUOROACETYL, allyloxycarbonyl, amidino or R11CO-O-(R12CR13)-O-CO-, where R11is alkyl with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, aryl or arylalkyl, R12is a hydrogen atom, alkyl, cycloalkyl with 5 to 7 carbon atoms or aryl and R13is a hydrogen atom, or R4together with R3mean the unbranched alkylene with 2 to 4 carbon atoms or methylene, if G2doesn't mean the relationship,

R5is a hydrogen atom, alkyl or aryl, or hydroxyl or alkoxyl, if G1no means of communication, or R4together with R5mean an additional bond, if G1means of communication,

R6is a hydrogen atom, alkyl or aryl or a chlorine atom, a hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G1means linking and R4together with R5mean an additional bond,

R7is a hydrogen atom, alkyl or aryl,

R8is a hydrogen atom, alkyl or aryl, or R8together with R4mean the unbranched alkylene with 2 to 5 carbon atoms,

R9is a hydrogen atom, alkyl or aryl, or hydroxyl or alkoxyl, if G2not twinny alkylen 2 - 4 carbon atoms,

R15is a hydrogen atom or chlorine, alkyl, aryl, hydroxyl, methoxyl, amino, alkylamino or dialkylamino,

R16is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkenyl with 3-7 carbon atoms in cycloalkyl parts, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl or arylalkyl,

R17is a hydrogen atom or alkyl, or R16together with R17mean an additional bond, if G4means of communication,

R18is a hydrogen atom, alkyl or fluorine atom, chlorine or bromine, hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G4means linking and R16and R17together denote an additional bond,

n is the number 1 or 2,

In - line, alkylene with 1 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH= N - can be replaced by a group-CO-NH-, and these heterocyclic groups may additionally be substituted by one or two alkyl what uppada, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one group is replaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl,

the second of the residues Ra- Rdmeans a group of the formula

F - E - D -,

where alkylene with 1 to 6 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, sulfinil, sulfonium or the group-NR19-, where R19means a hydrogen atom, alkyl, alkylaryl, alkylsulfonyl, arylcarbamoyl or arylsulfonyl, or in which one ethylene group may be replaced by a group-CO-NR20- or-NR20-CO-, where R20means a hydrogen atom or alkyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH-, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, indaniel, naftilan, 1,2,3,4-tetrahydronaphthalen or benzoguanamine, in which one of the rings is connected with the rest of E, and the other with cyclic and aromatic rings can be substituted by a fluorine atom, chlorine, bromine or iodine, alkyl, trifluoromethyl, hydroxyl, alkoxyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl or cyano, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one group is replaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, unsubstituted or substituted by one or two alkyl groups piperazinyl, which one is adjacent to the nitrogen atom of the methylene group may be replaced by a carbonyl, or alkilenkarbonatov with the total number of carbon atoms of 2 to 6, if E is a cyclic aminogroup, and a carbonyl linked to a nitrogen atom of a cyclic aminogroup group E, or a link, if E does not mean the relationship,

E - communication, alkylene with 1 to 6 carbon atoms which may be substituted by one or two alkyl groups with 1 to 6 carbon atoms, hydroxyl, amino or aryl, alkoxyl or alkylamino with 1 to 6 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 8, group HNR21- that one my part, allyloxycarbonyl with the total number of carbon atoms 2 and 5 cycloalkylcarbonyl or cycloalkylcarbonyl with 5 to 7 carbon atoms in cycloalkyl part, arylalkylamines, arylalkylamines, arylethoxysilanes, arylcarbamoyl or arylsulfonyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one group is replaced by a nitrogen atom linked to the carbon atom of the residue D, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups with 1 to 6 carbon atoms, hydroxyl, amino, aryl, alkoxyl or alkylamino with 1 to 6 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 8, group HNR21- or N-alkyl-NR21-, where R21has the above meaning, or is associated with the remainder of D through the remainder of W alkylen, in which W denotes an oxygen atom or sulfur, sulfinil, sulfonyl, the group-NR19, -NR20-CO - or-CO-NR20-, where R19and R20have the above meanings, with alkylene may be what aryl, alkoxyl or alkylamino with 1 to 6 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 8, group-HNR21- or N-alkyl-NR21-, where R21have the above significance, with an additional heteroatom substituent heteroatom is separated from the remainder of W by at least two carbon atoms, if D does not mean the relationship,

F - carbonyl, substituted by hydroxyl, alkoxyl with 1 to 6 carbon atoms, arialcategory or group R22O-, where R22means cycloalkyl with 4 to 7 carbon atoms and cycloalkyl with 3 to 7 carbon atoms in cycloalkyl part, in which cycloalkyl part may be substituted by alkyl, alkoxyl or dialkylamino, alkyl and 1 to 3 methyl groups, with one methylene group in the 5 - to 7-membered cycloalkyl part may be replaced by oxygen atom or alkylaminocarbonyl, benzocyclobutene from 9 to 11 carbon atoms, phosphono-, O-alkylphosphonate, O,O'-dialkylphosphorous, tetrazol-5-yl, or R23CO-O-CHR24-O-CO-, where R23means alkyl or alkoxy with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, cycloalkyl with 5 to 7 carbon atoms in cycloalkyl parts, aryl, aryloxy, arylalkyl or Allakaket and R
the third of the residues Ra- Rdmeans a hydrogen atom, alkoxyl that cannot be linked to a nitrogen atom, alkyl, trifluoromethyl, aryl, arylalkyl, thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl and

the fourth of the residue Ra- Rdmeans a hydrogen atom or alkyl,

and, if nothing else is mentioned,

under the above term "aryl" is to be understood phenyl, which can be monogamist the remainder R25mono-, di - or triamese the remainder R26or monogamist the remainder R25and additionally mono - or Disaese the remainder R26and the substituents may be the same or different, R25means cyano, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylsulphonyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl or trifluoromethyl, R26- alkyl, hydroxyl or alkoxy, fluorine atom, chlorine or bromine, and two residue R26if they are linked to adjacent carbon atoms, may also be alkylene with 3 to 6 carbon atoms, 1,3-butadiene-1,4-deelen or methylendioxy group

under the above term "Allen" should be understood phenylene, which can be monogamist astatke the puppy remainder R26and the substituents may be the same or different and have the above values,

and, if nothing else is mentioned, the above alkyl, alkylene or CNS groups can contain 1 to 4 carbon atoms and each of the carbon atoms in the above alkilinity and cycloalkenes groups associated at least one heteroatom,

the mixture of isomers or individual isomers or its salt,

in particular, compounds of General formula (I), in which

X - carbinieri, unsubstituted or substituted at the nitrogen atom by a cyano, carbonyl or sulfonyl,

Y is unsubstituted or substituted Rwithor Rcand Rdthe group-CH2CH2-, -CH2CH2CH2-, -CH=CH-, -CH2CO - or-COCH2-, unsubstituted or substituted Rcor Rdgroup-CO-NH-, -NH-CO-, -CH=N - or-N=CH-,

the first of the residues Ra- Rdmeans A group-B-, in which

A group of the formula

< / BR>
< / BR>
or

< / BR>
where pentostatin may be replaced by fluorine atom, chlorine or bromine, alkyl, cyano, trifluoromethyl, hydroxyl or alkoxyl or 1 - 3 methine group may be replaced by a nitrogen atom,

G1- bond or methylene, which may or methylene, substituted residues R7and R8,

G3is methylene, substituted residues R9and R10,

G4communications,

G5is a nitrogen atom or Metin, unsubstituted or substituted alkyl,

R2is a hydrogen atom or alkyl,

R3is a hydrogen atom or alkyl,

R4is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl parts, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N, N-dialkylaminoalkyl, arylalkyl, alkoxycarbonyl, allmediascotland, formyl, acetyl, TRIFLUOROACETYL or the group R11CO-O-(R12CR13)-O-CO-, where R11- alkyl, R12is a hydrogen atom or alkyl and R13is a hydrogen atom, or R4together with R3mean the unbranched alkylene with 2 or 3 carbon atoms,

R5is a hydrogen atom or alkyl, or R4together with R5mean an additional bond, if G1means of communication,

R6is a hydrogen atom or alkyl or amino, if G1means tie the B>8is a hydrogen atom or alkyl, or R8together with R4mean the unbranched alkylene with 3 or 4 carbon atoms,

R9is a hydrogen atom or alkyl,

R10is a hydrogen atom or alkyl, or R10together with R4mean the unbranched alkylene with 3 or 4 carbon atoms,

R14is a hydrogen atom or alkyl,

R15is a hydrogen atom or alkyl,

R16is a hydrogen atom or alkyl,

R17is a hydrogen atom or alkyl, or R16together with R17mean an additional bond,

R18is a hydrogen atom, alkyl or chlorine atom or amino, if R16and R17together denote an additional bond,

n is the number 1 or 2,

In - line, alkylene with 1 to 6 carbon atoms, Allen substituted by one or two alkyl groups peridinian, pyrimidinyl, personalen or pyridazinyl, unsubstituted or substituted by one or two alkyl groups cyclohexyl, unsubstituted or substituted by one or two alkyl groups piperidinyl in which one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl,

the second of the residues Ra- Rdmeans a group of the formula

F - E - D -,

where alkylen, Allen, substituted on the tilen, 1,2,3,4-tetrahydronaphthalen or benzoguanamine, in which one of the rings is connected with the rest of E, and the other with a cyclic residue of General formula (I), unsubstituted or substituted by one or two alkyl groups cycloalkyl with 4 to 7 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups in which one group is replaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by a carbonyl, or alkilenkarbonatov, if E is a cyclic aminogroup, and a carbonyl linked to a nitrogen atom of a cyclic aminogroup group E, or a link, if E does not mean the relationship,

E - communication, alkylene, which may be substituted by an alkyl group with 1 to 6 carbon atoms, amino, aryl, alkylamino, dialkylamino, group HNR21- or N-alkyl-NR21-, where R21means alkylsulphonyl or alkylsulfonyl with 1 to 6 carbon atoms in the alkyl part, allyloxycarbonyl with the total number of carbon atoms 2 and 5 cycloalkylcarbonyl or cycloalkylcarbonyl with 5 to 7 carbon atoms in cycloalkyl part, arylalkylamines, arylalkylamines, arylethoxysilanes, allcarbon killname groups peridinian, pyrimidinyl, personalen or pyridazinyl, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one group is replaced by a nitrogen atom linked to the carbon atom of the residue D, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups associated with the remainder of D through the remainder of W alkylen, in which W denotes an oxygen atom or sulfur, sulfinil, sulfonyl, the group-NR20-CO - or-CO-NR20-, where R20means a hydrogen atom or alkyl, with alkylene can be optionally substituted alkyl group with 1 to 6 carbon atoms, amino, aryl, alkylamino, dialkylamino, group-HNR21- or N-alkyl-NR21where R21have the above significance, with an additional heteroatom substituent heteroatom is separated from the remainder of W by at least two carbon atoms, if D does not mean the relationship,

F - carbonyl, substituted by hydroxyl, alkoxyl, arialcategory or group R22O-, where R22means cycloalkyl with 5 to 7 carbon atoms or cycloalkyl with 5 to 7 carbon atoms in cycloalkyl part, the group R23CO-O-CHR24-O-CO-, where R23means alkyl, and the 4 is a hydrogen atom or alkyl, phosphono or O-alkylphosphine,

the shortest distance between the residue of F and located at a maximum distance from the rest F the nitrogen atom of the group A-B - is at least 11 links,

the third of the residues Ra- Rdmeans a hydrogen atom, alkoxyl that cannot be linked to a nitrogen atom, alkyl, trifluoromethyl or aryl, and

the fourth of the residue Ra- Rdmeans a hydrogen atom or alkyl,

and, if nothing else is mentioned,

under the above term "aryl" is to be understood phenyl, which can be monogamist the remainder R25mono-, di - or triamese the remainder R26or monogamist the remainder R25and additionally mono - or Disaese the remainder R26and the substituents may be the same or different, R25means cyano, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylsulphonyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl or trifluoromethyl, R26- alkyl, hydroxyl or alkoxy, fluorine atom, chlorine or bromine, and two residue R26if they are linked to adjacent carbon atoms, may also constitute the unbranched alkylene with 3 or 4 atoms of carbon phenylene, which can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents may be the same or different and have the above values,

and, if nothing else is mentioned, the above alkyl, alkylene or CNS groups can contain 1 to 4 carbon atoms and each of the carbon atoms in the above alkilinity and cycloalkenes groups associated at least one heteroatom,

mixtures of their isomers or individual isomers or their salts.

Particularly preferred compounds of General formula (I) are those in which

X is carbonyl or sulfonyl,

Y is a group-CH2CH2-, -CH2CH2CH2-, -CH=CH-, -CH2CO - or-COCH2-, unsubstituted or substituted by one or two methylene groups, unsubstituted or substituted Rcgroup-CO-NH-, -CH=N - or-N=CH-,

the first of the residues Ra- Rcmeans A group-B-, in which

A group of the formula

< / BR>
< / BR>
or

< / BR>
where bancoestado one or two methine groups may be replaced by a nitrogen atom,

G1- bond or methylene,

G2the om hydrogen

R3is a hydrogen atom,

R4is a hydrogen atom, cyclopropyl or cyclopropylmethyl, alkyl with 1 to 6 carbon atoms, allyl, hydroxyalkyl, carboxyethyl, alkoxycarbonyl or benzyl,

R5is a hydrogen atom,

R6is a hydrogen atom,

R14is a hydrogen atom or alkyl,

R15is a hydrogen atom or alkyl,

R16is a hydrogen atom or alkyl,

R17is a hydrogen atom, or R16together with R17mean an additional bond,

R18is a hydrogen atom or amino, if R16and R17together denote an additional bond,

n is the number 1 or 2,

In - bond or phenylene,

the second of the residues Ra- Rcmeans a group of the formula

F - E - D-,

where D is alkylene, phenylene, cyclohexene or piperidinyl, where the ring nitrogen atom is connected with an unsubstituted or substituted unbranched by alkylene residue is E or connection,

E - the unbranched alkylene, which can be substituted by alkyl or phenyl, albaniles with 2 to 4 carbon atoms, phenylene or unbranched O-alkylene associated with the remainder of D through an oxygen atom, if D does not mean the relationship,

F - carbonyl, substituted by hydroxyl or alkoxyl,

the shortest distance between th least 11 links,

the third of the residues Ra- Rcmeans a hydrogen atom, alkoxyl that cannot be linked to a nitrogen atom, alkyl or phenyl,

and, if nothing else is mentioned, the above alkyl, alkylene or CNS groups can contain 1 to 4 carbon atoms and each of the carbon atoms in the above alkilinity and cycloalkenes groups associated at least one heteroatom,

mixtures of their isomers or individual isomers or their salts.

Particularly preferred compounds of General formula (I) are those in which

X is carbonyl,

Y is a group-CH2CH2-, -CH2CH2CH2-, -CH=CH-, -CH2CO - or-COCH2or unsubstituted or substituted stands a group-N=CH-,

the remainder Rameans A group-B-, in which

A group of the formula

< / BR>
< / BR>
or

< / BR>
where bancoestado one or two methine groups may be replaced by a nitrogen atom,

G1- bond or methylene,

G2communications,

G3is methylene,

G4communications,

G5- Metin,

R2is a hydrogen atom,

R3is a hydrogen atom,

R4is a hydrogen atom, alkyl with 1 to 4 carbon atoms, allyl or benzyl,

R5- atom water>/BR>R16together with R17communications,

R18is a hydrogen atom or amino,

n - 1,

B - link,

the remainder Rbmeans a group of the formula

F - E - D-,

where D is the group-CH2CH2-, 1,4-phenylene or 1,4-cyclohexyl,

E is unsubstituted or substituted by stands the group-CH2CH2- the group-CH=CH-, 1,4-phenylene or a group-O-CH2where the oxygen atom of the group-O-CH2- connected with the rest of the D,

F - carbonyl, substituted by hydroxyl or alkoxyl with 1 to 4 carbon atoms,

the shortest distance between the residue of F and located at a maximum distance from the rest F the nitrogen atom of the group A-B - is at least 11 links,

mixtures of their isomers or individual isomers or their salts.

As particularly preferred compounds include, for example, the following:

(and) 1-[4-[2-(methoxycarbonyl)ethyl] phenyl] -3-(1,2,3,4 - tetrahydroisoquinoline-6-yl)-imidazolidin-2-it,

(b) 1-[4-(2-carboxyethyl)phenyl] -3-(1,2,3,4 - tetrahydroisoquinoline-6-yl)-imidazolidin-2-it,

(C) 1-[4-(2-carboxyethyl)phenyl] -3-(2-methyl-1,2,3,4 - tetrahydroisoquinoline-6-yl)-imidazolidin-2-it,

(g) 1-[4-(2-isobutylketone)ethyl]phenyl]-3-(1,2,3,4 - tetrahydroisoquinoline-6-yl)-imidazolidin-2-it,

(d) 1-[4-(2-carboxyethyl,5-tetrahydro - 1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(W) 1-[4-(2-isopropoxycarbonyl)ethyl] phenyl]-3- (2,3,4,5-etrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(C) 1-[4-(2-carboxyethyl)phenyl] -3-(3-methyl-2,3,4,5-tetrahydro - 1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(or) 4-[4-(2-carboxyethyl)phenyl] -5-methyl-2-(2,3,4,5-tetrahydro - 1H-3-benzazepin-7-yl)-4H-1,2,4-triazole-3-one,

(th) 1-[TRANS-4-(2-carboxyethyl)cyclohexyl]-3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(K) 1-[4-(2-methoxycarbonyl)ethyl] phenyl] -3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(l) 1-[4-[2-(etoxycarbonyl)ethyl] phenyl] -3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(m) 1-[4-[2-(isopropoxycarbonyl)ethyl]phenyl]-3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(n) 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(o) 1-[TRANS-4-[2-(isopropoxycarbonyl)ethyl] cyclohexyl] -3-(3 - methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(p) 1-[TRANS-4-[2-(etoxycarbonyl)ethyl] cyclohexyl] -3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(R) 1-[TRANS-4-(2-(methoxycarbonyl)ethyl] cyclohexyl] -3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(C) 1-[TRANS-4-[(CT-(2-carboxyethyl)cyclohexyl] -1-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

(u) 1-[TRANS-4-(2-carboxyethyl)cyclohexyl]-3-(3-ethyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

their tautomers and their salts.

The new compounds of General formula (I) can be obtained, for example, in the following ways:

a) To obtain compounds of General formula (I), in which F denotes carboxyl,

the compound of General formula (II)

< / BR>
in which Ra, RbX and Y have the above values are under the condition that one of the residues Ra- Rdmeans a group F'-E-D-, where E and D have the above values and F' means the group transferred to the carboxyl group by hydrolysis, treatment with acids, thermolysis or hydrogenolysis,

transferred to the compound of General formula (I), in which F denotes carboxyl group.

Functional derivatives of carboxylic groups, such as the unsubstituted or substituted amides, esters, complex thioethers, complex trimethylsilyloxy esters, complex orthoepy, complex aminoether, amidine or anhydrides, or nitrile can be converted to carboxyl group by hydrolysis, esters with tertiary alcohols, for example, tert.butyl ether can be converted to carboxyl group by treatment with acid or by those whom the group by hydrogenolysis.

The hydrolysis is expediently carried out in the presence of acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, triperoxonane acid or their mixtures, or in the presence of a base, such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide in an environment suitable solvent, such as, for example, water, mixtures of water and methanol, a mixture of water and ethanol, a mixture of water and isopropanol, methanol, ethanol, a mixture of water and tetrahydrofuran or a mixture of water and dioxane at temperatures between -10 and 120oC, for example at temperatures between room temperature and the boiling temperature of the reaction mixture.

In the above reaction conditions possible N-acylamino - or N-alluminare, for example N-triptoreline, can be translated into the corresponding amino - or aminogroup. In addition, when processing organic acid, such as, for example, trichloroacetic acid or triperoxonane acid, possible alcoholic hydroxyl group can be simultaneously transferred to the corresponding alloctype as, for example, triptracker.

In that case, if the compound of the formula (II) F' is for example, the sodium nitrite, in the presence of acid, such as, for example, sulfuric acid, and suitable this acid is simultaneously used as the solvent in this reaction is carried out at temperatures between 0 and 50oC.

In that case, if the compound of the formula (II) F' means, for example, tert. butyloxycarbonyl, tert.butyl can be removed by treatment with acid, such as, for example, triperoxonane acid, formic acid, p-toluensulfonate, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, if necessary in an inert solvent, such as, for example, methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120oC, for example at temperatures between 0 and 60oC, or by heat treatment, if necessary, in an inert solvent, such as, for example, methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of catalytic amount of acid, such as, for example, p-toluensulfonate, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at tempah reactions possible available N-tert.butyloxycarbonyl - or N-tert. butyloxycarbonyl can be translated into the corresponding amino - or aminogroup.

In that case, if the compound of the formula (II) F' means, for example, benzyloxycarbonyl, benzyl can be split by hydrogenolysis in the presence of a hydrogenation catalyst, e.g. palladium on charcoal, in an environment suitable solvent, such as, for example, methanol, ethanol, a mixture of ethanol and water, glacial acetic acid, complex ethyl ester acetic acid, dioxane or dimethylformamide, preferably at temperatures between 0 and 50oC, for example at room temperature, and hydrogen pressure 1 - 5 bar. When the hydrogenolysis you can transfer other balances, for example, the nitro-group to the amino group, benzyloxy in the hydroxyl group and N-benzylamino-, N-benzylamino-, N-benzyloxycarbonylamino - or N-benzyloxycarbonylamino to the corresponding amino - or aminogroup.

b) To obtain compounds of General formula (I), where R16and R17together denote an additional bond, G4connection and at least one of the residues R15or R18is hydroxyl, methoxyl, amino group, alkylamino or dialkylamino with 1 to 4 carbon atoms in the alkyl is provided which one of the residues Ra- Rdmeans A group-B-, where B has the above value, and A denotes a group of the formula

< / BR>
where pentostatin and G5have the above values, Z1and Z2that may be the same or different, mean nucleophilic delete the group, such as, for example, halogen atom such as chlorine atom or bromine, in this case, however, the remainder of Z1may have the above for R15or the residue of Z2specified for R18values

subjected to interaction with the compound of General formula

H - R27(IV)

where R27means hydroxyl, methoxyl, amino group, formylamino, acetylamino, alkylamino or dialkylamino with 1 to 4 carbon atoms in the alkyl part.

Interaction expediently carried out in an environment of a solvent, such as, for example, water, acetone, ethanol, tetrahydrofuran, dioxane, dimethylformamide or dimethylsulfoxide, in case of necessity, however, in excess of the applied compounds of General formula (IV) as a solvent and, if necessary, in the presence of a base, such as, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium amide or guide is.

To obtain compounds of General formula (I), where R16and R17together denote an additional bond, G4connection and R18- chlorine atom or bromine:

The interaction of compounds of General formula

< / BR>
where Ra, RbX and Y have the above values are under the condition that one of the residues Ra- Rdmeans A group-B-, where B has the above value, and A denotes a group of the formula

< / BR>
where pentostatin and G5have the above meanings and R15means a hydrogen atom or the above for R15alkyl or aryl group, halogenerator acid.

As galodamadruga acid is used, for example, phosphoroxychloride or phosphoroxychloride, and the reaction can be performed in the presence of a solvent, such as, for example, benzene, dichlorobenzene, nitrobenzene, carbon tetrachloride and, if necessary, in the presence of a salt of the corresponding halogen acids, such as, for example, sodium chloride or sodium bromide, at elevated temperatures, e.g. at temperatures between 50 and 250oC, preferably, however, at the boiling temperature of the reaction mixture.

g) To obtain compounds of General formula (I), s ' Rcor Rdor Rcand Rdnonbranched alkylene with 2 to 4 carbon atoms:

Cyclization of compounds of General formula

< / BR>
where Raand Rbhave the above meanings, X' is replaced by a cyano carbiener, carbonyl or sulfonyl, one of the residues U1or U2- the hydrogen atom and the other of the residues U1or U2unsubstituted or substituted Rwithor Rdor Rwithand Rdnonbranched alkylene with 2 to 4 carbon atoms, which in the end is additionally associated with removed by nucleophilic group such as a halogen atom, e.g. chlorine atom, bromine or iodine, hydroxyl or ester sulfonic acids, for example, methanesulfonate or p-toluensulfonate.

The interaction is preferably carried out in an environment of a solvent, such as, for example, methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide, if necessary in the presence of a base, such as, for example, sodium hydride, potassium carbonate, tert.the potassium butyl or N-ethyldiethanolamine or, if necessary, in the presence of a dehydrating agent such as a mixture of triphenylphosphine and diethyl ether complex and oC.

d) To obtain compounds of General formula (I), where X is a carbonyl, a Y one of the above alkilinity or alkenylamine groups.

The interaction of compounds of General formula

R28- NH - T (VII)

with an isocyanate of General formula

O = C = N - R29(VII)

where one of the residues R28or R29is specified for Ravalues and other residues R28or R29have the above for Rbvalues and T denotes unsubstituted or substituted in alkylidenes part Rcor Rdor Rcand Rda group of the formula

-(CH2)m-HC(OR30)2,

where m represents the number 1, 2 or 3 and R30is alkyl with 1 to 4 carbon atoms,

followed, if necessary, by hydrogenation.

The interaction can be performed in an inert solvent like dioxane or toluene at temperatures between 20 and 200oC, preferably at temperatures between 20 and 160oC.

Urea with an open circuit, possibly obtained as an intermediate product resulting from the interaction of compounds of General formula (VII) with an isocyanate of General formula (VIII), then transferred into the desired connection, in case the necessity acid or hydrochloric acid, if necessary in the environment of a solvent, such as, for example, methanol, ethanol, tetrahydrofuran or methylene chloride, at temperatures between 0oC and the boiling temperature of the reaction mixture.

Further, if necessary, the hydrogenation is preferably carried out with hydrogen in the presence of a catalyst, such as, for example, palladium on coal or platinum, in the environment of a solvent, such as, for example, methanol, ethanol, complex ethyl ester of acetic acid or glacial acetic acid, if necessary with the addition of acid, such as hydrochloric, at temperatures between 0 and 100oC, preferably however at temperatures between room temperature and 50oC and a hydrogen pressure of 1 to 7 bar, preferably, however, 3 to 5 bar.

e) To obtain compounds of General formula (I) in which G1and G2mean valence, G3is methylene, unsubstituted or substituted by alkyl with 1 to 4 carbon atoms, R2, R4and R5a hydrogen atom, R3and R6that may be the same or different, is a hydrogen atom or alkyl with 1 to 4 carbon atoms:

Hydrogenation of compounds of General formula

< / BR>
where Ra, RbX and Y have the above value A denotes a group of the formula

< / BR>
where pentostatin has the above value, means Metin, unsubstituted or substituted by alkyl with 1 to 4 carbon atoms, and which may be identical or different, denote a hydrogen atom or alkyl with 1 to 4 carbon atoms.

The hydrogenation is preferably carried out in an environment suitable solvent, such as, for example, methanol, a mixture of methanol and water, acetic acid, ethyl acetate, ethanol, diethyl ether, tetrahydrofuran, dioxane or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst, such as, for example, Raney Nickel, platinum dioxide, platinum, rhodium or palladium on charcoal, if necessary with the addition of acid, such as hydrochloric, at temperatures between 0 and 100oC, preferably at temperatures between 20 and 80oC. When this is available, if necessary, in the compound of General formula (IX) unsubstituted or substituted alkanolamine group can be converted to unsubstituted or substituted alkylene group.

(W) To obtain the compounds of General formula (I), where F denotes alkoxy with 1 to 6 carbon atoms, arylalkyl with 1 to 4 carbon atoms in the CNS part, while the aryl part has the above meaning, or Carboni is>RbX and Y have the above values are under the condition that one of the residues Ra- Rdmean group F-E-D-, where E and D have the above values and F" means carboxyl or alkoxycarbonyl,

with alcohol of General formula

HO - R31, (XI)

where R31have the above for R22value, and means alkyl with 1 to 6 carbon atoms or arylalkyl, in which the aryl part has the above meaning and the alkyl part can contain 1 to 4 carbon atoms.

The interaction of the carboxyl compound with the alcohol is carried out, if necessary, in the environment of the solvent or mixture of solvents, such as, for example, methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, a mixture of benzene and tetrahydrofuran or dioxane, or, particularly preferably, in the corresponding alcohol of General formula (XI), if necessary in the presence of an acid as hydrochloric acid or in the presence of a dehydrating agent such as, for example, a complex isobutyl ether of Harborview acid complex tetraethyl ester orthogonal acid complex timetravel ether octoxynol acid, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimetallic closeclicked, a mixture of N,N'-dicyclohexylcarbodiimide and N-hydroxysuccinimide, a mixture of N,N'-dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or a mixture of triphenylphosphine and carbon tetrachloride, and, if necessary, with addition of bases, such as, for example, pyridine, 4-dimethylaminopyridine or triethylamine, expediently at temperatures between 0 and 150oC, preferably at temperatures between 0 and 100oC.

The interaction of alkoxycarbonyl connection with alcohol of General formula (XI) is preferably carried out in the environment of the corresponding alcohol as solvent, if necessary in the presence of an additional solvent, such as, for example, methylene chloride or diethyl ether, preferably in the presence of acid, such as hydrochloric, at temperatures between 0 and 150oC, preferably at temperatures between 50 and 100oC.

(C) To obtain compounds of General formula (I) where one of the residues R4, R14or R16means unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl or aralkyl.

The interaction of compounds of General formula

< / BR>
where Ra, RbX and Y have the above values are provided what R4, R14and R16means a hydrogen atom,

with a compound of General formula

Z3- R32(XIII)

where R32means alkyl with 1 to 8 carbon atoms, cycloalkyl or cycloalkenyl in which cycloalkyl part may contain 3 to 7 carbon atoms and the alkyl part is of 1 to 4 carbon atoms, alkenilovyh group with 3 to 8 carbon atoms, arylalkyl, hydroxyalkyl, alkoxyalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl or N, N-dialkylaminoalkyl, in which the aryl portion and the alkyl parts have the above meanings and Z3means nucleophilic remove the group as a halogen atom, e.g. chlorine atom, bromine or iodine, or an ester of sulfonic acids, such as, for example, methanesulfonamido or p-toluensulfonate, or Z3together with the adjacent hydrogen atom of the residue R32mean oxygen atom.

Alkylation of a compound of formula (XIII), where Z3means nucleophilic delete the group, it is advisable carried out in the environment of a solvent, such as, for example, methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide or dimethylformamide, if necessary in prostrating organic bases, such as, for example, N-ethyl-Diisopropylamine or N-methyl-morpholine, which may simultaneously serve as solvent, at temperatures between -30 and 150oC, preferably however at temperatures between 20 and 120oC.

Reductive alkylation of a carbonyl compound of General formula (XIII) is carried out in the presence of a complex metal hydride, such as, for example, sodium borohydride, lithium borohydride or cyanic sodium borohydride useful in the pH 6 - 7 and room temperature or in the presence of a hydrogenation catalyst, for example hydrogen in the presence of palladium on charcoal, at a hydrogen pressure 1 - 5 bar. Methylation, however, preferably carried out in the presence of formic acid as reducing agent at elevated temperatures, for example at temperatures between 60 and 120oC.

(and) To obtain compounds of General formula (I) in which X represents carbiener, substituted at the nitrogen atom by a cyano, carbonyl or sulphonyl:

The interaction of compounds of General formula

< / BR>
with a compound of General formula

Z4- R34(XV)

where Y has the above value, X represents carbiener, substituted atom has the UB>avalues and other residues R33or R34have the above for Rbvalues, a Z4means nucleophilic remove the group as halogen atom, hydroxyl or an ester of sulfonic acids, for example, fluorine atom, chlorine, bromine or iodine, methanesulfonamido or p-toluensulfonate.

The interaction is preferably carried out in an environment of a solvent, such as, for example, methylene chloride, acetonitrile, tetrahydrofuran, toluene, pyrimidine, dimethylformamide, dimethylsulfoxide or N-methyl-pyrrolidone, if necessary in the presence of one or more bases, such as, for example, sodium hydride, potassium carbonate, tert.the potassium butyl, N-ethyl-Diisopropylamine, Tris-[2-(2-methoxyethoxy)ethyl] amine or N,N,N',N'-tetramethylethylenediamine and, if necessary, in the presence of a dehydrating agent as a mixture of triphenylphosphine and diethyl ether complex of azodicarboxylic acid and, if necessary, in the presence of copper powder or one or more salts of copper as copper iodide (I) as an accelerator of the reaction at temperatures between -20 and 250oC, preferably however at temperatures between 0 and 60oC if Z4associated with aliphatic ATA, the rich in this case, Z4can only mean a halogen atom.

(s) To obtain compounds of General formula (I) in which R4or R14mean alkoxycarbonyl, allmediascotland, formyl, acetyl, TRIFLUOROACETYL, allyloxycarbonyl or group, R11CO-O-(R12CR13)-O-CO-, in which R11- R13and aryl part have the above values and CNS part may contain 1 to 4 carbon atoms:

The interaction of compounds of General formula

< / BR>
where Ra, RbX and Y have the above values are under the condition that R4or R14means a hydrogen atom,

with a compound of General formula

Z5- R35(XVII)

where R35means alkoxycarbonyl with the total number of carbon atoms 2-5, allmediascotland, in which the aryl part has the above meaning, formyl, acetyl, allyloxycarbonyl, the group R11CO-O-(R12CR13)-O-CO-, where R11- R13have the above significance, or TRIFLUOROACETYL, and Z5means nucleophilic remove the group as a halogen atom, aryloxy, aaltio, alkoxyl, alkoxycarbonyl, alcoxycarboxylates or N-imidazolyl, for example, a chlorine atom or bromine or 4-nitro-fenoxaprop drofuran, methylene chloride, chloroform, dimethylformamide, water or mixtures of these solvents, if necessary in the presence of a base, such as, for example, sodium carbonate, potassium carbonate or sodium lye or in the presence of tertiary organic bases, such as, for example, triethylamine, N-ethyl-Diisopropylamine, N-methyl-morpholine or pyridine, which may simultaneously serve as solvent, at temperatures between -30 and 100oC, preferably however at temperatures between -10 and 60oC.

(K) To obtain the compounds of General formula (I), in which F denotes a carbonyl, substituted CNS group with 1 to 6 carbon atoms, arylalkenes group, where the aryl part has the above meaning and CNS part may contain 1 to 4 carbon atom, a group R22O - or R23CO-O-CHR24-O-, R22- R24have the above values:

The interaction of compounds of General formula

< / BR>
where Ra, RbX and Y have the above values are under the condition that one of the residues Ra- Rdmean group F"'-E-D-, in which E and D have the above values and F"' means carboxyl,

with a compound of General formula

Z6- RIshukone value and the alkyl part can contain 1 - 4 carbon atoms, the group R22or R23CO-O-CHR24-, where R22- R24have the above meanings and Z6means nucleophilic remove the group as a halogen atom or an ester of sulfonic acids, such as, for example, chlorine atom or bromine, methysulfonylmethane or p-toluensulfonate.

The interaction is preferably carried out in an environment of a solvent, such as, for example, methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide or dimethylformamide, if necessary in the presence of a reaction accelerator as sodium iodide or potassium, and preferably in the presence of a base, such as, for example, sodium carbonate, potassium carbonate or sodium lye or in the presence of tertiary organic bases, such as, for example, N-ethyl-Diisopropylamine or N-methyl-morpholine, which may simultaneously also serve as solvent, or, if necessary, in the presence of silver carbonate or silver oxide at temperatures between -30 and 100oC, preferably however at temperatures between -10 and 80oC.

(l) To obtain compounds of General formula (I) in which X is carbonyl and Y is unsubstituted or substituted RcPA at the end is replaced by a carbonyl:

Cyclization of the formed if necessary in the reaction mixture of the compounds of General formula

< / BR>
where Raand Rbhave the above meanings, X represents carbonyl, one of the residues U3or U4- the hydrogen atom and the other of the residues U3or U4means unsubstituted or substituted Rcor Rdor Rcand Rdnonbranched alkylen with 2-4 carbon atoms, where a methylene group in the end replaced by a group of Z7-CO-, in which Z7means nucleophilic remove the group as halogen atom, hydroxyl, alkoxyl, aryloxy or arylalkyl, for example, a chlorine atom or bromine, hydroxyl, methoxy, ethoxy, phenoxy or benzyloxy.

The interaction is preferably carried out in an environment of a solvent, such as, for example, methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide, if necessary in the presence of a base, such as, for example, sodium hydride, potassium carbonate, tert.the potassium butyl or N-ethyl-Diisopropylamine or, if necessary, in the presence of a dehydrating agent such as, for example, a mixture of triphenylphosphine and diethyl ether complex of azodicarboxylic acid or N,N'-WHAT UP>C.

If according to the invention have the compound of General formula (I) containing an unsaturated carbon-carbon bond, it can be translated into the corresponding saturated compound of General formula (I) by catalytic hydrogenation.

The catalytic hydrogenation is preferably carried out with hydrogen in the presence of a catalyst like palladium on coal in the environment of a solvent, such as, for example, methanol, ethanol, complex ethyl ester of acetic acid or glacial acetic acid, if necessary with the addition of acid as hydrochloric acid at temperatures between 0 and 100oC, preferably however at temperatures between 20 and 60oC, at a pressure of hydrogen of 1 to 7 bar, preferably, however, at 3 to 5 bar.

When the above reactions may available reactive groups as hydroxyl, carboxyl, phosphono-, O-alkyl-phosphono-, amino-, alkylamino-, imino - or amidinopropane during the reaction can be protected customary protective groups, which are removed upon completion of the reaction.

As a protective residue to the hydroxyl group can be applied, for example, trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl,

as a protective residue to phosphonopropyl - alkyl, such as, for example, methyl, ethyl, isopropyl or n-butyl, phenyl or benzyl,

as a protective residue to amidinopropane, unsubstituted or substituted by alkyl, - benzyloxycarbonyl, and

as a protective residue for amino, alkylamino or aminogroup - formyl, acetyl, TRIFLUOROACETYL, etoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl to aminogroup additional methyl, and amino - ftlil.

Possible subsequent removal of the used protective residue is carried out, for example, by hydrolysis in aqueous solvent, such as, for example, water, a mixture of isopropanol and water, a mixture of acetic acid and water, a mixture of tetrahydrofuran and water or in a mixture of dioxane and water, in the presence of acid, such as, for example, triperoxonane acid, hydrochloric acid or sulphuric acid or in the presence of an alkaline base, such as, for example, sodium hydroxide or potassium, or by splitting a simple ether, for example in the presence of trimethylsilane iodide, at temperatures between 0 and 120oC, preferably at temperatures between 10 and 100oC.

Snatm hydrogenolysis, for example with hydrogen in the presence of a catalyst like palladium on coal in the environment of a solvent, such as, for example, methanol, ethanol, complex ethyl ester of acetic acid or glacial acetic acid, if necessary with the addition of acid as hydrochloric acid at temperatures between 0 and 100oC, preferably however at temperatures between 20 and 60oC, at a pressure of hydrogen of 1 to 7 bar, preferably, however, 3 to 5 bar. Removal of 2,4-dimethoxybenzamide balance exercise, however, preferably trifluoroacetic acid in the presence of anisole.

Removal of the tert. butyl or tert.butyloxycarbonyl residue is preferably carried out by treatment with acid, such as, for example, triperoxonane acid or hydrochloric acid, or by treatment with trimethylsilanol iodine, if necessary using a solvent such as, for example, methylene chloride, dioxane, methanol or ether.

Removing triftoratsetatov residue is preferably carried out by treatment with acid, such as hydrochloric, if necessary in the presence of a solvent, such as, for example, acetic acid or methanol, at temperatures between 50 and 120oC or by drofuran or methanol, at temperatures between 0 and 50oC.

Removing methyl groups from methylaminopropyl preferably carried out in the presence of complex 1-chloralkali esters of Harborview acid as a complex 1-hloretilova ether Harborview acid, preferably in the presence of a base such as 1,8-bis(dimethylamino)-naphthalene, in the presence of a solvent, such as, for example, methylene chloride, 1,2-dichloroethane, toluene or dioxane, at temperatures between 0 and 150oC, preferably at temperatures between 20oC and the boiling temperature of the reaction mixture, and subsequent treatment with alcohol, such as methanol, at temperatures between 20oC and the boiling point of the used alcohol.

Removing telelavoro residue is preferably carried out in the presence of hydrazine or a primary amine, such as, for example, methylamine, ethylamine or n-butylamine in a solvent environment, such as, for example, methanol, ethanol, isopropanol, a mixture of toluene and water, or dioxane, at temperatures between 20 and 50oC.

Removing only one alkyl residue with O,O'-dialkylphosphorous carried out, for example, sodium iodide in a solvent environment, such as, for example, acetone, ethylmethylketone, the arts between 60 and 100oC.

Removing both alkyl residues with O,O'-dialkylphosphorous carried out, for example, iodine trimethylsilanol, bromide by trimethylsilanol or a mixture of trimethylsilane chloride and sodium iodide in a solvent environment, such as, for example, methylene chloride, chloroform or acetonitrile, at temperatures between 0oC and the boiling temperature of the reaction mixture, preferably however at temperatures between 20 and 60oC.

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

For example, the mixture of CIS-/TRANS-isomers can be divided by chromatography on a separate CIS - and TRANS-isomers, the compounds of General formula (I), existing in the form of the racemates, by well-known methods (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", vol. 6, Wiley Intersience, 1971) - optical antipodes and compounds of General formula (I) with at least two asymmetric carbon atoms on the basis of their physical chemical differences by hoorie, if they are in the form of the racemates, can then, as videocasino, divided into 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 forming with the racemic compound, salt or derivative as, for example, esters or amides, optically active substance, in particular acid and their activated derivatives or alcohols, and by dividing the thus obtained diastereomeric mixture of salts or a derivative thereof, for example on the basis of different solubilities, and from the pure diastereomeric salts or derivatives, you can release the free antipodes impact through appropriate means. Especially used optically active acids are, for example, D - and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-trillina acid, malic acid, mandelic acid, camphor acid, glutamic acid, aspartic acid or Hinn acid. As the optically active alcohol can be called, for example, (+)- or (-)-menthol, and as optically active etilovogo balance Amidah - apria salt, particularly for pharmaceutical use into their physiologically tolerated salts with inorganic or organic acids. As acids can be used such as, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the thus obtained new compounds of formula (I), if the latter contain carboxyl, sulfo - phosphono - O-alkyl-phosphono or tetrazol-5-yl group, if desired, then translate into their salts with inorganic or organic bases, particularly for pharmaceutical use into their physiologically tolerated salts. As the bases can be used, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, dietel - amine and triethanolamine.

Used as starting substances compounds are partly known from the literature or can be obtained by known literature methods (see examples I-XVI).

For example, the corresponding cyclic derivative of urea are obtained by cyclization, respectively, substituted urea, which E interaction respectively substituted diamine with a derivative of carbonic acid, for example with phosgene, or an appropriate derivative triazolone by cyclization of the corresponding semicarbazide resulting from the interaction of the corresponding isocyanate with the appropriate hydrazide.

In the thus obtained derivative of a cyclic urea can then, if necessary, to translate to the corresponding carbonyl or thiocarbonyl carbamino group by known methods.

In the thus obtained cyclic original compounds or even necessary to obtain the source connection available ester can be converted to carboxy by hydrolysis or perhaps available carboxyl - ester.

As already mentioned above, the new cyclic nitrogen-containing derivatives of General formula (I) and their salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases, have valuable properties. For example, in addition to anti-inflammatory actions and inhibiting bone decay they, in particular, have antithrombotic, antiaggregatory, antitumor and protivoglistnym actions.

The biological activity of the United States-BIBU 52 with human platelets

In a suspension of human platelets in plasma add3H-BIBU 52 [= (3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] - 3-[(carboxy)methyl]-2-pyrrolidinone[3-3H-4-biphenylyl] ] , substitute known from the literature ligand125J-fibrinogen, and incubated with different concentrations of the studied compounds. Free and bound ligands are separated by centrifugation, and their number is determined by scintillation. Based on the results of the experiment determine the inhibition of binding3H-BIBU 52 of the investigated compound.

For the implementation of the experience by puncture anticubital Vienna extract the blood to delay the clotting process triatriatum (final concentration: 13 mmol). The blood is subjected to centrifugation at 170 x g for 10 minutes. Platelet-rich plasma is removed, and the residual blood for plasma again centrifuged. Platelet-rich plasma was diluted with autologous plasma at a ratio of 1 : 10. 750 μl of the fluid together with 50 μl of physiological saline, 100 μl of a solution of tested compound, 50 μl of14C-sucrose (3700 Bq) and 50 μl of3H-BIBU 52 (final concentration: 5 nmol) are incubated at room tempera who have 5 ál BIBU 52 (final concentration: 30 Microm). Samples are centrifuged at 10,000 x g for 20 sec, the supernatant removed. 100 μl of this liquid is subjected to measurement to determine the free ligand. Product centrifugation is dissolved in 500 μl of 0.2 N. of sodium hydroxide, to 450 μl of the resulting solution add 2 ml of scintillation fluid and 25 μl of 5 N. hydrochloric acid and measured. Still available in the product centrifugation, the plasma is determined from the contents of the14C, and the bound ligand - based3H. After subtraction of nonspecific binding compared the activity of centrifugate with the concentration of the compounds and determine the concentration at which the analyzed compound inhibits binding3H-BIBU 52 50% (concentration braking CT50).

2. Antithrombotic action

Technique

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

Induced collagen aggregation

The decrease in optical density of a suspension of platelets is measured photometrically and register after you add the as curve, showing the highest light transmission, calculates the optical density.

The amount of collagen choose more small, but sufficient for irreversible reaction curve. Use commercially available collagen firm Gormonami, , Munich/DE. Before adding collagen plasma together with a test compound are incubated at a temperature of 37oC for 10 minutes.

On the basis of the curves for concentration and effect determine the effective dose ED50in nmol, i.e., the dose that produces 50% inhibition of change of optical density.

The results of the experiment are shown in the following table.

In addition, the compounds of examples 7 and 19, for example, inhibit collagen-induced platelet aggregation ex vivo in Macaca-RH after giving oral 1 mg/kg over 5 and 8 hours, respectively.

The new compounds possess well tolerated by the body, as, for example, after intravenous giving three mice 30 mg / kg of the compounds according to examples 8 (1) or 19 none of the animals died.

Thanks inhibitory effect on the interaction between cells or between cells and matrix new heteroclita, when you have an aggregation of 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 disease, embolism of the pulmonary artery or its branches, myocardial infarction, arteriosclerosis, osteoporosis and metastasis of tumors or treatment of genetically determined or acquired disorders of interaction between cells or between cells and solid structures. In addition, these compounds are suitable for treatment of when thrombolyse when using fibrinolytic drugs or interventions in the vessels, for example, percutaneous balloon angioplasty of the coronary arteries, 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 per kg of body weight, preferably 1 μg to 15 mg per kg of body weight, in 1 to 4 doses per day. The new compounds of General formula (I) can be converted to known drugs, for example, tablets, pills, capsules, powders, suspensions, solutions, sprays or suppositories, in case the necessity is their synthesis of thromboxane substances or their mixture, the serotonin antagonists, antagonists of receptors, alkyl nitrate, for example, trinitrate, substances inhibiting phosphodiesterase, prostacyclines and their analogues, anti-fibrinolytic drugs such as tissue plasminogen activator, PUK, streptokinase, or inhibiting clotting medications, such as heparin sulfate of dermatan, activated protein C, vitamin K antagonists, hirudin, inhibitors of thrombin or other activated clotting factors, together with one or some of the 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 and glycerol with a mixture of water and sorbitol, a mixture of water and glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as utverzhdennym fat, or their suitable mixtures.

The following examples illustrate how to obtain the original compounds.

Example I

1-(isoquinoline-N-oxide-6-yl)-3-[4-[2-(methoxycarbonyl)ethyl]phenyl]- imidazolidin-2-he

oC is diluted with methylene chloride and extracted twice with a solution of sodium bicarbonate and sodium thiosulfate solution and then with water. The organic phase is separated, dried and evaporated in a rotary evaporator.

Yield: 2.4 g (88% of theory)

The value of Rf: of 0.15 (silica gel; a mixture of methylene chloride, methanol and ethyl acetate in a ratio of 20 : 1 : 1)

Example II

N-(2-hydroxyethyl) - N'-(isoquinoline-6-yl)-N-[4-[2-(methoxy - carbonyl)ethyl] phenyl]-urea

To 7.2 g of imidazole and 10.1 g of N,N'-carbonyldiimidazole in 100 ml of dimethylformamide at a temperature of 0 to 10oC was added dropwise 9.0 g of 6-aminoisoquinoline in 70 ml of dimethylformamide. After stirring for 2 hours at room temperature was added dropwise and 15.3 g of N-(2-hydroxyethyl)-4-[2-(methoxycarbonyl)ethyl] -aniline in 20 ml of dimethylformamide and stirred for 2.5 days at room temperature. Dissolve 750 ml of ethyl acetate and extracted twice with water and saturated salt solution. The organic phase is separated, dried and concentrated. The residue is purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate, metical; a mixture of methylene chloride, methanol and ethyl acetate in a ratio of 20 : 1: 1)

Similarly receive the following connections:

(1) N-2,2-diatexite)-N'-(isoquinoline-6-yl)-N-[4-[2- (methoxycarbonyl)ethyl] phenyl]-urea

The value of Rf: of 0.50 (silica gel; a mixture of methylene chloride and methanol in a ratio of 20:1)

(2) N-(3-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-N'-(2,2 - diatexite)-N'-[TRANS-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]- urea

Melting point: 101 - 104oC

The value of Rf: to 0.63 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia in the ratio of 90 : 10 : 2)

(3) N-(7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d] azepin-2-yl)- N'-2,2-diatexite)-N'-[TRANS-4-[2-(methoxycarbonyl)ethyl]- cyclohexyl]-urea

The reaction is carried out in the presence of 1,1'-carbonyl-di-(1,2,4-triazole)

Melting point: 100 - 102oC

The value of Rf: 0,41 (silica gel; a mixture of methylene chloride and methanol in the ratio 9:1)

Calculated: C 62,40; H 8,73; N 13,48.

Found: C 62,19; H 8,79; N 13,62.

(4) N-(7-benzyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2 - yl)-N'-diatexite)-N'-[TRANS-4-[2-(methoxycarbonyl)ethyl]- cyclohexyl]-urea

The reaction is carried out in the presence of 1,1'-carbonyl-di-(1,2,4-triazole)

Values of salt in the ratio 6 : 4)

Example III

N-(3-tert. butyloxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepin - 7-yl)-N-(2-hydroxyethyl)-N'-[4-[2-(methoxycarbonyl)ethyl]phenyl - urea

4.5 g of 3-(tert.butyloxycarbonyl)-7-[(2-hydroxyethyl)amino]- 2,3,4,5-tetrahydro-1H-3-benzazepine and 3.7 g of 4-[2-(methoxycarbonyl)ethyl]-phenylisocyanate (obtained from the corresponding amine by reacting with phosgene) is stirred in 35 ml of dioxane 3.5 hours at room temperature. The reaction mixture was concentrated, the residue is triturated with tert.butyl methyl ether and sucked off. The product is washed with tert.butyl methyl ether and dried.

Yield: 6.3 g (76% of theory)

Melting point: 115 - 117oC

The value of Rf: to 0.30 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

Similarly receive the following connections:

(1) 1-acetyl-4-[4-[2-(methoxycarbonyl)ethyl]phenyl]-semicarbazide

(The interaction of acetylhydrazine 4-[2-(methoxycarbonyl)ethyl]-phenylisocyanate)

Melting point: 159 - 165oC

The value of Rf: of 0.37 (silica gel; a mixture of methylene chloride and methanol in the ratio 9:1)

(2) N-(2-hydroxyethyl)-N-[TRANS-4-[2-(methoxycarbonyl)ethyl] - cyclohexyl]-N'-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin - 7-yl)-urea
the ratio of 1 : 1)

(3) N-(2,2-diatexite)-N-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro - 1H-3-benzazepin-7-yl)-N'-[TRANS-4-[2-(methoxycarbonyl)ethyl] - cyclohexyl]-urea

Used [TRANS-4-[2-(meloxicam bonyl)ethyl] cyclohexyl]-isocyanate is obtained from the corresponding amine in the form of the hydrochloride as a result of interaction with phosgene. Used 7-[(2,2-diatexite)amino]-3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3 - benzazepin [value Rf: 0,76 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 3 : 2)] is produced by the interaction of 7-amino-3-TRIFLUOROACETYL - 2,3,4,5-tetrahydro-1H-3-benzazepine with diethylacetal of bromoacetaldehyde in the presence of N-ethyl-Diisopropylamine.

The value of Rf: of 0.26 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 3 : 2)

(4) N-[TRANS-[[methoxycarbonyl)methyl]oxy]cyclohexyl]-N'- (2,2-diatexite)-N'(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3 - benzazepin-7-yl)-urea

Used [TRANS-4-[(methoxycarbonyl)methyl]oxy]cyclohexyl]- isocyanate is obtained from the corresponding amine in the form of the hydrochloride as a result of interaction with phosgene.

The value of Rf: of 0.20 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

(5) N-(2-hydroxyethyl)-N-[4-[TRANS-2-(methoxycarbonyl)ethynyl]- trihydro-1H-3-benzazepin-7-yl-isocyanate is obtained from the corresponding amine by the interaction with phosgene.

Melting point: starting with 118oC

The value of Rf: of 0.18 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

(6) N-[4-(2-etoxycarbonyl)-1-propyl] phenyl-N'-(2,2-diatexite)-N'-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-urea

Applied [4-[2-(etoxycarbonyl)-1-propyl]phenyl]-isocyanate produced by interaction of the corresponding amine with phosgene.

The value of Rf: of 0.35 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 2 : 1)

(7) N-[TRANS-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]-N'- [(benzyloxycarbonyl)methyl]-N'-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro - 1H-3-benzazepin-7-yl)-urea

Used 7-[[(benzyloxycarbonyl)methyl] amino] -3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin [value Rf: to 0.24 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio of 4 : 1] get as a result of the interaction of 7-amino-3-TRIFLUOROACETYL - 2,3,4,5-tetrahydro-1H-3-benzazepine with complex benzyl ether bromoxynil acid in the presence of N-ethyl-Diisopropylamine.

The value of Rf: of 0.51 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

(8) N-(3-hydroxypropyl)-N-[TRANS-4-[2-methoxycarbonyl)ethyl]- cyclohexyl]-N'-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-be logical] - the formation of

Melting point: 176 - 179oC

The value of Rf: to 0.24 (silica gel; a mixture of methylene chloride and methanol in the ratio 95:5)

(10) 1-formyl-4-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] - the formation of

Melting point: 169 - 171oC

(11) N-[4-[2-etoxycarbonyl)-1-phenyl-ethyl] phenyl] -N'-(2,2 - diatexite)-N'-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin - 7-yl)-urea

Applied [4-[2-(etoxycarbonyl)-1-phenyl-ethyl]phenyl]-isocyanate is obtained from the corresponding amine by reacting with phosgene. The crude product is directly used for obtaining the compound of example 5(6).

(12) 1-formyl-4-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3 - benzazepin-7-yl)-the formation of

The value of Rf: 0,41 (silica gel; a mixture of methylene chloride and methanol in the ratio 9:1)

Example IV

3-(tert. butyloxycarbonyl)-7-[(2-hydroxyethyl)amino] -2,3,4,5 - tetrahydro-1H-3-benzazepin

7.2 g of 7-amino-3-(tert.butyloxycarbonyl)-2,3,4,5-tetrahydro-1H - 3-benzazepine (obtained from 7-nitro-2,3,4,5-tetrahydro-1H-3 - benzazepine by interacting with a complex of di-tert.butyl ether pyrogallol acid and subsequent hydrogenation in the presence of palladium on charcoal) in 130 ml of methanol under stirring the IDA sodium and stirred for one hour at room temperature. The reaction mixture is evaporated, the residue is distributed between ethyl acetate and water. The organic phase is separated, washed twice with water, dried and evaporated in a rotary evaporator. The residue is purified by column chromatography on silica gel using as eluent a mixture of cyclohexane and ethyl acetate in the ratio of 4 : 6.

Output: 5,4 g (64% of theory)

Melting point: 86 - 89oC

The value of Rf: to 0.39 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 4 : 6)

Similarly receive the following connection:

Methyl ester of TRANS-4-[(2-hydroxyethyl)amino]-cinnamic acid

Melting point: 117 - 118oC

The value of Rf: of 0.25 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

Example V

(4aRS, 6RS, 8aRS)-6-[(2,2-dimethoxymethyl)amino] -2-methyl - 1,2,3,4,4 a, 5,6,7,8,8 a-decahydroquinoline

To a solution of 9.0 g (4RS,8RS)-2-methyl-6-oxo - 1,2,3,4,4 and,5,6,7,8,8 a-decahydroquinoline and 6.8 g of dimethylacetal amino-acetaldehyde in 90 ml of acetonitrile added 31 ml of 3 N. hydrochloric acid and stirred for 30 minutes at room temperature. Then cooled in an ice bath and portions add 4.4 g of laborgerate sodium. After 30 minutes stirring at room temperature the shape with ethyl acetate. The combined ethyl acetate extracts washed twice with a saturated solution of sodium chloride, dried and concentrated. The residue is purified by column chromatography on basic aluminum oxide.

Output: 7,35 g (53% of theory)

The value of Rf: 0,25 (alumina; ethyl acetate)

As a by-product of the example (V) allocate (4aRS,6SR,8aRS)-6-[(2,2-di-methoxyethyl)amino] -2-methyl - 1,2,3,4,4 and,5,6,7,8,8 a-decahydroquinoline.

The value of Rf: 0,56 (alumina; ethyl acetate)

Example VI

7-iodine-3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin

2.6 g of 7-amino-3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepine under stirring briefly heated with 50 ml of 10% hydrochloric acid, then cooled to 0oC and upon further cooling at 0oC add drops 695 mg of sodium nitrite in 14 ml of water. Then at 0oC was added dropwise a solution of 1.7 g of potassium iodide and 1.3 g of iodine in 10 ml of water and stirred over night at room temperature. Then decanted and the resulting residue is dissolved in methylene chloride. The organic phase is washed with a solution of disulfit sodium and water, separated, dried, filtered and evaporated in a rotary evaporator. The crude product is purified column chromatography on silica gel with the Oria)

Melting point: 80 - 82oC

The value of Rf: 0,61 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 4 : 1)

Example VII

7-amino-3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin

17.3 g of 7-nitro-3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3 - benzazepine hydronaut when the hydrogen pressure 3,52 kg/cm2and room temperature for one hour in 200 ml of ethyl acetate 3 g 10% palladium on active coal. The catalyst is sucked off and the filtrate evaporated. The residue is heated with tert. butylmethylamine ether and cooled. The precipitate is sucked off, washed with tert. butylmethylamine ether and dried.

Yield: 12.2 g (79% of theory)

Melting point: 102 - 104oC

The value of Rf: 0,31 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 2 : 1)

Similarly receive the following connections:

(1) 7-amino-3-tert.butyloxycarbonyl-2,3,4,5-tetrahydro-1H-3 - benzazepin

Used as the starting compound 3-tert. butyloxycarbonyl-7-nitro-2,3,4,5-tetrahydro-1H-3-benzazepin (melting point: 100 - 102oC) get the result of the interaction of the hydrochloride of 7-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine with a complex of di-tert.butyl ether pyrogallol acid in the presence of BR> (2) 7-amino-3-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin

Interaction on the Raney Nickel in the environment of methanol.

The value of Rf: of 0.58 (silica gel; a mixture of toluene, dioxane, methanol and conc. aqueous ammonia at a ratio of 20 : 50 : 20 : 3)

(3) Hydrochloride complex ethyl ester 3-(4-AMINOPHENYL)-3-phenyl-propionic acid

The implementation of the reaction in ethanol medium in the presence of ethanolic hydrochloric acid. The original compound, complex ethyl ester of 3-(4-nitrophenyl)-3-phenylacrylate acid (a value of Rf: of 0.36 (silica gel; a mixture of cyclohexane and methylene chloride in the ratio 1 : 1) receive the result of the interaction of 4-nitrobenzophenone with complex triethylamin ether phosphonooxy acid.

The value of Rf: 0,40 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

Example VIII

7-nitro-3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin

To a solution of 23.3 g of 3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3 - benzazepine [value Rf: 0,76 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1) obtained by reacting 2,3,4,5-tetrahydro-1H-3-benzazepine with anhydride triperoxonane acid in the presence of N-ethyl-visapro the ml conc. of sulfuric acid. Warmed to room temperature, served on 1 l of ice and extracted with ethyl acetate. United an ethyl acetate phases are washed with water and saturated common salt solution, dried and evaporated. The residue is heated with tert.butyl methyl ether. Then cooled, the product is sucked off and washed with tert.butyl methyl ether.

Yield: 16.2 g (59% of theory)

Melting point: 116 - 119oC

The value of Rf: or 0.57 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 2 : 1)

Similarly, you can obtain the following connection:

The hydrochloride of 7-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine

Receiving, using a mixture of sulfuric acid and potassium nitrate and isolation as hydrochloride

Melting point: 235 - 238oC (decomp.)

Calculated: C 52,52; H 5,74; N 12,25; Cl 15,50.

Found: C 52,44; H 5,80; N 12,07; Cl 15,36.

Example IX

4-[4-[2-(methoxycarbonyl)ethyl]phenyl]-5-methyl-4H-1,2,4-triazole-3-one

of 8.1 g of 1-acetyl-4-[4-[2-(methoxycarbonyl)ethyl]phenyl]- semicarbazide together with 60 ml of 1 N. sodium liquor is heated on the steam bath for 1.5 hours. Then slightly cooled, filtered and the filtrate is weakly acidified with citric acid. Filtered and the filtrate smeshivautsya overnight in methanol with a small amount of methanolic hydrochloric acid. The reaction mixture was concentrated and the residue triturated with tert. butyl methyl ether, sucked off and dried.

Output: to 4.98 g (65% of theory)

The value of Rf: to 0.40 (silica gel; a mixture of toluene, dioxane, ethanol and ethyl acetate in the ratio 90:10:10:6)

Calculated: 59,76; H 5,79; N 16,08.

Found: C 59,54; H 5,86; N Of 16.05.

Similarly receive the following connections:

(1) 4-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -5-methyl-4H - 1,2,4-triazole-3-one

Melting point: 179 - 181oC

(2) 4-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -4H-1,2,4 - triazole-3-one

Melting point: 142 - 144oC

(3) 4-(3-tert.butyloxycarbonyl-2,3,4,5-tetrahydro-1H-3 - benzazepin-7-yl)-4H-1,2,4-triazole-3-one

Initial connection: connection example III (12)

The intermediate product is subjected to interaction with a complex of di-tert.butyl ether pyrogallol acid (together with methanolic hydrochloric acid). Melting point: 185 - 186oC

The value of Rf: of 0.25 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 2 : 3)

Example X

N-[TRANS-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]-ethanolamine

5.0 g of N-benzyl-N-[TRANS-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]- ethanolamine hydronaut in 150 ml of methanol is effective angle. Filtered and evaporated.

Output: 3.3 grams (92% of theory)

The value of Rf: of 0.20 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia in a ratio of 9 : 1 : 0,4)

Similarly receive the following connections:

(1) Complex tert.butyl ether (TRANS-4-aminocyclohexane)exucuse acid

The original compound, complex tert.butyl ether [TRANS-(4 - dibenzylamino)cyclohexyl] exucuse acid [value Rf: of 0.51 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 4 : 1)], receive the result of the interaction of TRANS-4- (dibenzylamino)cyclohexanol with complex tert.butyl ether bromoxynil acid in a mixture of toluene and 50% aqueous sodium liquor in the presence of hydrogensulfate tetrabutylammonium.

The value of Rf: 0,56 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(2) N-(3-hydroxypropyl)-N-[TRANS-4-[2-(methoxycarbonyl)ethyl]- cyclohexyl]-amine

The value of Rf: to 0.10 (silica gel; a mixture of methylene chloride and methanol in the ratio 9:1)

(3) Hydrochloride difficult methyl ester [[TRANS-4-[2- (methoxycarbonyl)ethyl]cyclohexyl]amino]-acetic acid

Point pavlenishvili; a mixture of methylene chloride, methanol and conc. aqueous ammonia in a ratio of 95 : 5 : 1)

Example XI

N-benzyl-N-[TRANS-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]- ethanolamine

6.2 g of the hydrochloride of N-[TRANS-4-[2-(methoxycarbonyl)ethyl]- cyclohexyl] benzylamine, 12.8 g of N-ethyl-Diisopropylamine and 5.0 g of 2-bromoethanol stirred for 22 hours at 100oC and then cooled. Distributed between ethyl acetate and water, the aqueous phase is extracted with ethyl acetate and the combined an ethyl acetate phases are washed with a saturated solution of salt. An ethyl acetate phase is evaporated and the residue purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio 9 : 1.

Yield: 5.1 g (80% of theory)

The value of Rf: to 0.67 (silica gel; a mixture of methylene chloride and methanol in the ratio 9:1)

Similarly receive the following connections:

(1) N-(3-hydroxypropyl)-N-[TRANS-4-[2-(methoxycarbonyl)ethyl] - cyclohexyl]-benzylamine

The value of Rf: 0,70 (silica gel; a mixture of methylene chloride and methanol in the ratio 9:1)

(2) methyl ester of N-benzyl-[[TRANS-4-[(2 - methoxycarbonyl)ethyl] cyclohexyl]amino]-acetic acid

The value of Rf: 0,86 (silica gel; smesne Rf: of 0.32 (silica gel; a mixture of methylene chloride and methanol in the ratio 95:5)

Example XII

The hydrochloride of N-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]- benzylamine

8.0 g of the hydrochloride difficult methyl ester 3-(TRANS-4-aminocyclohexane)propionic acid) 4.3 g of benzaldehyde and 5.0 ml of triethylamine in 150 ml of methanol hydronaut for 4 hours under hydrogen pressure 3,52 kg/cm21.0 g of Raney Nickel at a temperature of 50oC. After cooling is sucked off and the filtrate evaporated. The residue is distributed between ethyl acetate and water, the aqueous phase by the addition of sodium liquor was adjusted to pH 8 to 9, and extracted with ethyl acetate. United an ethyl acetate phases are washed with saturated common salt solution, dried and evaporated in a rotary evaporator. The residue is suspended in diethyl ether and mixed with methanolic hydrochloric acid. The precipitate is sucked off, washed with simple diethyl ether and dried.

Output: 7,4 g (66% of theory)

Melting point: 170 - 172oC

Calculated: 65,47; H 8,40; N 4,49; Cl 11,37.

Found: C, Compared With 65.38; H 8,44; N 4,46; Cl 11,40.

Example XIII

Hydrochloride difficult methyl ester (TRANS-4-aminocyclohexane)exucuse acid

Over cooled in an ice bath, a solution of 59 hydrogen chloride for one hour and then stirred overnight at room temperature. Concentrated to dryness, the residue triturated with acetone and the solid is sucked off and dried.

Output: 34.3 g (59% of theory)

Melting point: 157 - 160oC

Example XIV

2-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- 3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxide

a) Diamed N-(2-chloroethyl)-N'-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro - 1H-3-benzazepin-7-yl)-sulfuric acid

To a mixture of 7.6 g of 7-amino-3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3 - benzazepine and 7.7 ml of N-ethyl-Diisopropylamine in 70 ml of methylene chloride was added dropwise 4.8 g [(2-chloroethyl)amino]sulphonylchloride in 30 ml of methylene chloride at a temperature of -5oC. is Stirred for one hour at 0oC and overnight at room temperature. The reaction mixture is diluted with methylene chloride and washed with water, 1 N. hydrochloric acid and again with water. The organic phase is dried, concentrated and the residue purified column chromatography on silica gel using as eluent a mixture of cyclohexane and ethyl acetate in the ratio of 1 : 1.

Yield: 7.8 g (72% of theory)

Melting point: 128 - 130oC

The value of Rf: of 0.64 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

b) 2-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- 3,4-dihydro-2H,5H-1,2,5 em.the butyl potassium. After stirring at room temperature for 3 hours serves 300 ml of 15% aqueous citric acid solution and extracted three times with ethyl acetate. The combined organic phases are dried, concentrated and the residue purified column chromatography on silica gel using as eluent a mixture of cyclohexane and ethyl acetate in the ratio of 1 : 1.

Yield: 2.1 g (30% of theory)

Melting point: 165 - 167oC

The value of Rf: to 0.30 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

Example XV

(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-boric acid

To 7,1 g 7-iodine-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine [value Rf: 0,85 (silica gel; a mixture of toluene, dioxane, methanol and conc. aqueous ammonia at a ratio of 20 : 50 : 20 : 5), obtained from the compound of example VI by the interaction of a mixture of sodium lye and methanol and subsequent interaction with a mixture of formaldehyde and formic acid] in 50 ml of diethyl ether was added dropwise 1.6 ml of n-utility in hexane at temperatures between -70 and -75oC. After 30 minutes of stirring at -70oC was added dropwise to 5.7 ml triisopropylsilane in 30 ml of diethyl ether. Is stirred for one hour at -75oC, then naked is s, then separate the aqueous phase, which is the addition of glacial acetic acid adjusted to pH 8 to 8.5. The product is sucked off, washed with little cold water and dried at 60oC.

Yield: 3.7 g (73% of theory)

The melting point: 153 - 155oC (sintering with 148oC)

The value of Rf: 0,80 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Example XVI

1-[2-(etoxycarbonyl)ethyl]-3-[4-(tripterocalyx)- phenyl]-imidazolidin-2-he

a) N-(2,2-diatexites-4-benzyloxy-aniline

Obtained from 4-benzyloxyaniline as a result of interaction with bromoacetaldehyde-diethylacetal in the presence of N-ethyl-Diisopropylamine.

The value of Rf: of 0.42 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 85:15)

b) N-(4-benzyloxyphenyl)-N-(2,2-diatexite)-N'-[2-(ethoxy - carbonyl)ethyl)-urea

Obtained from N-(2,2-diatexite)-4-benzyloxy-aniline as a result of interaction with [2-(etoxycarbonyl)ethyl]-isocyanate.

The value of Rf: to 0.45 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

C) 1-(4-benzyloxyphenyl)-3-[2-(etoxycarbonyl)ethyl]-3H-imidazole-2-he

Received in raskolotoe in methylene chloride.

Melting point: 66 - 68oC

The value of Rf: 0,41 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

g) 1-(4-hydroxyphenyl)-3-[2-(etoxycarbonyl)ethyl]- imidazolidin-2-he

Obtained from 1-(4-benzyloxyphenyl)-3-[2-(etoxycarbonyl)ethyl]-3H-imidazole-2-it is by catalytic hydrogenation in the presence of palladium on coal in ethanol at 40oC and hydrogen pressure 3,52 kg/cm2.

The value of Rf: of 0.20 (silica gel; a mixture of methylene chloride and methanol in the ratio of 100:2)

d) 1-[2-(etoxycarbonyl)ethyl] -3-[4-(tripterocalyx)- l-imidazolidin-2-he

Obtained from 1-(4-hydroxyphenyl)-3-[2-(etoxycarbonyl)ethyl]- imidazolidin-2-it is the result of interaction with the anhydride of triftoratsetata in pyridine at 0oC.

Melting point: 81 - 83oC

The value of Rf: 0,66 (silica gel; a mixture of methylene chloride and methanol in the ratio 100:1)

Calculated: C 43,90; H 4,18; N 6,83; S 7,81.

Found: C 43,92; H 4,20; N 6,98; S To $ 7.91.

The following examples illustrate how to obtain the cyclic nitrogen-containing derivatives of formula (I).

Example 1

1-(1-aminoisoquinoline-6-yl)-3-[4-(2-carboxyethyl)phenyl] - imidazolidin-2-he x 1 H2O x 1.2 CH3COOH

300 m is positive stirred in a mortar and then heated with stirring to 200oC for 3 hours in nitrogen atmosphere. After cooling, mixed with 20 ml of water and the addition of 1 N. hydrochloric acid adjusted to pH 8-9. The precipitate is sucked off and washed several times with water. After drying the residue is suspended in 50 ml of a mixture of methylene chloride and methanol in the ratio of 4 : 1 and treated in an ultrasonic bath for 30 minutes. The precipitate is sucked off and twice repeated treatment with a mixture of methylene chloride and methanol in an ultrasonic bath. The filter residue is mixed with a weak heating in a mixture of 30 ml of methanol and 10 ml of glacial acetic acid. Filtered from nerastvorim components and the mother liquor concentrated to dryness. The residue is again mixed with toluene and concentrated. Then dried in a vacuum at a temperature of 60oC.

Yield: 70 mg (20% of theory)

Melting point: > 250oC

The value of Rf: 0,78 (ortofena column chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 8 : 4)

Calculated: C 60,25; H 5,79; N 12,01.

Found: C 60,20; H 5,43; N 11,54.

Mass spectrum M+= 376

Example 2

3-[4-(2-carboxyethyl)phenyl]-1-(1-chloroisoquinoline-6-yl)- imidazolidin-2-he

1 g of 1-(1-chloroisoquinoline-6-yl)-3-[4-[2-(methoxycarbonyl)ethyl]- phenyl]-it is round. Add 9 ml of 1 N. hydrochloric acid, the mixture is concentrated and the precipitate is sucked off. The product is washed with water and dried at 50oC.

Output: 0,78 g (80% of theory)

Melting point: 236 - 240oC (decomp.)

The value of Rf: of 0.36 (silica gel; a mixture of methylene chloride, methanol and ethyl acetate in a ratio of 20:1:1)

Similarly receive the following connections:

(1) 1-[4-(2-carboxyethyl)phenyl]-3-(isoquinoline-6-yl)-3H-imidazole - 2-he

Melting point: 305 - 310oC

The value of Rf: of 0.49 (silica gel; a mixture of methylene chloride and methanol in the ratio 9:1)

Calculated: C 70,18; H Of 4.77; N Of 11.69.

Found: C 69,95; H Is 4.93; N 11,64.

(2) 1-[4-(2-carboxyethyl)phenyl] -3-(1,2,3,4-tetrahydroisoquinoline - 6-yl)-imidazolidin-2-he

The value of Rf: 0,44 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 67,54; H 6,21; N 11,25.

Found: C 67,58; H 6.42 Per; N 11,23.

(3) 2-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -5- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3,4-dihydro-2H,5H-1,2,5 - thiadiazol-1,1-dioxide

Getting in a mixture of methanol and sodium liquor; the original compound: compound of example 18.

The value of Rf: 0,36 (ortofena chromatog the

1-(1-chloroisoquinoline-6-yl)-3-[4-[2-(methoxycarbonyl)ethyl] phenyl] - imidazolidin-2-he

2.2 g of 1-(isoquinoline-N-oxide-6-yl)-3-[4-[2-(methoxycarbonyl)- ethyl]phenyl] -imidazolidin-2-she and 25 ml of phosphorus oxychloride for 2 hours and refluxed. The phosphorus oxychloride is then distilled off and the residue is served on ice. The pH of the mixture by the addition of saturated sodium bicarbonate solution was adjusted to 8-9. Several times extracted with methylene chloride, the organic phase is dried, concentrated and the residue purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in a ratio of 20 : 1.

Yield: 1.0 g (43% of theory)

The value of Rf: 0,66 (silica gel; a mixture of methylene chloride and methanol in a ratio of 20:1)

Example 4

1-(isoquinoline-6-yl)-3-[4-[2-(methoxycarbonyl)ethyl] phenyl] - imidazolidin-2-he

To a solution of 3.0 g of N-(2-hydroxyethyl)-N'-(isoquinoline-6-yl)-N-[4- [2-(methoxycarbonyl)ethyl] phenyl-urea and 2.0 g of triphenylphosphine in 105 ml of acetonitrile added 1.31 ml diethyl ether complex of azodicarboxylic acid in 36 ml of acetonitrile at an internal temperature 42-52oC. After stirring for 2 hours at 45oC is cooled to -5oC and continue to mix for another 2 hours. Sediment from CCA melting point: 213 - 215oC

The value of Rf: of 0.60 (silica gel; a mixture of methylene chloride and methanol in a ratio of 20:1)

Similarly receive the following connections:

(1) 1-(3-tert.butyloxycarbonyl-2,3,4,5-tetrahydro-1H-3 - benzazepin-7-yl)-3-[4-[2-(methoxycarbonyl)ethyl]phenyl]-imidazolidin-2-he

Melting point: 165 - 167oC

The value of Rf: 0,77 (silica gel; a mixture of methylene chloride and ethyl acetate in the ratio 9:1)

(2) 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]-3-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin - 2-he

Melting point: 250 - 255oC (decomp.)

The value of Rf: to 0.45 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

(3) 1-[4-[TRANS-2-(methoxycarbonyl)ethynyl] phenyl]-3-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-he

Melting point: 216 - 220oC

The value of Rf: of 0.38 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

(4) 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]-3-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- 3,4,5,6-tetrahydro-1H-pyrimidine-2-he

Melting point: 125 - 127oC

The value of Rf: of 0.54 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 2)

Example 5

Output: 4,45 g (76% of theory)

Melting point: 158 - 161oC

The value of Rf: to 0.29 (silica gel; a mixture of methylene chloride and methanol in the ratio 95:5)

Calculated: C 70,76; H 5,13; N 11,25.

Found: C 70,52; H 5,08; N 11,35.

Similarly receive the following connections:

(1) 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl)-3-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3H-imidazole - 2-he

Getting by dry heat up to 160 - 170oC.

Melting point: 121 - 124oC

The value of Rf: of 0.35 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

(2) 1-[TRANS-4-[[(methoxycarbonyl)methyl]oxy]cyclohexyl]-3-(3 - TRIFLUOROACETYL-2,3,4,5-etrahydro-1H-3-benzazepin-7-yl)-3H-imidazole-2 - he

Melting point: 148 - 149oC

The value of Rf: to 0.28 (silica gel; a mixture of ethyl acetate and cyclohexane in the ratio 2 : 1)

(3) 1-[4-[2-{ etoxycarbonyl)-1-propyl] phenyl)-3-(3-TRIFLUOROACETYL - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3H-im is) 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -3-(3-ethyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3H-imidazole-2-he

The value of Rf: 0,30 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(5) 1-(TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl)-3-(7-ethyl - 6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)-3H-imidazole-2-he

Melting point: 135 - 136oC

Calculated: C 64,61; H 7,78; N 16,38.

Found: C 64,82; H To 7.84; N 16,27.

(6) 1-[4-[2-(etoxycarbonyl)-1-phenyl-ethyl] phenyl]-3-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3H-imidazole - 2-he

The value of Rf: to 0.24 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 7 : 3)

(7) 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -3-(7-benzyl - 6,7,8,9-tetrahydro-5H-pyrimido[4-5-d]azepin-2-yl) -3H-imidazole-2-he

Melting point: 131 - 134oC

The value of Rf: of 0.38 (silica gel; a mixture of methylene chloride and methanol in a ratio of 20 : 1)

Example 6

Acetate 1-[4-[2-(methoxycarbonyl)ethyl]phenyl]-3-(1,2,3,4-tetrahydro - isoquinoline-6-yl)-imidazolidin-2-it

2.0 g of 1-(isoquinoline-6-yl)-3-[4-[2-(methoxycarbonyl)ethyl]phenyl]- 3H-imidazole-2-it in 50 ml of glacial acetic acid hydronaut under pressure to 3.52 kg/cm to 0.5 g of platinum oxide at room temperature for 40 minutes. Filtered from the catalyst, concentrated and the residue PIR>C (decomp.)

Calculated: C 65,59; H Of 6.65; N 9,56.

Found: C 65,90; H Is 6.78; N RS 9.69.

The value of Rf: to 0.30 (silica gel; a mixture of toluene, dioxane, methanol and conc. aqueous ammonia at a ratio of 20 : 50 : 20 : 5)

Mass spectrum: M+= 379

Similarly receive the following connections:

(1) 1-[TRANS-4-(2-carboxyethyl] cyclohexyl] -3-(3-methyl - 2,3,4,5,5 and 6,7,8,9,9 and decahydro-1H-3-benzazepin-7-yl)-imidazolidin - 2-he x 1.35 HCl x 1,9 H2O

Getting in a mixture of dioxane and water with the use of a platinum-rhodium catalyst.

As the starting compound used compound of example 19.

Mass spectrum: M+= 405

Calculated: 56,49; H 9,10; N 8,59; Cl 9,79.

Found: C 56,63; H 8,81; N 8,60; Cl 9,92.

(2) 1-[TRANS-4-(2-carboxyethyl]cyclohexyl]-3- (2,3,4,5,5 and,6,7,8,9,9 and decahydro-1H-3-benzazepin-7-yl)-imidazolidin - 2-he x 1,05 HCl x 0.9m H2O

Getting in a mixture of dioxane and water with the use of a platinum-rhodium catalyst.

As the starting compound used compound of example 14 (1).

Mass spectrum: M+= 391

Calculated: C 59,43; H 9,03; N 9,45; Cl 8,05.

Found: C 59,49; H 8,83; N 9,35; Cl 8,30.

Example 7

Hydrochloride of 1-[4-(2-(isobutylketone)ethyl] phenyl]-3- (1,2-3-1,2,3,4-tetrahydroisoquinoline-6-yl)- imidazolidin-2-she 4.6 ml of Isobutanol under stirring for 30 minutes passed hydrochloric acid. Stirred over night at room temperature, mixed with acetone and the precipitate is sucked off. The product is suspended in acetone, sucked off, washed with acetone and diethyl ether and dried.

Yield: 140 mg (77% of theory)

Calculated: C 65,56; H? 7.04 Baby Mortality; N 9,18; Cl 7,74.

Found: C, Compared With 65.38; H 7,03; N For 9.47; Cl 7,92.

The value of Rf: 0,19 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

Mass spectrum: M+= 421

Similarly receive the following connections:

(1) Hydrochloride 1-[4-[2-(isopropoxycarbonyl)ethyl]phenyl]-3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it

Calculated: C 63,08; H 7,20; N 8,83; Cl 7,45.

Found: C 62,79; H 7,14; N 8,83; Cl 7,80.

The value of Rf: 0,21 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

Mass spectrum: M+= 421

(2) the Hydrochloride of 1-[4-[2-(methoxycarbonyl)ethyl] phenyl] -3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it x 0.75 H2O

Melting point: 248 - 250oC

Calculated: C 63,01;H 6,94,; N 9,19; Cl 7,75.

Found: C 63,09; H 6,98; N Which 9.22; Cl 7,88.

The value of Rf: 0,28 (ortofena chromated 1-[4-[2-(etoxycarbonyl)ethyl] phenyl] -3-(3-methyl - 2,3,4,5-etrahydro-3H-3-benzazepin-7-yl)-imidazolidin-2-it

The value of Rf: 0,22 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

(4) Hydrochloride 1-[4-[2-(isopropoxycarbonyl)ethyl]phenyl]-3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it

The value of Rf: 0,19 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

(5) the Hydrochloride of 1-[TRANS-4-[2-(isopropoxycarbonyl)ethyl] cyclohexyl] -3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- imidazolidin-2-it

The use of thionyl chloride and hydrogen chloride.

Melting point: > 250oC

The value of Rf: 0,17 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 65,32; H 8,43; N 8,79; Cl 7,42.

Found: 65,10; H To 8.41; N 8,91; Cl 7,66.

(6) the Hydrochloride of 1-[TRANS-4-[2-(etoxycarbonyl)ethyl]cyclohexyl]- 3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin - 2-it

The use of thionyl chloride and hydrogen chloride.

Melting point: > 250oC

The value of Rf: 0,24 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution powerin>/P>(7) the Hydrochloride of 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]- 3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it

The use of thionyl chloride and hydrogen chloride.

Melting point: > 250oC

The value of Rf: 0,29 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 64,05; H 8,04; N 9,34; Cl 7,88.

Found: C 64,10; H Of 7.97; N 9,52; Cl 8,11.

(8) the Hydrochloride of 1-[TRANS-4-[2-(isopropoxycarbonyl)ethyl] cyclohexyl] -3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin - 2-it

The use of thionyl chloride and hydrogen chloride.

The value of Rf: 0,20 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

(9) the Hydrochloride of 1-[TRANS-4-[2-(etoxycarbonyl)ethyl] cyclohexyl] - 3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it

The use of thionyl chloride and hydrogen chloride.

The value of Rf: 0,23 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 64,05; H Of 8.06; N 9,34; Cl 7,88.

Found: C 63,77; H 8,23 N 9,07; Cl To $ 7.91.

(10) the Guide is

The use of thionyl chloride and hydrogen chloride.

The value of Rf: 0,26 (ortofena chromatography on silica gel; a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 63,36; H 7,86; N For 9.64; Cl 8,13.

Found: C 63,34; H 7,88; N 9,73; Cl 8,11.

Example 8

1-[4-(2-carboxyethyl)phenyl] -3-(2-methyl - 1,2,3,4-tetrahydroisoquinoline-6-yl)-imidazolidin-2-he x 0.2 H2O

350 mg of the acetate of 1-[4-[2-(methoxycarbonyl)ethyl]phenyl]-3- (1,2,3,4-tetrahydroisoquinoline-6-yl)-imidazolidin-2-it, 0.7 ml of water, 0.15 ml of formic acid and 0.7 ml of 37% aqueous formaldehyde solution is stirred for one hour at 65oC. Add toluene and thicken. Mixed with toluene and again evaporated. The residue is mixed with 2 ml of tetrahydrofuran, 1 ml of water and 0.8 ml of 4 N. sodium liquor at room temperature for 2.5 days. Add 220 mg of ammonium chloride in 1 ml of water and stirred for 2 hours. The reaction mixture was partly evaporated in a rotary evaporator, cooled with ice, the solid product is sucked off, then washed with water, acetone and diethyl ether, and then dried.

Output: 220 ml (72% of theory)

Melting point: 245 - 248oC

Calculated: C 68,98; H Of 6.68; N 10,97.

Found: C 68,91; H is solution of sodium chloride in the ratio 6 : 4)

Mass spectrum: M+= 379

Similarly receive the following connection:

Hydrochloride of 1-[4-(2-(carboxyethyl)phenyl] -3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it x 1.5 water

Subsequent cleavage of ester carried out with a mixture of glacial acetic acid and hydrochloric acid instead of sodium lye).

Calculated: 60,45; H 6,84; N 9,20; Cl 7,76.

Found: C 60,45; H 6,86; N 9,18; Cl 8,09.

The value of Rf: 0,31 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia in the ratio of 4 : 1 : 0,2)

Mass spectrum: M+= 393

Example 9

1-[4-(2-(carboxyethyl)phenyl] -3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-he

800 mg of the hydrochloride of 1-[4-[2-(methoxycarbonyl)ethyl]phenyl]-3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it is mixed with 10 ml policecontributing hydrochloric acid and 10 ml of glacial acetic acid. After 2 hours, add another 5 ml policecontributing hydrochloric acid and 5 ml of glacial acetic acid and stirred at room temperature overnight. The reaction mixture is evaporated and the residue suspended in 10 ml of water. The addition of 2 N. sodium liquor pH was adjusted to 6, the solid product is sucked off, washed with ice in the on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Mass spectrum: M+= 379

Similarly receive the following connections:

(1) Hydrochloride 1-[4-(2-(carboxyethyl)phenyl] -3-(4RS, 6RS, 8RS)and -1,2,3,4,4,5,6,7,8,8 a - decahydroquinoline-6-yl)-imidazolidin-2-it

Allocation as hydrochloride

The value of Rf: 0,41 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Mass spectrum: M+= 371

(2) the Hydrochloride of 1-[4-(2-carboxyethyl)phenyl] -3-(3-ethyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it

The value of Rf: 0,36 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Mass spectrum: M+= 407

(3) the Hydrochloride of 3-[TRANS-4-(2-(carboxymethyl)cyclohexyl]-1- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

Melting point: > 250oC

The value of Rf: 0,36 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 60,61; H 6,94; N For 9.64; Cl 8,13.

Found: C 60,45; H 6,90; N Being 9.61; Cl 8,28.

(4) 1-[TRANS-4-(2-(carboxyethyl)cyclohexa: 283 - 286oC

The value of Rf: 0,46 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 52,36; H 7,35; N 13,88; Cl 14,05.

Found: C 52,70; H 7,44; N 13,86; Cl 14,01.

(5) the Hydrochloride of 1-[TRANS-4-(2-(carboxymethyl)cyclohexyl] -3-(3-ethyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3H-imidazole-2-it x 0.5 H2ABOUT

The value of Rf: 0,38 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 63,08; H 7,22; N 9,19; Cl 7,76.

Found: C 63,26; H Of 7.69; N, 9.28 Are; Cl Of 7.64.

(6) the Hydrochloride of 1-[TRANS-4-(2-(carboxymethyl)cyclohexyl]-3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

The value of Rf: of 0.16 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia at a ratio of 80 : 20 : 2)

Calculated: C 60,61; H 6,94; N For 9.64; Cl 8,13.

Found: C 60,34; H 6,94; N 9,58; Cl 8,27.

(7) 1-[TRANS-4-(2-carboxyethyl)cyclohexyl]-3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3,4,5,6-tetrahydro-1H - pyrimidine-2-he x 1.65 HCl x 0.7 H2ABOUT

Melting point: 230 - 235oC

The value of Rf: 0,40 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution pavarino the

(8) Hydrochloride 1-(2-carboxyethyl)-3-[4-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) phenyl]-imidazolidin-2-it

Melting point: > 250oC

The value of Rf: 0,20 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(9) the Hydrochloride of 1-[TRANS-4-(2-carboxyethyl)cyclohexyl]-3-(6,7,8,9-tetrahydro-5H - pyrimido[4,5-d]azepin-2-yl)-imidazolidin-2-it

The value of Rf: 0,60 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(10) of the Hydrochloride of 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(3 - ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it

Melting point: > 270oC

The value of Rf: 0,35 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(11) 1-[TRANS-4-(2-carboxyethyl)cyclohexyl]-3-(3-propyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-he x 1,07 HCl x 1H2ABOUT

Melting point: > 250oC

The value of Rf: 0,32 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 61,96; H 8,33; N 8,67; Cl is etrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-he x 1,1 HCl x 1.5 H2O

Melting point: > 250oC

The value of Rf: 0,30 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 60,94; H 8,00; N 8,53; Cl To $ 7.91.

Found: C 61,32; H 7,63; N Of 8.47; Cl Of 7.82.

(13) of the Hydrochloride of 1-[TRANS-4-(2-carboxyethyl)cyclohexyl]-3-[3- (2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]- imidazolidin-2-it

Melting point: 257 - 260oC

The value of Rf: 0,46 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(14) of the Hydrochloride of 1-[TRANS-4-(2-carboxyethyl)cyclohexyl]-3-[3- (carboxymethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin - 2-it

Melting point: > 280oC

The value of Rf: 0,39 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(15) of the Hydrochloride of 1-[TRANS-4-(2-carboxyethyl)cyclohexyl]-3-(3 - benzyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin-2-it

Melting point: > 250oC

The value of Rf: 0,21 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in footnotesize-7-yl] - imidazolidin-2-it

Melting point: > 280oC

The value of Rf: 0,31 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Example 10

Hydrochloride of 1-[4-[2-(methoxycarbonyl)ethyl] phenyl]-3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin-2-it

2.3 g of 1-(3-tert.butyloxycarbonyl-2,3,4,5-tetrahydro-1H-3 - benzazepin-7-yl)-3-[4-[2-(methoxycarbonyl)ethyl] phenyl]-imidazolidin - 2-it is stirred in 30 ml of methanolic hydrochloric acid for 2 hours at room temperature. The reaction mixture is evaporated, the residue is mixed with ice water, sucked off, washed with a small amount of methanol and tert.butylmethylamine ether, and then dried.

Yield: 1.8 g (90% of theory)

Calculated: C 64,25; H 6,56; N 9,77; Cl 8,25.

Found: C 64,08; H 6,60; N 9,92; Cl 8,51.

The value of Rf: 0,26 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Mass spectrum: M+= 393

Example 11

Hydrochloride of 1-[(4aRS, 6RS, 8aRS)- 1,2,3,4,4 a,5,6,7,8,8 a-decahydroquinoline-6-yl]-3-[4-[2- (methoxycarbonyl)ethyl]phenyl]-imidazolidin-2-it

To 216 mg of 1-[4-[2-(methoxycarbonyl)ethyl]phenyl]-3-[(4RS,6RS,8RS)- 2-methyl-1,2 the Tana add 0,09 ml complex 1-hloretilova ether Harborview acid, stirred for 20 minutes at room temperature and then heated for 2.5 hours under reflux. The reaction mixture was concentrated, the residue is mixed with 10 ml of methanol and heated for 3 hours under reflux. The reaction mixture was acidified with methanolic hydrochloric acid, concentrated and purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in a ratio of 92:8.

Yield: 200 mg (87% of theory)

The value of Rf: 0,35 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Example 12

1-(4-[2-(methoxycarbonyl)ethyl] phenyl] -3-[(4RS, 6RS, 8RS)- 2-methyl-1,2,3,4,4 and,5,6,7,8,8 a-decahydroquinoline-6-yl]-imidazolidin - 2-he

950 mg of 1-[4-[2-(methoxycarbonyl)ethyl] phenyl] -3-[(4RS,6RS,8RS)-2-methyl-1,2,3,4,4 a, 5,6,7,8,8 and-decahydroquinoline-6-yl]-3H-imidazole - 2-it in 50 ml of ethyl acetate hydronaut when the hydrogen pressure 3,52 kg/cm2in the presence of palladium on active coal for 5 hours at room temperature and then for 5 hours at 50oC. the Catalyst was filtered and the filtrate concentrated. The residue is briefly heated in the presence of tert.butyl methyl ether, then cooled under stirring. Solid CCA melting point: 155 - 157oC

The value of Rf: 0,29 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Similarly receive the following connections:

(1) 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]-3-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin - 2-he

Melting point: 165 - 168oC

The value of Rf: of 0.44 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

(2) 1-[TRANS-4-[[(methoxycarbonyl)methyl]oxy]cyclohexyl]-3-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin - 2-he

Melting point: 146 - 147oC

The value of Rf: of 0.62 (silica gel; a mixture of ethyl acetate and cyclohexane in the ratio 3 : 1)

(3) 1-[4-[2-(etoxycarbonyl)-1-propyl] phenyl] -3-(3-TRIFLUOROACETYL - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3H-imidazolidin-2-he

The value of Rf: of 0.32 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 2 : 1)

(4) 1-[2-[4-(methoxycarbonyl)phenyl]ethyl]-3-(3-TRIFLUOROACETYL - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin-2-he

Melting point: 143 - 144oC

The value of Rf: 0,46 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

(5) the Hydrochloride of 1-[/BR> Melting point: from 230oC (decomp.)

The value of Rf: 0,22 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(6) 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -3-(7-ethyl - 6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl]-imidazolidin-2-he

Melting point: 136 - 138oC

The value of Rf: 0,33 (silica gel; a mixture of methylene chloride and methanol in the ratio 9:1)

(7) 1-[4-[2-(etoxycarbonyl)-1-phenyl-ethyl] phenyl]-3-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-benzazepin-7-yl]-imidazolidin-2-he

The value of Rf: 0,22 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 7 : 3)

Example 13

1-[4-[2-(methoxycarbonyl)ethyl] phenyl] -3-[(4RS, 6RS, 8RS)-2-methyl - 1,2,3,4,4 and,5,6,7,8,8 a-decahydroquinoline-6-yl]-3H-imidazole-2-it

To 6,9 g (4RS,6RS,8RS)-6-[(2,2-dimethoxymethyl)amino]-2-methyl - 1,2,3,4,4 a, 5,6,7,8,8 and-decahydroquinoline in 30 ml of dioxane is added 6.4 g of 4-[2-(methoxycarbonyl)ethyl] -phenylisocyanate and stirred for 2 hours at room temperature. The reaction mixture is thickened, served in 100 ml of methanol, mixed with methanolic hydrochloric acid and heated for 20 minutes under reflux. The reaction mixture was concentrated and the residue is stirred with 200 ml of water. Odasi is the target of potassium carbonate and extracted several times with ethyl acetate. The combined ethyl acetate extracts are washed with saturated common salt solution, dried and concentrated. The crude product is purified by column chromatography on basic alumina using ethyl acetate as eluent and subsequent rubbing with tert.butyl methyl ether.

Output: 1,03 g (9% of theory)

The value of Rf: of 0.55 (silica gel; a mixture of toluene, dioxane, methanol and conc. aqueous ammonia at a ratio of 20 : 50 : 20 : 5)

Similarly receive the following connections:

(1) 1-[4-[2-(methoxycarbonyl)ethyl] phenyl]-3-[(4RS,6RS,8RS)-2 - methyl-1,2,3,4,4 and,5,6,7,8,8 a-decahydroquinoline-6-yl]-3H-imidazole-2-he x 0.3 H20

Melting point: 140 - 145oC

Calculated: C 68,56; H To $ 7.91; N 10,43.

Found: C 68,49; H Of 7.97; N 10,51.

(2) 1-[2-[4-(methoxycarbonyl)phenyl] ethyl]-3-(3-TRIFLUOROACETYL - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3H-imidazole-2-he

Amine and isocyanate are stirred in dioxane at room temperature, then on a steam bath. In contrast to example 13, the reaction mixture is treated with methanolic hydrochloric acid. Source [2-[4-(methoxycarbonyl)phenyl] ethyl]-isocyanate produced by interaction of the corresponding amine in the form of the hydrochloride with phosgene.

ratio of 1 : 1)

Example 14

Hydrate hydrochloride 4-[4-[2-(carboxyethyl)phenyl]-5-methyl-2- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4H-1,2,4-triazole-3-one

410 mg of 4-[4-[2-(methoxycarbonyl)ethyl]phenyl]-5-methyl]-2-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4H-1,2,4 - triazole-3-it is mixed with 10 ml of glacial acetic acid and 10 ml policecontributing hydrochloric acid for 7 hours at 90oC. After cooling, evaporated, the residue is stirred with water, sucked off and washed with water and acetone.

Yield: 240 mg (57% of theory)

Melting point: > 250oC

The value of Rf: 0,43 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 59,12; H 6,09; N 12,53; C l7,93.

Found: C 58,96; H 6,13; N 12,31; Cl 7,74.

Similarly receive the following connections:

(1) the Hydrochloride of 1-[TRANS-4-(2-carboxyethyl)cyclohexyl]-3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin-2-it

Melting point: > 250oC

The value of Rf: 0,46 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 62,62; H Of 7.64; N 9,98; Cl 8,40.

Found: C 62,24; H To 7.67; N 10,01;Cl 8,86.


The value of Rf: 0,50 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(3) the Hydrochloride of 1-[TRANS-4-[(carboxymethyl)oxy] cyclohexyl] -3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin-2-it

Melting point: 316 - 317oC (decomp.)

The value of Rf: 0,66 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 59,50; H 7,13; N To 9.91; Cl At 8.36.

Found: C 59,26; H 7,13; N 9,94; Cl 8,44.

(4) Hydrochloride 1-[4-(TRANS-2-carboxyethyl]phenyl]-3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin-2-it

The value of Rf: 0,64 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Mass spectrum: M+= 377

(5) the Hydrochloride of 1-[4-(2-carboxy-1-propyl)phenyl]-3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-imidazolidin-2-it-x H2O

The value of Rf: 0,34 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 61,66; H Of 6.71; N 9,38; Cl To $ 7.91.

Found: 61,56; H Of 6.75; N Of 9.30; CL 8,14.

(6) the Hydrochloride of 2-[TRANS-4-(Finance 2 N. hydrochloric acid

Parent compound: compound of example 18 (1)

Melting point: > 220oC

The value of Rf: 0,50 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 59,92; H 6,94; N 13,31; Cl 8,42.

Found: C 60,03; H 6,99; N 13,32; Cl 8,46.

(7) Hydrochloride 4-[TRANS-4-(2-carboxyethyl)cyclohexyl] -2- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4H-1,2,4-triazole-3-one

Melting point: > 240oC

The value of Rf: 0,64 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

(8) Hydrochloride 4-[TRANS-4-(2-carboxyethyl)cyclohexyl] -2- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-5-methyl-4H-1,2,4-triazole - 3-one

The value of Rf: 0,48 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 60,75; H 7,18; N 12,88; Cl 8,15.

Found: C They Accounted For 60,54; H 7,26; N 12,68; Cl 8,54.

(9) the Hydrochloride of 1-[4-(2-carboxy-1-phenyl-ethyl) - phenyl] -3- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it

The value of Rf: 0,31 (ortofena chromatography on silica gel; a mixture of methanol and 5% water rastuzen-7-yl)-imidazolidin-2-it-x H2ABOUT

The value of Rf: 0,40 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Mass spectrum: M+= 379

Calculated: C 60,89; H 6,50; N 9,68; Cl 8,17.

Found: C 60,57; H 6,62; N 9,77; Cl By 8.22.

Example 15

4-[4-[2-(methoxycarbonyl)ethyl] phenyl] -5-methyl-2-(3-TRIFLUOROACETYL - 2,3,4,5-etrahydro-1H-3-benzazepin-7-yl)-4H-1,2,4-triazole-3-one

1.6 g of 7-iodine-3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepine, 1.1 g of 4-[4-[2-(methoxycarbonyl)ethyl] phenyl] -5-methyl-4H-1,2,4-triazole - 3-one, 0,19 ml of Tris-[2-(2-methoxyethoxy)ethyl] -amine, 130 mg of copper chloride (I), 130 mg of copper iodide (I) and 1.1 g of potassium carbonate are heated under reflux in 30 ml of dimethylformamide for 2 hours. After cooling, evaporated and the residue partitioned between water and methylene chloride. The solid product is sucked off, the organic phase is separated, washed with water, dried, filtered and evaporated in a rotary evaporator. The residue is purified by column chromatography on silica gel using as eluent a mixture of cyclohexane and ethyl acetate in the ratio of 1 : 1.

Yield: 340 mg (16% of theory)

Melting point: 160 - 162oC

The value of Rf: of 0.51 (silica gel; a mixture of cyclohexane and ethoxycarbonyl)ethyl]cyclohexyl)-2-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-5-methyl-4H - 1,2,4-triazole-3-one

Melting point: 175 - 177oC

The value of Rf: of 0.50 (silica gel; a mixture of methylene chloride and ethyl acetate in the ratio 90:10)

(2) 4-[TRANS-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]-2-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4H - 1,2,4-triazole-3-one

The value of Rf: to 0.40 (silica gel; a mixture of methylene chloride and methanol in the ratio 100:1)

Example 16

1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -3-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

To 4.1 g of (3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7 - yl)-isocyanate and 3.7 g of the hydrochloride difficult methyl ester [[TRANS-4-[2-(methoxycarbonyl)-ethyl] cyclohexyl] amino-acetic acid in 50 ml of acetonitrile, add 3.2 ml of N-ethyl-Diisopropylamine and stirred for 2.5 days at room temperature. The reaction mixture was concentrated, the residue is served in ethyl acetate and washed with water and common salt solution. The organic phase is dried, concentrated and the residue is crystallized with a small amount of methanol in an ice bath. The product is sucked off, washed with cold methanol and dried.

Yield: 4.1 g (56% of theory)

Melting point: 118 - 120oC

The value of Rf: 0,85 (silica gel; ethyl acetate)

Example 17

Hydrochloride of 1-[TPHA

230 mg of the hydrochloride of 1-[TRANS-4-[2-(isopropoxycarbonyl)ethyl] cyclohexyl]-3-(3-allyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- imidazolidin-2-it hydronaut in 10 ml isopropanol at a pressure of hydrogen 3,52 kg/cm250 mg of 10% palladium on active coal at a temperature of 30oC for 6 hours. The catalyst is sucked off and the filtrate evaporated.

Yield: 240 mg

The value of Rf: of 0.55 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia in a ratio of 95 : 5 : 1)

Example 18

2-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -5-(3 - TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3,4-dihydro - 2H, 5H-1,2,5-thiadiazole-1,1-dioxide

To 1,25 g of 2-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin - 7-yl)-3,4-dihydro-2H, 5H-1,2,5-thiadiazole-1,1-dioxide, 0.64 g complex methyl ester 3-(CIS-4-hydroxycyclohexyl)propionic acid [value Rf: of 0.58 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1), separated from a mixture of CIS - and TRANS - isomers by column chromatography on silica gel using as eluent a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)] and 0.90 g of triphenylphosphine in 2 ml of acetonitrile was added dropwise 0.54 ml diethyl ether complex of azodicarboxylic acid. Dobrovelitchka and 0.54 ml of diethyl ether complex of azodicarboxylic acid in 2 ml of acetonitrile. After 30 minutes stirring at room temperature add again a mixture of 0.90 g of triphenylphosphine and 0.54 ml of diethyl ether complex of azodicarboxylic acid. After stirring at room temperature overnight, evaporated in a rotary evaporator and the residue purified by column chromatography on silica gel using as eluent a mixture of cyclohexane, ethyl acetate and methylene chloride in the ratio of 1 : 1 : 1.

Yield: 700 mg (38% of theory)

Melting point: 169 - 173oC

The value of Rf: 0,61 (silica gel; a mixture of cyclohexane, ethyl acetate and methylene chloride in the ratio of 1 : 1 : 1)

Similarly receive the following connections:

(1) 2-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -4-(3 - tert.butyloxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4H - 1,2,4-triazole-3-one

Melting point: 162 - 164oC

The value of Rf: of 0.43 (silica gel; a mixture of cyclohexane, ethyl acetate and methylene chloride in the ratio of 1 : 1 : 1)

Example 19

Hydrochloride of 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it

To a mixture of 5.0 g of the hydrochloride of 1-[TRANS-4-(2-carboxyethyl) cyclohexyl]-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazole is the home of 2.0 g of sodium bicarbonate and heated to 65oC. After 8 hours, cooled, stirred overnight and the mixture is evaporated on a rotary evaporator. The residue is stirred with water and again evaporated. Then the residue is again stirred with water and the addition of hydrochloric acid adjusted to pH 1. Evaporated on a rotary evaporator, the residue is mixed with a small amount of water and sucked off. The filter residue is mixed with acetone, the product is sucked off, washed with acetone and dried in vacuum.

Yield: 3.7 g (71% of theory)

Melting point: 292 - 295oC (decomp.)

The value of Rf: 0,38 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Similarly receive the following connections:

(1) the Hydrochloride of 1-[TRANS-4-[(carboxymethyl)oxy]cyclohexyl]- 3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it x NaCl x 0.5 H2O

The value of Rf: 0,62 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4).

Calculated: C 52,28; H To 6.58; N 8,31; Cl 13,49.

Found: C 52,28; H Of 6.68; N 8,33; Cl 14,03.

(2) the Hydrochloride of 1-[4-(2-carboxy-1-propyl)phenyl]-3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazole and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: 63,63; H Of 6.90; N, 9.28 Are; Cl 7,83.

Found: C 63,32; H 6,99; N To 9.32; Cl 7,81.

(3) the Hydrochloride of 3-[TRANS-4-(2-carboxyethyl)cyclohexyl] -1-(3 - methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

Melting point: > 250oC

The value of Rf: 0,32 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4).

Calculated: C 61,39; H 7,17; N 9,34; Cl 7,88.

Found: C 61,39; H 7,25; N 9,37; Cl 7,92.

(4) Hydrochloride 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(3 - methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

The value of Rf: of 0.37 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia at a ratio of 80 : 20 : 2).

Calculated: C 61,39; H 7,17; N 9,34; Cl 7,88.

Found: C 61,11; H 7,26; N 9,36; Cl 7,86.

(5) the Hydrochloride of 2-[TRANS-4-(2-carboxyethyl)cyclohexyl] -4-(3 - methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4H-1,2,4-triazole-3-it x 1.1 H2O

Melting point: > 220oC

The value of Rf: 0,48 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4).

Calculated: C 58,10; H Of 7.36; N 12,32; Cl 7,80.

Found: C 58,07; H Of 7.36; N To 12.28; Cl 7,83.

(6) Gaiden-2-it

The value of Rf: 0,56 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4).

Mass spectrum: M+= 401

(7) 4-[TRANS-4-(2-carboxyethyl)cyclohexyl] -2-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-5-methyl-4H-1,2,4-triazole-3-one x 1,1 HCl x 0.2 H2O

Melting point: 238 - 240oC

The value of Rf: 0,37 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4).

Calculated: C 60,55; H 7,40; N To 12.28; Cl 8,55.

Found: C 60,68, H 7,53; N 12,31; Cl At 8.36.

(8) 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3,4,5,6-tetrahydro-1H - pyrimidine-2-he x 1,05 HCl x 0.3 H2O

Melting point: 237 - 240oC

The value of Rf: 0,37 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4).

Calculated: C 63,04; H 8,07; N 9,18; Cl 8,14.

Found: C 62,97; H 8,05; N 9,15; Cl 8,16.

Example 20

1-(3-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3-[4-[2- (methoxycarbonyl)ethyl]phenyl-imidazolidin-2-he

600 mg of the hydrochloride of 1-[4-[2-(methoxycarbonyl)ethyl]phenyl]-3- (2,3,4,5-tetrahydro-1H-3-benzac is to see in an ultrasonic bath for 2.5 hours. Add 125 ál of ethyliodide and continue treatment for an additional 2.5 hours. The reaction mixture is mixed with 50 ml water, the precipitate is sucked off, washed with water and dried. The crude product is purified by column chromatography on silica gel using as eluent a mixture of methylene chloride, methanol and conc. aqueous ammonia in a ratio of 9 : 1 : 0,1.

Yield: 260 mg (44% of theory)

Melting point: 168 - 170oC

The value of Rf: to 0.45 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia in the ratio of 4 : 1 : 0,2)

Similarly receive the following connections:

(1) 1-(3-butyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3-[4- [2-(methoxycarbonyl)ethyl]phenyl]-imidazolidin-2-he

The value of Rf: of 0.64 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia in the ratio of 4 : 1 : 0,2)

(2) the Hydrochloride of 1-[TRANS-4-[2-(isopropoxycarbonyl)ethyl] cyclohexyl]-3-(3-allyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- imidazolidin-2-it

Obtaining using a mixture of allylbromide and N-ethyl-Diisopropylamine in acetonitrile

The value of Rf: to 0.63 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia in a ratio of 95 : 5 : 1)

(3) the Hydrochloride of 1-[TRANS-4-[2-(methoxycarbonyl is 30 (silica gel; a mixture of methylene chloride and methanol in the ratio 95 : 5)

(4) Hydroiodic 1-(TRANS-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]- 3-[3-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- imidazolidin-2-it

Getting in acetonitrile using cyclopropanemethylamine in the presence of sodium iodide and N-ethyl-Diisopropylamine

Melting point: 225 - 230oC (decomp.)

The value of Rf: to 0.72 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia in the ratio of 90 : 10 : 2)

(5) Hydroiodic 1-[TRANS-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]- 3-[3-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- imidazolidin-2-it

Getting in acetonitrile using 2-bromoethanol in the presence of sodium iodide and N-ethyl-Diisopropylamine

Melting point: > 200oC

The value of Rf: of 0.55 (silica gel; a mixture of methylene chloride, methanol and conc. aqueous ammonia in the ratio of 90 : 10 : 2)

(6) 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]-3-[3 - methoxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- imidazolidin-2-he

Getting in acetonitrile with compound methyl ester 2-bromoxynil acid in the presence of sodium iodide and N-ethyl-Diisopropylamine. The release of free bases.


Example 21

Hydrochloride 3-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] - 1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

Over 920 mg of 3-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -1- (3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as in 50 ml of methanol is passed hydrogen chloride for 10 minutes and then heated under reflux for 5 hours. Cool, the product is sucked off, washed with methanol and diethyl ether and dried at 80oC. Yield: 770 mg (95% of theory)

Melting point: > 250oC

The value of Rf: 0,23 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Similarly receive the following connections:

(1) the Hydrochloride of 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]- 3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

Melting point: > 250oC

The value of Rf: 0,43 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Calculated: C 61,39; H 7,17; N 9,34; Cl 7,88.

Found: C 61,10; H 7,21; N 9,29; Cl 8,03.

(2) ro-1H - pyrimidine-2-it

The value of Rf: 0,31 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Example 22

3-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -1-(3 - TRIFLUOROACETYL - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

To 2.1 g of N-[TRANS-4-[2-(methoxycarbonyl)ethyl]cyclohexyl)-N'-[( benzyloxycarbonyl)methyl] -N'-(3-TRIFLUOROACETYL-2,3,4,5-tetrahydro-1H - 3-benzazepin-7-yl)-urea in 25 ml of boiling toluene to add 40 mg of tert.the butyl potassium and heated under reflux for 30 minutes. The reaction mixture is cooled, mixed with a few drops of glacial acetic acid, concentrated and purified by column chromatography on silica gel using as eluent a mixture of cyclohexane and ethyl acetate in a ratio of from 8 : 2 to 7 : 3, as well as by crystallization from methanol.

Yield: 0.95 g (55% of theory)

Melting point: 132 - 134oC

The value of Rf: 0,59 (silica gel; a mixture of cyclohexane and ethyl acetate in the ratio 1 : 1)

Similarly receive the following connections:

(1) the Hydrochloride of 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]- 3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-as

Melting point: > 250othe thief of salt in the ratio 6 : 4)

Calculated: C 61,39; H 7,17; N 9,34; Cl 7,88.

Found: C 61,10; H 7,21; N 9,29; Cl 8,03.

(2) the Hydrochloride of 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]- 3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3,4,5,6-tetrahydro-1H - pyrimidine-2-it

The value of Rf: 0,31 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Example 23

1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl] -3-(6,7,8,9 - tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-imidazolidin-2-he

1.0 g of 1-[TRANS-4-[2-(methoxycarbonyl)ethyl] cyclohexyl]-3-(7 - benzyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d] azepin-2-yl)-3H-imidazole - 2-it hydronaut in 15 ml of methanol under hydrogen pressure 3,52 kg/cm2in the presence of 500 mg of palladium on active coal (10% palladium) for 17 hours at room temperature. Filtered from the catalyst and the filtrate evaporated. The residue is directly used to obtain the compound of example 9 (16).

The value of Rf: 0,44 (ortofena chromatography on silica gel; a mixture of methanol and 5% aqueous solution of sodium chloride in the ratio 6 : 4)

Example 24

1-[2-(etoxycarbonyl)ethyl] -3-[4-(3-methyl - 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-phenyl]-imidazolidin-2-he

3.1 g (3-methyl-2,3,4,5-is Il]-imidazolidin-2-it, 3.5 g tetrakis-(triphenylphosphine)-palladium and 6.5 ml of triethylamine is stirred in 25 ml of dimethylformamide in a nitrogen atmosphere for 4 hours at 100oC. the Reaction mixture is cooled, concentrated in vacuo and the residue is served in methylene chloride. The mixture is filtered over kieselguhr, the filtrate is concentrated and the residue purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 100 : 7.

Yield: 2.7 g (63% of theory)

The value of Rf: 0,31 (silica gel; a mixture of methylene chloride and methanol in the ratio of 100 : 7).

1. Cyclic nitrogen-containing derivatives of General formula I

< / BR>
where X is carbinieri, substituted at the nitrogen atom by a cyano, carbonyl, sulfonyl;

Y is unsubstituted or substituted by a residue RcRdor Rcand Rda group of the formula-CH2-CH2-, -CH2-CH2-CH2-, -CH= CH-, -CH2CO - or-COCH2-, unsubstituted or substituted by a radical Rcor Rda group of the formula-CO-NH-, -NH-CO-, -CH=N - or-N=CH-,

one of the residues Ra- Rdmeans A group-B-, in which A group of the formula

< / BR>
< / BR>
or

< / BR>
where pentostatin these groups may be substituted by fluorine atom, chlorine or replaced by a nitrogen atom;

G1- bond or methylene which may be mono - or Disaese-alkyl, and the substituents may be the same or different;

G2- bond or methylene, substituted residues R7and R8;

G3is methylene, substituted residues R9and R10;

G4- connection;

G5is a nitrogen atom or Metin, unsubstituted or substituted alkyl;

R2is a hydrogen atom or alkyl;

R3is a hydrogen atom or alkyl;

R4is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl parts, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N, N-dialkylaminoalkyl, arylalkyl, alkoxycarbonyl, allmediascotland, formyl, acetyl, TRIFLUOROACETYL or the group R11CO-O-(R12CR13)-O-CO-, where R11is alkyl with 1 to 4 carbon atoms, R12is a hydrogen atom or alkyl, R13is a hydrogen atom, or R4together with R3mean the unbranched alkylene with 2 or 3 carbon atoms;

R5- aasi;

R6is a hydrogen atom, or alkyl, or amino group, if G1means linking and R4together with R5mean additional connection;

R7is a hydrogen atom or alkyl;

R8is a hydrogen atom or alkyl, or R8together with R4mean the unbranched alkylene with 3 or 4 carbon atoms;

R9is a hydrogen atom or alkyl;

R10is a hydrogen atom or alkyl, or R10together with R4mean the unbranched alkylene with 3 or 4 carbon atoms;

R14is a hydrogen atom or alkyl;

R15is a hydrogen atom or alkyl;

R16is a hydrogen atom or alkyl;

R17is a hydrogen atom or alkyl, or R16together with R17mean additional connection;

R18is a hydrogen atom, or alkyl, or fluorine atom, or amino, when R16and R17together denote an additional bond;

n = 1 or 2;

B - line, alkylen, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, unsubstituted or substituted by one or two alkyl groups, cyclohexyl, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups piperidinyl, which is related with at ACET group of the formula

F-E-D-,

where D is alkylene with 1 to 4 carbon atoms, Allen, unsubstituted or substituted by one or two alkyl groups peridinian, pyrimidinyl, personalen and pyridazinyl, indaniel, naftilan, 1,2,3,4-tetrahydronaphthalen or benzoguanamine, in which one of the rings is connected with the rest of E, and the other with a cyclic residue of General formula I, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one group is replaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings adjacent to the nitrogen atom of the methylene group may be replaced by a carbonyl, or alkilenkarbonatov with the total number of carbon atoms of 2 to 6, if E is cyclic aminogroup, and a carbonyl linked to a nitrogen atom of a cyclic aminogroup group of the residue E, or communication, if E does not mean the connection;

E - communication, alkylene with 1 to 4 carbon atoms which may be substituted by alkyl with 1 to 6 carbon atoms, amino, aryl, alkylamino with 1 to 4 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 8, group HNR21- or N-alkyl - NR21- arbonyl with the total number of carbon atoms of 2 5, cycloalkylcarbonyl or cycloalkylcarbonyl with 5 to 7 carbon atoms in cycloalkyl part, arylalkylamines arylalkylamines, arylethoxysilanes, arylcarbamoyl or arylsulfonyl, albaniles with 2 to 4 carbon atoms, Allen, unsubstituted or substituted by one or two alkyl groups peridinian, pyrimidinyl, personalen and pyridazinyl, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one group is replaced by a nitrogen atom linked to the carbon atom of the residue D, cycloalkyl with 4 to 7 carbon atoms in cycloalkanones part, unsubstituted or substituted by one or two alkyl groups with 1 to 4 carbon atoms, or, if D does not imply a relationship that is associated with the remainder of D through the remainder of W alkylen, in which W denotes an oxygen atom or sulfur, sulfinil, sulfonyl, the group-NR20-CO - or-CO - NR20-, where R20means a hydrogen atom or alkyl, with alkylene may be optionally substituted by alkyl with 1 to 6 carbon atoms, amino, aryl, alkylamino with 1 to 4 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 8, group-HNR21- or N-alkyl - NR21-, where R21has the specified znachenie carbon;

F - carbonyl, substituted by hydroxyl, alkoxyl with 1 to 4 carbon atoms, arialcategory or group R22O-, where R22means cycloalkyl with 5 to 7 carbon atoms and cycloalkenyl with 5 to 7 carbon atoms in cycloalkyl part, phosphono, O-alkylphosphine, R23CO-O-CHR24-O-CO-, where R23means alkyl or alkoxy with 1 to 4 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, cycloalkyl with 5 to 7 carbon atoms in cycloalkyl part and R24is a hydrogen atom or alkyl, with the shortest distance between the residue of F and located at a maximum distance from the rest F the nitrogen atom of the group A-B - is at least 11 ties;

the third of the residues Ra- Rdmeans a hydrogen atom, alkyl with 1 to 4 carbon atoms, trifluoromethyl, aryl, or alkoxy with 1 to 4 carbon atoms, which may not be linked to a nitrogen atom;

the fourth of the residue Ra- Rdmeans a hydrogen atom or alkyl with 1 to 4 carbon atoms, and if nothing else is mentioned, under the specified term "aryl" is to be understood phenyl, which can be monogamist the remainder R25that represents cyano, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alquiler the 26
that represents alkyl, hydroxyl, alkoxy, fluorine atom, chlorine or bromine, and two residue R26if they are linked to adjacent carbon atoms, may also constitute the unbranched alkylene with 3 or 4 carbon atoms, 1,3-butadiene-1,4-deelen or methylenedioxy, or monogamist the said remainder R25and additionally mono - or Disaese the said remainder R26and these substituents may be the same or different, under the specified term aralen" should be understood phenylene, which can be monogamist the specified residue R25mono - or Disaese the specified residue R26or monogamist the specified residue R25and additionally monogamist the specified residue R26and the substituents may be the same or different and have the abovementioned meaning, and, if nothing else is mentioned, the above alkyl, alkylene or CNS groups contain 1 to 4 carbon atoms and each of the carbon atoms in these alkilinity and cycloalkenes groups associated at least one heteroatom,

mixtures of their isomers, or individual isomers, or their salts.

2. Cyclic nitrogen-containing derivatives of the General formula the mi group-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-, -CH2CO - or-COCH2-, a group-CO-NH-, -CH=N - or-N=CH-, unsubstituted or substituted by a residue Rcone of the residues Ra- Rcmeans A group-B-, in which A group of the formula

< / BR>
< / BR>
or

< / BR>
where one or two methine groups in bancoestado the above-mentioned groups may be replaced by a nitrogen atom;

G1- bond or methylene;

G2- connection;

G3is methylene;

G4- connection;

G5is a nitrogen atom or Metin;

R2is a hydrogen atom;

R3is a hydrogen atom;

R4is a hydrogen atom, cycloalkyl, cyclopropylmethyl, alkyl with 1 to 6 carbon atoms, allyl, hydroxyalkyl, carboxyethyl with 1 to 4 carbon atoms in the alkyl part, alkoxycarbonyl with 1 to 4 carbon atoms in the CNS and alkyl parts, or benzyl;

R5is a hydrogen atom;

R6is a hydrogen atom;

R14is a hydrogen atom or alkyl with 1 to 4 carbon atoms;

R15is a hydrogen atom or alkyl with 1 to 4 carbon atoms;

R16is a hydrogen atom or alkyl with 1 to 4 carbon atoms;

R17is a hydrogen atom, or R16together with R17mean additional connection;

R18- atom vodorodych or phenylene,

the second of the residues Ra- Rcmeans a group of the formula

F-E-D-,

where D - link, alkylene with 1 to 4 carbon atoms, phenylene, cyclohexene or peridinin, with the ring nitrogen atom is associated with unsubstituted or substituted by alkylene residue is E;

E - the unbranched alkylene with 1 to 4 carbon atoms which may be substituted by one alkyl group with 1 to 4 carbon atoms or phenyl, albaniles with 2 to 4 carbon atoms, phenylene or unbranched O-alkylene, linked through the nitrogen atom, with the remainder of D, if D does not mean the connection;

F - carbonyl, substituted by hydroxyl or alkoxyl with 1 to 4 carbon atoms, with the shortest distance between the residue of F and located at a maximum distance from the rest F the nitrogen atom of the group A-B - is at least 11 ties;

the third of the residues Ra- Rcmeans a hydrogen atom, alkoxy with 1 to 4 carbon atoms, which may not be linked to a nitrogen atom, alkyl with 1 to 4 carbon atoms or phenyl, and, if nothing else is mentioned, each of the carbon atoms in these alkilinity and cycloalkenes groups associated at least one heteroatom,

the mixture of isomers, or individual isomers, or their salts.

3. SUB>-, -CH2-CH2-CH2-, -CH=CH-, -CH2CO - or-COCH2-, unsubstituted or substituted stands a group-N=CH-, the remainder Rameans A group-B-, in which A group of the formula

< / BR>
< / BR>
or

< / BR>
where 1 or 2 methine group bancoestado the above-mentioned groups may be replaced by a nitrogen atom;

G1- bond or methylene;

G2- connection;

G3is methylene;

G4- connection;

G5- Metin;

R2is a hydrogen atom;

R3is a hydrogen atom;

R4is a hydrogen atom, alkyl with 1 to 4 carbon atoms, allyl or benzyl;

R5is a hydrogen atom;

R6is a hydrogen atom;

R14is a hydrogen atom or methyl;

R15is a hydrogen atom;

R16together with R17mean communication;

R18is a hydrogen atom or amino;

n - 1;

B - connection;

the remainder Rbmeans a group of the formula

F-E-D,

where D is the group-CH2-CH2-, 1,4-phenylene or 1,4-cyclohexyl;

E - the group CH2-CH2-, unsubstituted or substituted stands, the group-CH= CH-, 1,4-phenylene or a group-O-CH2- where the oxygen atom is linked to the remainder of D;

F - carbonyl, substituted by hydroxyl or alkoxyl with 1 to 4 carbon atoms, with times the s A-B - is at least 11 links,

the mixture of isomers, or individual isomers, or their salts.

4. Cyclic nitrogen-containing derivatives of General formula I on p. 1. representing:

(and) 1-[4-[2-(methoxycarbonyl)ethyl] phenyl]-3-(1,2,3,4-tetrahydroisoquinoline-6-yl)-imidazolidin-2-it,

(b) 1-[4-(2-carboxyethyl)phenyl]-3-(1,2,3,4-tetrahydroisoquinoline-6-yl)-imidazolidin-2-it,

(C) 1-[4-(2-carboxyethyl)phenyl] -3-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-imidazolidin-2-it,

(g) 1-[4-(2-isobutylketone)ethyl)phenyl] -3-(1,2,3,4-tetrahydroisoquinoline-6-yl)-imidazolidin-2-it,

(d) 1-[4-(2-carboxyethyl)phenyl]-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(e) 1-[4-(2-methoxycarbonyl)ethyl)phenyl] -3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(W) 1-[4-(2-isopropoxycarbonyl)ethyl)phenyl] -3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(C) 1-[4-(2-carboxyethyl)phenyl] -3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(or) 4-[4-(2-carboxyethyl)phenyl] -5-methyl-2-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4H-1,2,4-triazole-3-one,

(th) 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

() 1-[4-[2-(methoxycarbonyl)ethyl] phenyl] -3-(3-methyl-2,3,4,5-Tetra benzazepin-7-yl)-imidazolidin-2-it,

(m) 1-[4-[2-(isopropoxycarbonyl)ethyl] phenyl]-3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(n) 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(o) 1-[TRANS-4-(2-isopropoxycarbonyl)ethyl] cyclohexyl]-3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(p) 1-[TRANS-4-(2-etoxycarbonyl)ethyl]cyclohexyl]-3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(R) 1-[TRANS-4-(2-methoxycarbonyl)ethyl] cyclohexyl] -3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(C) 1-[TRANS-4-[(carboxymethyl)oxy] cyclohexyl] -3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

(t) 3-[TRANS-4-[(carboxymethyl)cyclohexyl] -1-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-and as

(u) 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(3-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it,

their tautomers or their salts.

5. 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazolidin-2-it, its difficult methyl, ethyl and isopropyl esters and its salts.

6. 1-[TRANS-4-(2-carboxyethyl)cyclohexyl] -3-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-imidazo the

 

Same patents:

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain

The invention relates to the derivatives of pyrazine formula I, where R1- H or C1-8-alkyl, R2- C1-8-alkyl, unsubstituted or substituted C1-4-alkoxyl, hydroxyl, fenoxaprop, which in turn is one - or multi-substituted C1-4-alkyl, C1-4-alkoxyl, alkoxyalkyl or cyano, aminowhere R3- H or C1-4-alkyl, R4-phenyl, repeatedly substituted C1-4-alkyl, a substituted amino group dichlorobenzenesulfonyl, C1-4-alkyl, unsubstituted or substituted residues selected from the group of hydroxyl, fenoxaprop, in turn multiply substituted by halogen or alkoxyalkyl, carbonylation formula II, where X is oxygen or-NH-, piperidinyl, N-substituted C1-8-alkyl, and phenyl unsubstituted or substituted C1-4-alkoxyl, amidinopropane formulawhere R5is phenyl, substituted by halogen or C1-4-alkyl, and a group of the formula III, where R1- H, or R1and R2together with the nitrogen atom to which they are bound, form a pieperazinove ring, unsubstituted or substituted in position 4 by a group IV, V,-alkyl, or alkoxyalkyl, and-naftussya, and if R1- H, R2does not mean alkyl, benzyl, fluorine - or chlorbenzyl, phenethyl, hydroxyethyl or HOCH2- (CHOH)4- CH2or if R1- C1-3-alkyl, R2does not mean C1-4-alkyl, and an acid additive salt

The invention relates to new N-substituted derivatives of 3-azabicyclo[3.2.0] -heptane and its salts with physiologically tolerated acids, possessing neuroleptic activity

The invention relates to 2-/2-imidazolin-2-yl/benzoheterocycles compounds, which have the following structure:

< / BR>
in which: R1is hydrogen, CI/C1-C4/ alkylamino,

C1-C12the alkyl may be substituted by one to three substituents: C1-C4alkoxy, C1-C4alkylthio, halogen, hydroxy, C1-C4cycloalkyl, benzoyloxy, fullam, phenyl, possibly substituted by nitro, one to three halogen, C1-C4alkyl groups or C1-C4alkoxy groups, carboxy, C1-C4alkoxycarbonyl, cyano or three/C1-C4/ alkylammonium a halide;

C3-C12alkenyl may be substituted by one to three substituents: C1-C4alkoxy, phenyl, halogen or C1-C4alkoxycarbonyl;

C3-C6cycloalkyl, can be substituted one to three C1-C4alkyl groups;

C3-C16the quinil may be substituted by one to three halogen or a cation;

R2is C1-C4by alkyl;

R3is C1-C4the alkyl or C3-C6cyclo is the best C1-C4cycloalkyl possibly replaced by stands;

B is hydrogen, COR4or SO2R5with the proviso that when B is COR4or SO2R5, R1is other than hydrogen or a cation, and R9different from hydrogen;

R4is C1-C11the alkyl, chlorochilon or phenyl, possibly substituted with halogen, nitro or C1-C4by alkyl;

R5is C1-C4the alkyl or phenyl, possibly substituted C1-C4by alkyl;

X, Y and Z each independently is CR6, CR7R8, N or NR9with the proviso that at least one of X, Y and Z must be N or NR9;

configuration is either a simple bond or double bond with the proviso that when any of X, Y or Z is CR7R8or NR9then === configuration, attached to it, is a simple connection, with one proviso that at least one of the === configuration represents a simple bond;

R6, R7and R8are independently hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl may be substituted one is;

R9is hydrogen or C1-C4the alkyl possibly substituted by hydroxy or one to three halogen, C1-C4alkoxy groups, or C1-C4alkylthio groups;

Q is hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl, possibly substituted by one to three of the following substituents: halogen, C1-C4alkoxy, C1-C4alkylthio or C2-C4alkenyl;

their optical isomers, when R2and R3not the same or when R7and R8unequal;

their tautomers and geometric isomers, and their attached salts of acids, except when R1is salabrasion cation

The invention relates to new substituted pyrazolylborate, and to their use as herbicide compositions

The invention relates to a helical compounds of General formula 1

< / BR>
where a denotes an integer of 0 or 1, b denotes an integer equal to 2 to 5 inclusive, c is an integer of 0 or 1, and d denotes an integer of 0 to 2, inclusive; Z meansan atom of oxygen or sulfur, where R1means a hydrogen atom, an amino group, monoalkylamines from 1 to 6 carbon atoms, dialkylamino containing 1 to 6 carbon atoms in the alkyl group, hydroxyl group, alkoxygroup from 1 to 6 carbon atoms or a hydroxyalkyl group of 1 to 6 carbon atoms; R2means a hydrogen atom, alkyl group of 1 to 6 carbon atoms, a hydroxyalkyl group of 1 to 6 carbon atoms, haloalkyl group of 1 to 6 carbon atoms, formyl group or alkylcarboxylic group of 2 to 7 carbon atoms, R3means a hydrogen atom or alkyl group of 1 to 6 carbon atoms; Q represents a structural fragment of formula II

< / BR>
where R4means an alkyl group of 1 to 6 carbon atoms, alkenylphenol group of 2 to 6 carbon atoms, Halaal substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, alkoxygroup from 1 to 6 carbon atoms or alkylamino from 1 to 6 carbon atoms; R5means a hydrogen atom, a substituted or an unsubstituted amino group, a hydroxyl group, alkoxygroup of 1 -6 carbon atoms or a halogen atom; A denotes a nitrogen atom or awhere R7means a hydrogen atom, alkyl group of 1 to 6 carbon atoms, a halogen atom, alkoxygroup of 1 -6 carbon atoms, haloalkyl group of 1 to 6 carbon atoms or cyano; R4may, taken together with R5and/or R7to form a substituted or unsubstituted ring, which may include an oxygen atom, nitrogen or sulfur, where the Deputy is an alkyl group of 1 to 6 carbon atoms or haloalkyl group of 1 to 6 carbon atoms; X represents a halogen atom, preferably a fluorine atom; Y represents a hydrogen atom, alkyl group of 1 to 6 carbon atoms, alkoxyalkyl group of 1 to 6 carbon atoms, phenylalkyl group containing 1 to 6 carbon atoms in its alkyl fragment, group dihalides boron, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonylethyl, politikatol-4-ylmethylene group or 3-acetoxy-2-oxobutyl group, and the salts of these compounds

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to new derivatives of pyrazole and their pharmaceutically acceptable salts

The invention relates to pharmacology and describes a new tool for the treatment of irritable bowel syndrome

The invention relates to new compounds with dual activity, namely the activity of inhibiting angiotensin converting enzyme, and the activity of inhibiting neutral endopeptidase and to methods of producing these compounds

The invention relates to new chemical substances possessing valuable pharmacological properties, in particular a derivative of benzimidazole of General formula I

< / BR>
where

R1is alkyl with 1 to 3 carbon atoms,

R2- oxazol-4-yl, thiazol-4-yl, unsubstituted or substituted in position 2 by alkyl with 1-6 carbon atoms or phenyl, imidazol-4-yl unsubstituted or substituted in position 2 by alkyl with 1-6 carbon atoms or phenyl, and imidazol-4-yl in position 1 substituted by alkyl with 1 to 7 carbon atoms, in which position 1, 2, 3, 4, 5, 6 or 7 may be replaced by alkoxycarbonyl or aminocarbonyl, alkyl with 2 to 4 carbon atoms, which is in position 2, 3 or 4 substituted by hydroxyl, alkoxyl, alkoxyalkyl, dialkylamino, pyrrolidino, piperidino or morpholino,

R3is alkyl with 2 to 4 carbon atoms, alkoxyl, alkylthio, each with 2 or 3 carbon atoms in the alkyl part, cyclopropyl or cyclobutyl and

R4- translated in vivo in carboxyl group, carboxyl, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl,

their salts, particularly for pharmaceutical use the physiologically case

The invention relates to medicine and AIDS for the treatment of elevated intraocular pressure and/or glaucoma

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

Up!